Welcome to this Science-to-Strategy Summit

Clotting, Cancer, and Clinical Strategies 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

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

Program Educational Objectives As a result of this session, physicians will be able to: Specify 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. 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. Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy.

Program Faculty Craig M. Kessler, MD John Fanikos, RPh, MBA Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Washington, DC John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Samuel Z. Goldhaber, MD Professor of Medicine Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Unit

Faculty COI Financial Disclosures Craig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, Octapharma Consultant: sanofi-aventis, Eisai, NovoNordisk John Fanikos, RPh, MBA Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Company Samuel Z. Goldhaber, MD Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Sanofi-Aventis; Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; Sanofi-Aventis

Clots and Cancer—A 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.

Introduction and Chairman’s Overview Clotting, Cancer, And Controversies: What The Cascade Of Evidence And Current Thinking Tell Us The Evolving Science, Epidemiology, and Foundation Role of Low Molecular Weight Heparin in the Setting of Cancer Program Chairman 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

Comorbidity Connection CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder Thrombophilia Surgery History of DVT Other SUBSPECIALIST STAKEHOLDERS Infectious diseases Oncology Cardiology Pulmonary medicine Hematology Oncology/hematology Interventional Radiology Hospitalist Surgeons EM PCP

Epidemiology of First-Time VTE Variable Finding Seasonal Variation Possibly more common in winter and 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 White R. Circulation. 2003;107:I-4 –I-8.)

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

Comorbidity Connection Overview Comorbidity Connection

Acute Medical Illness and VTE Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Acute Medical Illness Relative Risk X2 P value Heart failure NYHA class III NYHA class IV 1.08 (0.72-1.62) 0.89 (0.55-1.43) 1.48 (0.84-2.60) 0.05 0.12 1.23 .82 .72 .27 Acute respiratory disease 1.26 (0.85-1.87) 1.03 .31 Acute infectious disease 1.50 (1.00-2.26) 3.54 .06 Acute rheumatic disease 1.45 (0.84-2.50) 1.20 Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968

Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds Ratio (95% CI) X2 Age > 75y Cancer Previous VTE 1.03 (1.00-1.06) 1.26 (0.93-2.75) 2.06 (1.10-3.69) 0.0001 0.08 0.02 Acute infectious disease 1.74 (1.12-2.75) Chronic respiratory disease 0.60 (0.38-0.92) 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%. The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med.  2002 Jun 10;162(11):1245-8.  Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

VTE Recurrence Hazard Ratio Baseline Characteristic Predictors of First Overall VTE Recurrence Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 (1.11-1.24) Body Mass Index 1.24 (1.04-1.47) Neurologic disease with extremity paresis 1.87 (1.28-2.73) Malignant neoplasm None With chemotherapy Withot chemotherapy 1.00 4.24 (2.58-6.95) 2.21 (1.60-3.06) Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768

Clotting, Cancer, and Clinical Strategies Cancer, Thrombosis, and the Biology of Malignancy Scientific Foundations for the Role of Low-Molecular-Weight Heparin John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA

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

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

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

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

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

Cancer, Mortality, and VTE Epidemiology and Risk Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patients Patients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patients Cancer patients undergoing surgery have a 2-fold increased risk for postoperative VTE Death rate from cancer is four-fold higher if patient has concurrent VTE VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection) Heit et.al. Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. Blood 2002;100:3484-3488; White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al. Medicine 1999;78:285-291; Khorana et.al. J Thromb Haemost 2007;5:632-4

Mechanisms of Cancer-Induced Thrombosis The Interface Pathogenesis? Biological significance? Potential importance for cancer therapy?

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

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

Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s Triad Stasis Prolonged bed rest Extrinsic compression of blood vessels by tumor Vascular Injury Direct invasion by tumor Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium Hypercoagulability Tumor-associated procoagulants and cytokines (tissue factor, CP, TNF, IL-1, VEGF, etc.) Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S) Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages

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

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

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

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

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

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

Correlation of Tissue Factor Expression with the Expression of Other Angiogenesis Cariables in Resected Pancreatic Cancer High TF Expression Low TF Expression P VEGF expression Negative Positive 13 53 41 15 <0.0001 Microvessel density V6 per tissue core >6 per tissue core Median 27 39 8 33 23 6 0.47 0.01 Khorana et.al. Clin CA Res 2007:13:2870

