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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:

1 Welcome to this Science-to-Strategy Summit

2 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 Clotting, Cancer, and Controversies Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry The Thrombosis Research Institute London, UK Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry The Thrombosis Research Institute London, UK

3 CME-accredited symposium jointly sponsored by the Postgraduate Institute of Medicine and CMEducation Resources 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

4 Program Educational Objectives As a result of this session, physicians will be able to: Review recent trials, research, and expert analysis of issues focused on thrombosis and cancer. Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer. 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. As a result of this session, physicians will be able to: Review recent trials, research, and expert analysis of issues focused on thrombosis and cancer. Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer. 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.

5 Program Faculty Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry Thrombosis Research Institute London, UK 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 Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry Thrombosis Research Institute London, UK 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 Alex C. Spyropoulos, MD, FACP, FCCP Chair, Department of Clinical Thrombosis Lovelace Medical Center Clinical Associate Professor of Medicine University of New Mexico Albuquerque, New Mexico Distinguished Panel Member, Consultant, and Visiting Professor Samuel Z. Goldhaber, MD Professor of Medicine, Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Group Director, Anticoagulation Service Brigham and Womens Hospital Boston, MA Alex C. Spyropoulos, MD, FACP, FCCP Chair, Department of Clinical Thrombosis Lovelace Medical Center Clinical Associate Professor of Medicine University of New Mexico Albuquerque, New Mexico Distinguished Panel Member, Consultant, and Visiting Professor Samuel Z. Goldhaber, MD Professor of Medicine, Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Group Director, Anticoagulation Service Brigham and Womens Hospital Boston, MA

6 Faculty COI Financial Disclosures Ajay Kakkar, MBBS, PhD, FRCS Grants/research support: sanofi-aventis, AstraZeneca, Pfizer Consultant: Pfizer, sanofi-aventis Craig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, Octapharma Consultant: sanofi-aventis, Eisai, NovoNordisk Alex C. Spyropoulos, MD, FACP, FCC Consultant: sanofi-aventis, Eisai, Bayer, Boehringer-Ingelheim Speakers Bureau: sanofi-aventis Eisai Samuel Z. Goldhaber, MD Grant/Research Support: sanofi-aventis, GSK, Eisai Consultant: sanofi-aventis, BMS, Emisphere, Boehringer-Ingelheim Ajay Kakkar, MBBS, PhD, FRCS Grants/research support: sanofi-aventis, AstraZeneca, Pfizer Consultant: Pfizer, sanofi-aventis Craig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, Octapharma Consultant: sanofi-aventis, Eisai, NovoNordisk Alex C. Spyropoulos, MD, FACP, FCC Consultant: sanofi-aventis, Eisai, Bayer, Boehringer-Ingelheim Speakers Bureau: sanofi-aventis Eisai Samuel Z. Goldhaber, MD Grant/Research Support: sanofi-aventis, GSK, Eisai Consultant: sanofi-aventis, BMS, Emisphere, Boehringer-Ingelheim

7 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 Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry The Thrombosis Research Institute London, UK Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry The Thrombosis Research Institute London, UK

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

9 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

10 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.

11 Comorbidity Connection ComorbidityConnection Overview Overview

12 Acute Medical Illness and VTE Acute MedicalRelative Risk Illness Risk X 2 P Value Illness Risk X 2 P Value Heart failure 1.08 ( ) NYHA class III 0.89 ( ) NYHA class IV 1.48 ( ) Acuterespiratory disease 1.26 ( ) Acuteinfectious disease 1.50 ( ) Acuterheumatic disease 1.45 ( ) Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Ineffective Antithrombotic Therapy Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

13 Acute Medical Illness and VTE Risk FactorOdds RatioX 2 (95% CI) Age >75 y 1.03 ( ) Cancer 1.62 ( ) 0.08 Previous VTE 2.06 ( ) 0.02 Acuteinfectious disease 1.74 ( ) 0.02 Chronicrespiratory disease 0.60 ( ) 0.02 Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