Symptomatic VTE in Pancreatic Cancer 5/19 Rate of VTE 1/22 Khorana et.al. Clin CA Res 2007;13:2872

Activation of Blood Coagulation in Cancer: Malignant Transformation Epiphenomenon? Linked to malignant transformation? 1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio et. al. Nature 2005;434:396-400) 2. Pten loss produces TF activation and pseudopalisading necrosis in human glioblastoma (Rong et.al. Ca Res 2005;65:1406-1413) 3. K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma (Yu et.al. Blood 2005;105:1734-1741)

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

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

Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Transgene Parameter Time after Transduction (days) 0 30 90 GFP _________ MET Platelets (x103) 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 Trousseau’s Syndrome “MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” Mouse model of Trousseau’s Syndrome Genome-wide expression profiling of hepatocytes expressing MET upregulation of PAI-1 and COX-2 genes with 2-3x  circulating protein levels Using either XR5118 (PAI-1 inhibitor) or Rofecoxib (Vioxx; COX-2 inhibitor) resulted in inhibition of clinical and laboratory evidence for DIC in mice

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

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

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

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

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

Activation of Blood Coagulation in Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” Activation of K-ras oncogene and inactivation of p53 tumor suppressor  TF expression in human colorectal cancer cells Transforming events dependent on MEK/MAPK and PI3K Cell-associated and MP-associated TF activity linked to genetic status of cancer cells TF siRNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype Yu, Mackman, Rak et.al. Blood 2005;105:1734-41

Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status Mean Channel TF Flourescence TF Activity (U/106 cells) del/+ mut/+ mut/+ +/+ +/+ del/del Yu, Mackman, Rak et.al. Blood 2005;105:1734-41

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

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

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

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

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

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

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

A Systematic Overview of VTE Prophylaxis In The Setting of Cancer Clotting, Cancer, and Clinical Strategies 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 56

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

DVT and PE in Cancer Facts, Findings, and Natural History VTE is the second leading cause of death in hospitalized cancer patients1,2 The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2 Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 Let’s continue examining the association between DVT/PE and cancer. Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE. As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer. Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer. Ambrus JL et al. J Med. 1975;6:61-64 Donati MB. Haemostasis. 1994;24:128-131 Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 Prandoni P et al. Ann Intern Med. 1996;125:1-7 58

Clinical Features of VTE in Cancer VTE has significant negative impact on quality of life VTE may be the presenting sign of occult malignancy 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 25% have bilateral DVT Bura et. al., J Thromb Haemost 2004;2:445-51 59

Risk Factors for Cancer-Associated VTE Type Men: prostate, colon, brain, lung Women: breast, ovary, lung Stage Treatments Surgery 10-20% proximal DVT 4-10% clinically evident PE 0.2-5% fatal PE Systemic Central venous catheters (~4% generate clinically relevant VTE) 60

Thrombosis and Survival: Likelihood of Death After Hospitalization 0 20 40 60 80 100 120 140 160 180 0.00 0.20 0.40 1.00 0.80 0.60 DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

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

VTE Risk And Cancer Type: “Solid And Liquid” Relative Risk of VTE Ranged From 1.02 to 4.34 4.5 4 3.5 3 2.5 2 1.5 1 0.5 Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder Relative Risk of VTE in Cancer Patients Stein PD, et al. Am J Med 2006; 119: 60-68

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

Prevention and Management of VTE in Cancer 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 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

Antithrombotic Therapy: Choices Pharmacologic (Prophylaxis & Treatment) Nonpharmacologic (Prophylaxis) Elastic Stockings Unfractionated Heparin (UH) Low Molecular Weight Heparin (LMWH) Intermittent Pneumatic Compression Several classes of agents have been used for prophylaxis and treatment of VTE Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter Most commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs) Inferior Vena Cava Filter Oral Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.? 66

Incidence of VTE in Surgical Patients Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: Outcome No Cancer N=16,954 Cancer N=6124 P-value Post-op VTE 0.61% 1.26% <0.0001 Non-fatal PE 0.27% 0.54% <0.0003 Autopsy PE 0.11% 0.41% Death 0.71% 3.14% Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 67

Natural History of VTE in Cancer Surgery: The @RISTOS Registry Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings 2.1% incidence of clinically overt VTE (0.8% fatal) Most events occur after hospital discharge Most common cause of 30-day post-op death Agnelli, abstract OC191, ISTH 2003 68

Colorectal Cancer Resection Overall, 1% incidence of VTE with 3.8 fold mortality Transfused women 1.8-fold more likely to develop VTE than non-transfused women Association Between Transfusion and Venous Thromboembolism Stratified by Sex in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000 Variable Incidence of VTE, % P Value Stratified OR Adjusted (95% CI)* P Value Male Sex No Transfusion (n = 5683) 0.7 Referent Transfusion (n = 1156) 0.8 .84 0.9 (0.5-1.9) .85 Female Sex No Transfusion (n = 5565) 0.9 Referent Transfusion (n = 1610) 2.1 <.001 1.8 (1.2-2.6) .004 Nilsson: Arch Surg, 142;2007:126–132

VTE Risk Factors in Surgical Oncology Patients Age >40 years Cancer procoagulants Thrombophilias Adjuvant chemotherapy or hormonal treatment Complicated, lengthy surgery (tissue trauma, immobilization) Debilitation and slower recovery Indwelling venous access 70

Surgical Prophylaxis LMWH better UFH better Asymptomatic DVT Clinical PE Clinical thromboembolism Cancer Death Non-cancer Major hemorrhage Total hemorrhage Wound hematoma Transfusion 0 1.0 2.0 3.0 4.0 Mismetti P et al. Br J Surg 2001;88:913–30 71

Prophylaxis in Surgical Patients LMWH vs. UFH Abdominal or pelvic surgery for cancer (mostly colorectal) LMWH once daily vs. UFH tid for 7–10 days post-op DVT on venography at day 7–10 and symptomatic VTE Study N Design Regimens ENOXACAN 1 631 double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:438-444 72

Prophylaxis in Surgical Patients 18.2% P>0.05 ENOXACAN 14.7% Incidence of Outcome Event N=319 2.9% 4.1% N=312 VTE Major Bleeding ENOXACAN Study Group. Br J Surg 1997;84:1099–103 73

Prophylaxis in Surgical Patients Canadian Colorectal DVT Prophylaxis Trial 16.9% 13.9% P=0.052 Incidence of Outcome Event N=234 N=241 1.5% 2.7% VTE Major Bleeding (Cancer) (All) McLeod R, et al. Ann Surg 2001;233:438-444 74

Prophylaxis in Surgical Patients Extended prophylaxis Abdominal or pelvic surgery for cancer LMWH for ~ 7 days vs. 28 days post-op Routine bilateral venography at ~day 28 Study N Design Regimens ENOXACAN 1 332 double-blind Enoxaparin vs. placebo FAME 198 Open-label Dalteparin vs. no prophylaxis 1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 2. Rasmussen M, et al (FAME) Blood 2003;102:56a 75

Extended Prophylaxis in Surgical Patients 12.0% ENOXACAN II P=0.02 Incidence of Outcome Event N=167 4.8% 5.1% 3.6% N=165 1.8% NNT = 14 0.6% 0% 0.4% VTE Prox Any Major DVT Bleeding Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 76

Major Abdominal Surgery: FAME Investigators—Dalteparin Extended A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment RESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012). CONCLUSIONS: 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1. 77

Gynecological Cancer Surgery Paucity of level I/II studies in this population Based on small historical studies: Postoperative risk of DVT/PE varies 12%–35% LDUH (5000 u bid) ineffective LDUH 5000 u tid reduces risk by 50%–60% Once-daily LMWH comparable to LDUH for efficacy and safety 78

Gynecological Surgery Cochrane Systematic Review Meta-analysis of 8 randomized controlled trials Heparin reduces risk of DVT by 70% (95% CI 0.10–0.89) No evidence that anticoagulation reduces risk of PE No statistical difference between LDUH and LMWH in efficacy and bleeding Oates-Whitehead et al. Cochrane Database Syst Rev 2003;4:CD003679 79

Urological Cancer Surgery Poorly studied population Risk of VTE varies with type of surgery and diagnosis Small studies have suggested prophylaxis with either LDUH or LMWH is effective and safe Possible increased risk of pelvic hematoma and lymphocele formation DVT PE Fatal PE Radical retropubic prostatectomy 1–3% 0.6% Cystectomy 8% 2–4% 2% Radiological studies 51% 22% Kibel, Loughlin. J Urol. 1995;153:1763-1774 80