14 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 occurrence 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 Jun 10;162(11): Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

15 VTE Recurrence BaselineHazard Ratio Characteristic (95% CI) Age1.17 ( ) Body Mass Index1.24 ( ) Neurologic disease with1.87 ( ) extremity paresis Malignant neoplasm None 1.00 None 1.00 With chemotherapy4.24 ( ) With chemotherapy4.24 ( ) Without chemotherapy2.21 ( ) Without chemotherapy2.21 ( ) Predictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med. 2000;160:

16 Cancer Surgery, Thrombosis, and the Biology of Malignancy A Science-to-Strategy PerspectiveThe Foundation Role of LWMH at the Interface of Thrombosis and Cancer Cancer Surgery, Thrombosis, and the Biology of Malignancy A Science-to-Strategy PerspectiveThe Foundation Role of LWMH at the Interface of Thrombosis and Cancer Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry The Thrombosis Research Institute London, UK Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Marys School of Medicine and Dentistry The Thrombosis Research Institute London, UK Clotting, Cancer, and Controversies

17 AuthorYear No. of studies Cancer mortality UFHLMWH Green /67 (31%) 21/67 (31%) 7/62 (11%) 7/62 (11%) Siragusa /81 (28%) 23/81 (28%) 10/74 (14%) 10/74 (14%) Meta-analysis of DVT Treatment Studies

18 Famous: Trial Design Treatment for 1 year or until death 1º Endpoint: 1 year mortality (50% 35%) 2º Endpoints: VTE and bleeding R Advanced solid tumour malignancy N/Saline placebo Dalteparin 5000 IU od Kakkar AK, et al. J Clin Oncol. 2004;22:

19 Kaplan–Meier survival curves for all ITT patients in dalteparin and placebo groups Kaplan–Meier survival distribution function estimate Time from randomisation (months) No. at risk: DalteparinPlacebo Dalteparin Placebo Kakkar AK, et al. J Clin Oncol. 2004;22:

20 Survival Analysis: Good Prognosis Patients Kaplan–Meier survival distribution estimate Placebo Dalteparin Time from randomisation (months) No. at risk: DalteparinPlacebo Kakkar AK, et al. J Clin Oncol. 2004;22:

21 LMWH and Survival: Further Studies (2003) Solid tumor malignancy and acute VTE All patients received dalteparin 200 IU/kg od 5–7 days R Dalteparin 1 month 200 IU/kg od 5 months 160 IU/kg od Oral anticoagulant 6 months Small cell lung cancer (SCLC) Patients with responsive limited disease received thoracic radiotherapy Chemotherapy plus dalteparin 5000 IU od 18 weeks Chemotherapy (cyclophosphamide, epirubicin, vincristine) 18 weeks Solid tumor malignancy Nadroparin 2 weeks therapeutic dose 4 weeks 1/2 therapeutic dose Placebo 6 weeks CLOT SCLC study MALT R R Klerk CPW, et al. J Clin Oncol. 2005;23: Altinbas M, et al. J Thromb Haemost. 2004;2:1-6. Lee, et.al. N Engl J Med, 2003;349:146

22 SCLC Study Survival Curves Months after randomization Probability of survival Good prognosis population limited disease Months after randomization Probability of survival Overall population p=0.01 p=0.007 Dalteparin Placebo Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.

23 CLOT Survival Curves Probability of survival (%) Dalteparin OAC Days after randomization OAC Dalteparin Probability of survival (%) Overall population Good prognosis population without metastases p=0.62 p=0.03 Days after randomization Lee, et.al. N Engl J Med, 2003;349:146

24 MALT Survival Curves Probability of Survival Months after randomization Placebo Nadroparin p= Months after randomization Probability of Survival Placebo Nadroparin p=0.021 Overall populationGood prognosis population >6 months survival Klerk CPW, et al. J Clin Oncol. 2005;23:

25 Mechanistic explanations VTE Coagulation Protease Direct Heparin Other LMWH and Prolonged Cancer Survival

26 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 = 7x OR for VTE vs. non-CA patients Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 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

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

28 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 Interface of Biology and Cancer

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

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

31 Activation of Blood Coagulation in Cancer Biological Significance? Epiphenomenon? Epiphenomenon? Is this a generic secondary event (as in inflammation, where clot formation is an incidental finding) Is this a generic secondary event (as in inflammation, where clot formation is an incidental finding) Or, is clotting... Or, is clotting... A Primary Event? A Primary Event? Linked to malignant transformation Linked to malignant transformation

32 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 Biology and Cancer

33 Coagulation Cascade and Tumors TFThrombin Clotting- dependent Clotting- independent Clotting- dependent ANGIOGENESIS Fibrin Clotting- independent PARs Tumor Growth And Metastasis Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31

34 Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor 1.TF regulates VEGF expression in human melanoma 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:

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

36 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: ) (Boccaccio et. al. Nature 2005;434: ) 2. Pten loss produces TF activation and pseudopalisading necrosis in human glioblastoma (Rong et.al. Ca Res 2005;65: ) (Rong et.al. Ca Res 2005;65: ) 3. K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma (Yu et.al. Blood 2005;105: ) (Yu et.al. Blood 2005;105: )

37 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) l Drives physiological cellular program of invasive growth (tissue morphogenesis, angiogenesis and repair) l Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transformation, invasion, and metastasis Boccaccio et al Nature 2005;434: 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

38 Mouse model of Trousseaus Syndrome Mouse model of Trousseaus Syndrome l Targeted activated human MET to the mouse liver with lentiviral vector and liver-specific promoter slowly, progressive hepatocarcinogenesis l Preceded and accompanied by a thrombohemorrhagic syndrome thrombohemorrhagic syndrome l Venous thrombosis in tail vein occurred early and was followed by fatal internal hemorrhage l 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

39 Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Transgene Parameter Parameter Time after Transduction (days) Time after Transduction (days) GFP_________MET Platelets (x10 3 ) D-dimer (µg/ml) PT (s) ________________ Platelets (x10 3 ) D-dimer (µg/ml) PT (s) <0.05 <0.05 < _______________________________ <

40 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 Rong, Brat et.al. Ca Res 2005;65:

41 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

42 Results: 1.Hypoxia and PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTEN 2.PTEN effect independent of lipid phosphatase activity; dependent on protein phosphatase 3.Both Akt and Ras pathways modulated TF in sequentially transformed astrocytes. 4.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

43 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 Yu, Mackman, Rak et.al. Blood 2005;105:

44 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: Mean Channel TF Flourescence TF Activity (U/10 6 cells) del/+mut/+mut/+ +/++/+del/del

45 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: Activation of Blood Coagulation in Cancer: Malignant Transformation Activation of Blood Coagulation in Cancer: Malignant Transformation

46 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: %VWF-Positive Area

47 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:

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

49 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 Controversies

50 VTE and Cancer: Epidemiology Of all cases of VTE: Of all cases of VTE: l About 20% occur in cancer patients l Annual incidence of VTE in cancer patients 1/250 Of all cancer patients: Of all cancer patients: l 15% will have symptomatic VTE l As many as 50% have VTE at autopsy Compared to patients without cancer: Compared to patients without cancer: l Higher risk of first and recurrent VTE l Higher risk of bleeding on anticoagulants l 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

51 1.Ambrus JL et al. J Med. 1975;6: Donati MB. Haemostasis. 1994;24: Johnson MJ et al. Clin Lab Haem. 1999;21: 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

52 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

53 Risk Factors for Cancer-Associated VTE Cancer Cancer l Type Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung Women: breast, ovary, lungWomen: breast, ovary, lung l Stage Treatments Treatments l Surgery 10-20% proximal DVT10-20% proximal DVT 4-10% clinically evident PE4-10% clinically evident PE 0.2-5% fatal PE0.2-5% fatal PE l Systemic l Central venous catheters (~4% generate clinically relevant VTE)

54 Thrombosis and Survival: Likelihood of Death After Hospitalization 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