Neurosurgery and VTE OBSERVATIONS Majority of patients undergoing neurosurgery for malignancy Risk of venographic VTE ~30%-40% High risk of intracranial or intraspinal hemorrhage Mechanical prophylaxis preferred method Use of anticoagulant prophylaxis remains controversial in this setting 81

Neurosurgery and VTE Prophylaxis Meta-analysis of three (3) RCTs evaluating LMWH prophylaxis One major bleeding event observed for every 7 proximal DVTs prevented with LMWH ES LMWH RR NNT/NNH P VTE 28.3% 17.5% 0.6 9 0.001 Proximal DVT 12.5% 6.2% 0.5 16 <0.01 Total bleeding 3.0% 6.1% 2.0 33 0.02 Major bleeding 1.3% 2.2% 1.7 115 0.30 Iorio A, Agnelli G. Arch Intern Med. 2000;160:2327-2332 82

7th 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 No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Patients hospitalized with an acute medical illness should receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S 83

Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these events: Fibrin sheath formation Superficial phlebitis Ball-valve clot Deep vein thrombosis (DVT) • Incidence up to 60% from historical data • ACCP guidelines recommended routine prophylaxis with low dose warfarin or LMWH Geerts W, et al. Chest 2001;119:132S-175S 84

Prophylaxis for Venous Catheters Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* 2002 Dalteparin 5000 U od placebo 285 140 11 (3.7) 5 (3.4) Couban* 2002 Warfarin 1mg od 130 125 6 (4.6) 5 (4.0) ETHICS† 2004 Enoxaparin 40 mg od 155 22 (14.2) 28 (18.1) *symptomatic outcomes; †routine venography at 6 weeks Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730 85

Central Venous Catheters: Warfarin Tolerability of Low-Dose Warfarin 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily INR measured at baseline and four time points 10% of all recorded INRs >1.5 Patients with elevated INR 2.0–2.9 6% 3.0–4.9 19% >5.0 7% Masci et al. J Clin Oncol. 2003;21:736-739 86

Prophylaxis for Central Venous Access Devices Summary Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) Routine prophylaxis is not warranted to prevent catheter-related thrombosis, but catheter patency rates/infections have not been studied Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis 87

7th 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 No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Patients hospitalized with an acute medical illness should receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S 88

Primary Prophylaxis in Cancer Radiotherapy in the Ambulatory Patient No recommendations from ACCP No data from randomized trials (RCTs) Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas-colorectal, pancreatic, lung, renal cell, ovarian) Recommendations extrapolated from other groups of patients if additional risk factors present (e.g. hemiparesis in brain tumors, etc.)

Risk Factors for VTE in Medical Oncology Patients Tumor type Ovary, brain, pancreas, lung, colon Stage, grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment Multiagent regimens, hormones, anti-VEGF, radiation Miscellaneous VTE risk factors Previous VTE, hospitalization, immobility, infection, thrombophilia 90

Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery w/ institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study. This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data. Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included. What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE. Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of 4.05. In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE. Heit JA et al. Thromb Haemost. 2001;86:452-463 91

VTE Incidence In Various Tumors Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further treatment 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Non-Hodgkin’s lymphomas w/ chemo 3% Hodgkin’s disease w/ chemo 6% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-VEGF + chemo) 47% Wilms tumor (cavoatrial extension) 4% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

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

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

Incidence of VTE: USA and Canada >Israel, Australia, and Europe rEPO used more in USA and Canada L+Dex: 23% VTE with EPO vs 5% w/o EPO Placebo + Dex: 7% VTE with EPO vs 1% without EPO Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma Treatment Odds Ratio P Value (95% CI) Lenalidomide plus 3.51 (1.77-6.97) <0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01) <0.001 Knight: N Engl J Med.2006,354:2079

Thrombotic Outcomes from rEPO or Darbopoietin Use in Cancer Patients 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) Bohlius: The Cochrane Library, Volume (4).2006

Standard Treatment of VTE Can We Do Better Than This? Initial treatment 5 to 7 days LMWH or UFH Long-term therapy > 3 months Vitamin K antagonist (INR 2.0 - 3.0) Slide #6 97