55 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: Cancer Patients Noncancer Patients

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

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

58 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

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

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

61 Natural History of VTE in Cancer Surgery: 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

62 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, 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) ( ).85 Transfusion (n = 1156) ( ).85 Female Sex No Transfusion (n = 5565)0.9Referent No Transfusion (n = 5565)0.9Referent Transfusion (n = 1610)2.1< ( ).004 Transfusion (n = 1610)2.1< ( ).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

63 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

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

65 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– McLeod R, et al. Ann Surg 2001;233: Prophylaxis in Surgical Patients StudyNDesignRegimens ENOXACAN 1 631double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475double-blind enoxaparin vs. UFH

66 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

67 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: P=0.052 Incidence of Outcome Event VTEMajor Bleeding VTEMajor Bleeding (Cancer) (All) Prophylaxis in Surgical Patients

68 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 Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346: 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

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

70 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 InvestigatorsDalteparin Extended Rasmussen, J Thromb Haemost Nov;4(11): Epub 2006 Aug 1.

71 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: l Postoperative risk of DVT/PE varies 12%–35% l LDUH (5000 u bid) ineffective l LDUH 5000 u tid reduces risk by 50%–60% l Once-daily LMWH comparable to LDUH for efficacy and safety Gynecological Cancer Surgery

72 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

73 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: DVTPE Fatal PE Radical retropubic prostatectomy 1–3% 0.6% Cystectomy 8% 2–4% 2% Radiological studies 51%22%

74 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

75 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% Proximal DVT 12.5% 6.2% 6.2% <0.01 Total bleeding 3.0% 3.0% 6.1% 6.1% Major bleeding 1.3% 1.3% 2.2% 2.2% Iorio A, Agnelli G. Arch Intern Med. 2000;160: Neurosurgery and VTE Prophylaxis

76 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

77 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

78 Placebo-Controlled Trials StudyRegimenN CRT (%) CRT (%) Reichardt* 2002 Dalteparin 5000 U od placebo (3.7) 11 (3.7) 5 (3.4) 5 (3.4) Couban*2002 Warfarin 1mg od placebo (4.6) 6 (4.6) 5 (4.0) 5 (4.0) ETHICS ETHICS 2004 Enoxaparin 40 mg od placebo (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

79 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:

80 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

81 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

82 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.)

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

84 Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery w/ institutionalization 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:

85 VTE Incidence In Various Tumors 47% Solid tumors (anti-VEGF + chemo) 43% Renal cell carcinoma 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% 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 VTEIncidence 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

86 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

87 DVT Len + D(%) D (%) Len + D(%) D (%) MM-009 MM PE Weber D. ASCO 2005 Annual Meeting MM-009/010: Thromboembolic Events

88 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 ( )<0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 ( )<0.001

89 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)

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

91 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 Hutten et.al. J Clin Oncol 2000;18:3078

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

93 Oral Anticoagulant Therapy in Cancer Patients: Problematic Warfarin (Coumadin®) therapy is complicated by: Warfarin (Coumadin®) therapy is complicated by: l Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. l Frequent interruptions for thrombocytopenia and procedures l Difficulty in venous access for monitoring l 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?

94 CLOT: Landmark Cancer/VTE Trial CANCER PATIENTS WITH ACUTE DVT or PE Randomization Randomization Dalteparin Dalteparin Oral Anticoagulant Dalteparin [N = 677] 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

95 Landmark CLOT Cancer Trial Reduction in Recurrent VTE Days Post Randomization Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

96 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

97 Treatment of Cancer-Associated VTE StudyDesign Length of Therapy (Months)N Recurrent VTE (%) Major Bleeding (%)Death(%) CLOT Trial (Lee 2003) DalteparinOAC CANTHENOX (Meyer 2002) EnoxaparinOAC LITE (Hull ISTH 2003) TinzaparinOAC ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC NS 0.03 NS NS NR

98 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

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

100 Days Post Randomization Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Lee A, et al. ASCO Patients Without Metastases (N=150)