Events per 100 patient years 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 27.1 9.0 0.003 Hutten et.al. J Clin Oncol 2000;18:3078 98

Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies Major Bleeding Events per 100 patient years P-value Malignant Non-malignant 13.3 2.1 0.002 Hutten et.al. J Clin Oncol 2000;18:3078 99

Oral Anticoagulant Therapy in Cancer Patients: Problematic Warfarin (Coumadin®) therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? 100

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

Landmark CLOT Cancer Trial Reduction in Recurrent VTE 5 10 15 20 25 Days Post Randomization 30 60 90 120 150 180 210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = 0.0017 Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 102

Bleeding Events in CLOT Dalteparin N=338 OAC N=335 P-value* Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact test Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 103

Treatment of Cancer-Associated VTE Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding (%) Death CLOT Trial (Lee 2003) Dalteparin OAC 6 336 9 17 4 39 41 CANTHENOX (Meyer 2002) Enoxaparin 3 67 71 11 21 7 16 23 LITE (Hull ISTH 2003) Tinzaparin 80 87 8 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) 32 36 34 3.4 3.1 6.7 0.002 NS NS 0.09 0.09 0.03 0.03 NS NS NS NS NR 104

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

CLOT 12-month Mortality All Patients Dalteparin OAC 10 20 30 40 50 60 70 80 90 100 120 180 240 300 360 Dalteparin OAC HR 0.94 P-value = 0.40 Days Post Randomization Probability of Survival, % Lee A, et al. ASCO. 2003 106

Anti-Tumor Effects of LMWH CLOT 12-month Mortality Patients Without Metastases (N=150) 10 20 30 40 50 60 70 80 90 100 Dalteparin OAC Probability of Survival, % HR = 0.50 P-value = 0.03 30 60 90 120 150 180 240 300 360 Days Post Randomization Lee A, et al. ASCO. 2003 107

LMWH for Small Cell Lung Cancer Turkish Study 84 patients randomized: CEV +/- LMWH (18 weeks) Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemo + Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 Median survival, m 13.0 8.0 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266. 108

VTE Prophylaxis Is Underused in Patients With Cancer [1/Kakkar. Oncologist.2003/ p381/c1/line A1-A24; p383/c1/line 44-46, c2/line 1-3] [2/Stratton. ArchInternMed. Feb.2000/ p336/c2/line 7-11] [3/Bratzler. ArchInternMed. Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3] [4/Rahim.ThrmbRes. 2003/p3/c2/line 1-5] [5/Goldhaber. AmJCardiol.Jan.2004/ p261/c2/line 6-8] Cancer: FRONTLINE Survey1— 3891 Clinician Respondents Major Surgery2 Cancer: Surgical Major Abdominothoracic Surgery (Elderly)3 Confirmed DVT (Inpatients)5 Rate of Appropriate Prophylaxis, % Medical Inpatients4 Cancer: Medical VTE prophylaxis is underused in patients with cancer The Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1 Data from 3891 completed questionnaires were available for analysis1 The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1 These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies A retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2 A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3 A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4 In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5 [1/Kakkar.Oncologist. 2003/p381/c1/ line A5-A22] [1/Kakkar/p381/c1/ line A23-A24] [1/Kakkar/p383/c1/ line 44-46, c2/line 1-3] [2/Stratton.ArchIntern Med.Feb.2000/ p334/c1/line A14-A19, c2/line A1-A2; p336/c2/line 7-11] [3/Bratzler.ArchIntern Med.Sept.1998/ p1909/c1/line A10-A15, c2/line A1-A3] [4/Rahim.ThrmbRes. 2003/p1/line A1-A12; p3/c2/line 1-5] [5/Goldhaber.AmJ Cardiol.Jan.2004/ p259/c1/line A1-A10; p261/c2/line 6-8] 1. Kakkar AK et al. Oncologist. 2003;8:381-388 2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 4. Rahim SA et al. Thromb Res. 2003;111:215-219 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262 1. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8:381-388. 2. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160:334-340. 3. Bratzler DW, Raskob GE, Murray CK, Bumpus LJ, Piatt DS. Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting. Arch Intern Med. 1998;158:1909-1912. 4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res. 2003;111:215-219. 5. Goldhaber SZ, Tapson VF, for the DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93:259-262. 109