101 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, % y overall survival, % Median survival, m CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily

102 VTE Prophylaxis Is Underused in Patients With Cancer 1.Kakkar AK et al. Oncologist. 2003;8: Stratton MA et al. Arch Intern Med. 2000;160: Bratzler DW et al. Arch Intern Med. 1998;158: Cancer: FRONTLINE Survey 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: Goldhaber SZ et al. Am J Cardiol. 2004;93:

103 Venous Thromboembolism (VTE) Prophylaxis in the Cancer Patient Guidelines and Implications for Clinical Practice Venous Thromboembolism (VTE) Prophylaxis in the Cancer Patient Guidelines and Implications for Clinical Practice Alex C Spyropoulos, MD, FACP, FCCP Chair, Department of Clinical Thrombosis Lovelace Medical Center Clinical Associate Professor of Medicine Associate Professor of Pharmacy University of New Mexico Health Sciences Center Albuquerque, NM, USA Alex C Spyropoulos, MD, FACP, FCCP Chair, Department of Clinical Thrombosis Lovelace Medical Center Clinical Associate Professor of Medicine Associate Professor of Pharmacy University of New Mexico Health Sciences Center Albuquerque, NM, USA Clotting, Cancer, and Controversies

104 Outline of Presentation VTE prophylaxis in cancer VTE prophylaxis in cancer l Surgical, CVC, medical Guidelines for VTE prophylaxis in the cancer patient Guidelines for VTE prophylaxis in the cancer patient l ACCP, NCCN Performance to date Performance to date Opportunities for improvement Opportunities for improvement

105 Thromboprophylaxis in Cancer vs Non- Cancer Surgical patients Non-Cancer (%) N=16,954 Cancer (%) N=6124 P Post-op VTE < Non-fatal PE < Autopsy PE Death Cancer patients have a 2-fold increased risk Of VTE and 3-fold increased risk of fatal PE despite prophylaxis Haas S et al Thromb Haemost 2005;94: Kakkar AJ et al Thromb Haemost 2005;94:867-71

106 Thromboprophylaxis in Surgical Patients ARISTOS ARISTOS l Prospective cohort of 2373 patients Overall symptomatic VTE 2.1% and death 1.7% Overall symptomatic VTE 2.1% and death 1.7% Advanced tumor Advanced tumor l OR 4.4 (95% CI 1.4 – 5.2) Agnelli G Ann Surg 2006; 243:85-89

107 In-hospital Thromboprophylaxis in Cancer Surgery ENOXACAN Canadian Colorectal Study P=NSNNT=29 P=0.05NNT=33 ENOXACAN Study Group Br J Surg 1997;84: Mcleod R et al Ann Surg 2001;233:436-44

108 Extended Thromboprophylaxis in Cancer Surgery ENOXACAN II FAME P= 0.02 NNT=14 P<0.03 NNT= 9 Berquvist D et al NEJM 2002;346: Rasmusan M et al Blood 2003;102;52a

109 Systematic Review of DVT Prophylaxis of Surgical Cancer Patients 26 RCTs of 7,639 patients 26 RCTs of 7,639 patients l Overall DVT of pharmacological Px vs controls % vs 35.2% l High dose vs Low dose LMWH for DVT 7.9% vs 14.5% (p<0.01) l No differences in LMWH vs UFH in efficacy, DVT location, or bleeding l Overall bleeding complications 3% Leonardi MJ et al Ann Surg Oncol 2007;14(2):929-36

110 Thromboprophylaxis for CVC Prior studies with ~ 5% incidence of symptomatic catheter-related thrombosis Prior studies with ~ 5% incidence of symptomatic catheter-related thrombosis RegimenN Cath Thrombosis (%) Kathaus 2006 dalteparin 5000U qd placebo (3.7) 5 (3.4) Couban 2005 warfarin 1mg QD Placebo (4.6) 5 (4.0) Verso 2005 enoxaparin 40mg qd placebo (14.2) 28 (18.1) Karthaus et al Oncol 2006;17: Couban et al JCO 2006: 23: Verso et al JCO 2006;23:

111 Thromboprophylaxis in Hospitalized Medical Cancer Patients There are no randomized trials in hospitalzed medical oncology patients There are no randomized trials in hospitalzed medical oncology patients Randomized, placebo controlled trials in acutely ill hospitalized medical patients (of which cancer patients area percentage ) Randomized, placebo controlled trials in acutely ill hospitalized medical patients (of which cancer patients area percentage ) Pt no Cancer (%) 1455

112 Dentali, F. et. al. Ann Intern Med 2007;146: Fatal Pulmonary Embolism During Anticoagulant Prophylaxis Favors Treatment Favors Placebo Study, Year (Reference) Prophylaxis n/n Placebo n/n RR Fixed (95% CI) RR Fixed (95% CI) Dahan et al, 1986 (41) 1/132 3/ (0.03 to 3.14) Garlund at al, 1996 (35) 3/ / (0.07 to 0.91) Leizorovic et al, 2004 (23) 0/1829 2/ (0.01 to 4.11) Mahe et al, 2005 (22) 10/ / (0.27 to 1.29) Cohen at, 2006 (42) 0/321 5/ (0.01 to 1.65) Total (95% CI) 0.38 (0.21 to 0.69) Total events 14 39

113 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 l BID VTE event rate: 2.34 events per 1,000 patient days l TID event rate: 0.86 events per 1,000 patient days P=0.05 P=0.05 NNT NNT l 676 hospital prophylaxis days with UFH TID to prevent l 1 major bleed with 1,649 hospital prophylaxis days of TID dosing King CS et al. CHEST 2007;131:

114 Incidence and Economic Implications of HIT Creekmore FM, et al. Pharmacotherapy. 2006;26: N = 10,121 P = P < 0.001

115 2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A) l General, Gynecologic, Urologic Surgery Low Dose Unfractionated Heparin 5,000 units TIDLow Dose Unfractionated Heparin 5,000 units TID LMWH > 3,400 units DailyLMWH > 3,400 units Daily –Dalteparin 5,000 units –Enoxaparin 40 mg –Tinzaparin 4,500 units GCS and/or IPCGCS and/or IPC Surgical patients may receive post-discharge prophylaxis with LMWH (Grade 2A) No routine prophylaxis for central venous catheters, including LMWH (Grade 2B) and fixed-dose warfarin (Grade 1B) Cancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A) Low Dose Unfractionated HeparinLow Dose Unfractionated Heparin LMWHLMWH Contraindication to anticoagulant prophylaxis (Grade 1C+) GCS or IPCGCS or IPC Geerts WH et al. Chest. 2004;126(suppl):338S-400S

116 NCCN Practice Guidelines in VTE Disease At Risk Population Initial Prophylaxis Adult patient Adult patient Diagnosis or clinical suspicion of cancer Diagnosis or clinical suspicion of cancer Inpatient Inpatient Relative contra- indication 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 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

117 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 cubcutaneous daily Pentasaccharide Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily Unfractioned heparin 5,000 units subcutaneous 3 times daily Unfractioned heparin 5,000 units subcutaneous 3 times daily

118 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

119 Compliance With ACCP VTE Prophylaxis Guidelines Is Poor 9.9% 6.7% 35,124 62, ,000 10,000 70,000 Number of patients At risk for DVT/PE Received compliant care 15.3% 12.7% 52.4% 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

120 VTE Prophylaxis Use According to Primary Admission: The IMPROVE Registry Anderson F et al Blood 2003

121 In-Hospital Prophylaxis by Medical Condition – IMPROVE Registry Tapson V et al Chest 2007 (in press)

122 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 Effect Odds Ratio (95% CI) Predictors of the Use of Thromboprophylaxis Kahn SR et Al. Thromb Res 2007; 119:

123 Independent factors present at admission for in-hospital bleeding – multivariate analysis (IMPROVE Registry) Adjusted Odds Ratio (95% CI) Adjusted Odds Ratio (95% CI) Bleeding disorder5.11 (2.38, 10.98) Active G-duodenal ulcer 4.93(2.86, 8.50) Adm platelets<50 x (1.67, 5.41) Hepatic failure2.79(1.57, 4.95) ICU/CCU stay2.41(1.60, 3.63) Current cancer1.99(1.39, 2.85) Central venous catheter1.98(1.33, 2.95) Age 85 years1.91(1.29, 2.85) S. creatinine 2.5 mg/dL1.88(1.26, 2.79) Decousus H et al Blood 2005

124 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 l Major risk: Cancer, prior VTE, hypercoagulability (3 points) l Intermediate risk: Major surgery (2 points) l 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

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

126 Cohen A et al Thromb Haemost 2005;94(4):750-9 VTE Risk Assessment for Hospitalized Medical Patients All medical patients should be routinely assessed and considered for thromboprophylaxis Is the patient > 40 years old with acute medical illness and reduced mobility? Does the patient have one of the following acute medical illnesses/conditions? Evidence-based: Acute MIAcute MI Acute heart failureNYHA III/IVAcute heart failureNYHA III/IV Active cancer requiring therapyActive cancer requiring therapy Severe infection/sepsisSevere infection/sepsis Respiratory disease (respiratory failure with/without mechanical ventilation, exacerbations of chronic respiratory disease)Respiratory disease (respiratory failure with/without mechanical ventilation, exacerbations of chronic respiratory disease) Rheumatic disease (including acute arthritis of lower extremities and vertebral compression)Rheumatic disease (including acute arthritis of lower extremities and vertebral compression) Ischemic strokeIschemic stroke ParaplegiaParaplegia Consensus view only: Inflammatory disorder with immobilityInflammatory disorder with immobility Inflammatory bowel diseaseInflammatory bowel disease YES Does the patient have one of the following risk factors? Evidence-based in acutely ill medical patients: History of VTEHistory of VTE History of malignancyHistory of malignancy Concurrent acute infectious diseaseConcurrent acute infectious disease Age > 75 yearsAge > 75 years Consensus view only: Prolonged immobilityProlonged immobility Age > 60 yearsAge > 60 years Varicose veinsVaricose veins ObesityObesity Hormone therapyHormone therapy Pregnancy/postpartumPregnancy/postpartum Nephrotic syndromeNephrotic syndrome DehydrationDehydration ThrombopiliaThrombopilia ThrombocytosisThrombocytosis

127 Cohen A et al Thromb Haemost 2005;94(4): VTE Risk Assessment for Hospitalized Medical Patients Is pharmacological thromboprophylaxis contraindicated? YES Mechanical thromboprophylaxis with graduated compression stockings or intermittent pneumatic compression is recommended YES LMWH (enoxaparin 40 mg o.d. or dalteparin 5000 IU o.d.) or UFH (5000 IU t.i.d.) (LMWH preferred due to better safety profile) NO No evidence for the benefits of thromboprophylaxis. However, patients should be considered for thromboprophylaxis on a case-by- case basis NO

128 Conclusions Current practices of VTE prophylaxis in the cancer pat ient Current practices of VTE prophylaxis in the cancer pat ient Cancer surgical patients have an increased risk of VTE and fatal PE despite prophylaxis Cancer surgical patients have an increased risk of VTE and fatal PE despite prophylaxis Prophylaxis with LMWH or UFH reduces venographic VTE but not CVC-related thrombosis Prophylaxis with LMWH or UFH reduces venographic VTE but not CVC-related thrombosis Out-of-hospital prophylaxis with LMWH is warranted in specific surgical cancer populations Out-of-hospital prophylaxis with LMWH is warranted in specific surgical cancer populations Prophylaxis in hospitalized non-surgical cancer patients is suboptimal Prophylaxis in hospitalized non-surgical cancer patients is suboptimal Compliance with ACCP and NCCN guidelines is poor Compliance with ACCP and NCCN guidelines is poor


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