Cancer and Venous Thrombosis VTE Prophylaxis in the Cancer Patient and Beyond Guidelines and Implications for Day-to-day Practice Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School

Learning Objectives Scope of the problem Tools in the toolkit: drugs, devices Guidelines: ASCO, NCCN, ACCP Implementation: voluntary or mandatory

Scope of the Problem Epidemiology Long-term sequelae Failure to prophylax Medical Service patients, especially Medical Oncology patients

Annual Patients At-Risk For VTE U.S. Hospitals 7.7 million Medical Service inpatients 4.3 million Surgical Service inpatients Based upon ACCP guidelines for VTE prophylaxis Anderson FA Jr, et al. Am J Hematol 2007; 82: 777-782

Patients At-Risk For VTE An 86-year-old man underwent successful gastrectomy for newly diagnosed stomach cancer. He was recovering uneventfully. On POD #4, he had a witnessed cardiac arrest while transferring from commode to bed. ACLS yielded repeated PEA. After 35 minutes, the code was “called.” An autopsy was obtained.

ICOPER Cumulative Mortality 5 10 15 20 25 17.5% Mortality (%) 7 14 30 60 90 Days From Diagnosis Lancet 1999; 353: 1386-1389

Chronic Venous Insufficiency Progression Of Chronic Venous Insufficiency                                                                             (From UpToDate 2006)

VTE Prophylaxis: Underused Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines.

The Amin Report VTE Prophylaxis Rates in USA Studied 196,104 Medical Service discharges from 227 hospitals. VTE prophylaxis rate was 62%. ACCP-deemed appropriate prophylaxis rate was 34%. J Thromb Haemostas 2007; 5: 1610-6)

The Amin Report Medical Oncology Patients Of 196,104 Medical Service discharges, 30,708 were medical oncology patients. Only 56% received any VTE prophylaxis. Only 28% received ACCP-deemed appropriate prophylaxis J Thromb Haemostas 2007; 5: 1610-6

Medical Patient Prophylaxis In Canada Studied 1,894 Medical Service discharges from 29 hospitals. VTE prophylaxis was indicated in 90% of patients. ACCP-deemed appropriate prophylaxis rate was 16%. Thrombosis Research 2007; 119: 145-155

Cancer: Medical Patient Prophylaxis In Canada 19% of the 1,894 Medical Service patients had cancer, either as the admission diagnosis (9%) or an active comorbid condition (19%). The most common cancers were: lung, breast, prostate, and colon. Thrombosis Research 2007; 119: 145-155

Cancer: Decreased Likelihood Of VTE Prophylaxis In Canada Multivariable analysis: 60% less likely to prescribe VTE prophylaxis (95% CI: 32% to 76% less likely; p=0.0007). Perhaps MDs fear an increased risk of bleeding in cancer patients? Thrombosis Research 2007; 119: 145-155

VTE in Cancer Patients Prospective registry of 5,451 consecutive ultrasound-confirmed DVT patients at 183 U.S. institutions. (Am J Cardiol 2004; 93:259-262 ) Cancer occurred in 1,768 (39%), of whom 1,096 (62%) had active cancer, of whom 599 (55%) were receiving chemotherapy. Thromb Haemost 2007; 98: 656-661

VTE in Cancer Patients Lung, colorectal, and breast cancer were the most common cancers. Cancer patients less often received VTE prophylaxis (28%) compared with the other DVT Registry patients (35%) (p<0.0001). Cancer patients were more likely to receive IVC filters (22% vs. 14%; p<0.0001) than non-cancer patients. Thromb Haemost 2007; 98: 656-661

Tools in the Toolkit LMWH, Unfractionated Heparin, Fondaparinux, Warfarin IVC Filters Graduated Compression Stockings and Intermittent Pneumatic Compression Devices

VTE Prophylaxis In 19,958 Medical Patients/ 9 Studies (Meta-analysis) 62% reduction in fatal PE 57% reduction in fatal or nonfatal PE 53% reduction in DVT Dentali F, et al. Ann Intern Med 2007; 146: 278-288

Dalteparin Prophylaxis in 3,706 Medical Patients Cancer Subgroup Dalteparin 5,000 U/d vs. placebo 6 of 72 placebo patients (8.3%) developed VTE, compared with 2 of 65 dalteparin patients (3.1%) Dalteparin was effective in all subgroups. Vascular Medicine 2007; 12: 123-128

Filters Filter insertion has increased, especially retrievable filters. Filters prevent PE but increase DVT rate (and do not halt the thrombotic process). Main indications: Severe bleeding that precludes anticoagulation Recurrent PE despite therapeutic anticoagulation Prophylaxis

Retrievable Filters Prospective Series (N=228) Retrieval attempted in only 25% Filter tilting: 5.7% Puncture site hematoma: 4.2% Filter migration: 1.4% Infection: 0.9% DVT: 15% Fatal PE: 2.3% Mismetti P et al. Chest 2007; 131: 223-229

Intermittent Pneumatic Compression Meta-analysis In Postop Patients 2,270 patients in 15 randomized trials IPC devices reduced DVT risk by 60% (Relative Risk 0.40, 95% CI 0.29-0.56, p< 0.001) Urbankova J. Thromb Haemost 2005; 94: 1181-5

Guidelines ASCO NCCN ACCP

National Comprehensive Cancer Network (NCCN) The NCCN “recommends prophylactic anticoagulation for all inpatients with a diagnosis of active cancer who do not have a contraindication.” “Anticoagulation should be administered throughout hospitalization.” “VTE prophylaxis after hospital discharge should be strongly considered.” J NCCN 2006; 4: 838-869

American Society Of Clinical Oncology (ASCO) “Consider all hospitalized cancer patients for VTE prophylaxis with anticoagulants, in absence of bleeding…” “Give routine prophylaxis to outpatients receiving thalidomide or lenalidomide.” “LMWH represents the preferred agent.” “Impact of anticoagulants on cancer patient survival requires additional study.” JCO 2007; 25: 5490-5505

American College Of Chest Physicians (ACCP) VTE prophylaxis while hospitalized Treat acute DVT or PE with LMWH as monotherapy without warfarin for at least 3-6 months Continue anticoagulant therapy indefinitely or until the cancer resolves. CHEST 2004; 126: 338S-400S CHEST 2004; 126: 401S-428S

Implementation Electronic (computerized) alerts to physicians Human Alerts JCAHO Medicare payments “Opt out” strategies

Implementation The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” emphasize the need for improved preventive efforts. Failure to institute prophylaxis is a much bigger problem with Medical Service patients, especially medical oncology patients, than Surgical Service patients.

Implementation We have initiated trials to change MD behavior and improve implementation of VTE prophylaxis—not trials of specific types of prophylaxis—eAlert RCT, eAlert cohort, human Alert, 3-screen eAlert.

Quality Improvement Initiative to Improve Clinical Practice Randomized (“eAlert”) controlled trial to issue or withhold electronic alerts to MDs whose high-risk patients were not receiving DVT prophylaxis. Kucher N, et al. NEJM 2005;352:969-977

Definition of “High Risk” VTE risk score ≥ 4 points: Cancer 3 (ICD codes) Prior VTE 3 (ICD codes) Hypercoagulability 3 (Leiden, ACLA) Major surgery 2 (> 60 minutes) Bed rest 1 (“bed rest” order) Advanced age 1 (> 70 years) Obesity 1 (BMI > 29 kg/m2) HRT/OC 1 (order entry)

DVT Prophylaxis at BWH There were 13,922 patients with a VTE risk score ≥ 4 from September 2000 to January 2004 11,416 (82%) patients received DVT prophylaxis 2506 (18%) patients did not receive DVT prophylaxis Kucher N, et al. NEJM 2005;352:969-977

Randomization VTE risk score > 4 No prophylaxis INTERVENTION Single alert n = 1255 CONTROL No alert n = 1251 Kucher N, et al. NEJM 2005;352:969-977

Baseline Characteristics Median age = 62.5 years Medical services: 83% Surgical services: 17% Comorbidities Cancer: 80% Hypertension: 34% Infection: 30% Prior VTE: 20% Kucher N, et al. NEJM 2005;352:969-977

90-Day Primary Endpoint Intervent. Control Hazard Ratio p N=1255 N=1251 (95% CI) Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001 Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004 Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08 Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10 UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90 Kucher N, et al. NEJM 2005;352:969-977

Primary End Point Time (days) 30 60 90 92 94 96 98 100 Number at risk Intervention Control Time (days) 30 60 90 %Freedom from DVT/ PE 92 94 96 98 100 Number at risk Intervention 1255 977 900 853 Control 1251 976 893 839 Kucher N, et al. NEJM 2005;352:969-977

Conclusions Electronic alerts Facilitated the detection of patients at high risk of DVT/PE Increased the rate of DVT prophylaxis from 14.5% to 33.5% Reduced the incidence of DVT/PE by 41%, without increasing bleeding Kucher N, et al. NEJM 2005;352:969-977

JCAHO Performance Measures VTE-07143 June 25, 2007 JCAHO Performance Measures [1/www.nqf.org.Standards ForVTE.May.2006/ p23/line 5-7] [2/jointcommission.org/ p1/line 12-15; 16-35] Prophylaxis (Approved in May 2006) Surgery patients with recommended VTE prophylaxis ordered Surgery patients who received appropriate VTE prophylaxis within 24 hours preop to 24 hours after surgery Risk Assessment/Prophylaxis (Pending) VTE risk assessment/ prophylaxis within 24 hours of hospital admission VTE risk assessment/ prophylaxis within 24 hours of transfer to ICU The 2 performance measures endorsed in May, 2006 by The Joint Commission and the National Quality Forum were1: Surgery patients with recommended VTE prophylaxis ordered Surgery patients who received appropriate VTE prophylaxis within 24 hours prior to surgery to 24 hours after surgery The 8 measures selected to undergo pilot testing in 55 hospitals from January to June of 2007 are2: Risk assessment/prophylaxis measures VTE risk assessment/prophylaxis within 24 hours of hospital admission VTE risk assessment/prophylaxis within 24 hours of transfer to ICU Treatment measures Documentation of inferior vena cava filter indication VTE patients with overlap therapy VTE patients receiving UFH with platelet count monitoring VTE patients receiving UFH management by nomogram/protocol VTE discharge instructions Outcome measures Incidence of potentially preventable hospital-acquired VTE [1/www.nqf.org.Standards ForVTE.May.2006/ p23/line 5-7] [2/jointcommission.org/ p1/line 12-15; 16-35] _________________________________________________________________________________ National Quality Forum. National Quality Forum endorses consensus standards for prevention and care of venous thromboembolism [press release]. May 18, 2006. Available at: http://www.qualityforum.org/news/prDVTendorsed05-18-06.pdf. Accessed September 21, 2006. Joint Commission on Accreditation of Healthcare Organizations. National Consensus Standards for Prevention and Care of Venous Thromboembolism (VTE). October 18, 2006. Available at: http://www.jointcommission.org/PerformanceMeasurement/PerformanceMeasurement/National+Consensus+Standards+for+Prevention+and+Care+of+Venous+Thromboembolism+(VTE).htm. Accessed January 5, 2007. 146

Quality Measures 2 measures are in current use VTE-07143 June 25, 2007 Quality Measures 2 measures are in current use SCIP VTE 1: Was DVT/PE prophylaxis ordered? SCIP VTE 2: Was DVT/PE prophylaxis received? Implementation by Medicare Hospitals must report on the 2 measures beginning January 2007 to receive full payment in 2008 Medicare adjusted rate increase will be reduced by 2.0% for noncompliance [1/www.premierinc. com.SCIPProcess&OutcomeMeasures.Oct.2005/p1/c1/line 21-24] [2/nqf.org.StandardsFor VTE.May.2006/p3/c1/ line 5-7; p1/line 17-19] [3/www.cms.hhs.gov. SCIP-reporting.Aug.2006/ p2/c1/line 21-26; p1/c1/line 1-5, 9-12] 147

Default (“Opt Out”) Options Flu, pneumonia vaccines. Remove urinary catheters within 72h. Head of bed at 30-45 angle in ICU. Interrupt sedatives daily: vented pts. Prophylax against VTE. Halpern SD et al. NEJM 2007; 357: 1340

Summary Cancer and VTE is a disabling and at times deadly combination. VTE prophylaxis is safe and effective. ASCO, NCCN, and ACCP endorse VTE prophylaxis in cancer patients. For unclear reasons, VTE prophylaxis is underutilized. VTE prophylaxis of cancer patients will increase, through a combination of voluntary initiatives and regulatory mandates.