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The Science and Medicine of Thrombosis in Cancer The Evolving and Foundation Role of LMWHs in Cancer and Thrombosis: Applying Science, Expert Analysis,

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Presentation on theme: "The Science and Medicine of Thrombosis in Cancer The Evolving and Foundation Role of LMWHs in Cancer and Thrombosis: Applying Science, Expert Analysis,"— Presentation transcript:

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2 The Science and Medicine of Thrombosis in Cancer The Evolving and Foundation Role of LMWHs in Cancer and Thrombosis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Specialty Practice Program Chairman Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Lombardi Comprehensive Cancer Center Washington, DC Mechanisms Mortality Therapeutics

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

4 Program Educational Objectives As a result of this session, participants will: Learn about recent trials, research, and expert analysis of issues focused on thrombosis and cancer.Learn about recent trials, research, and expert analysis of issues focused on thrombosis and cancer. Learn about mechanisms, morbidity, mortality, and therapeutic issues focused on thrombosis and cancer.Learn about mechanisms, morbidity, mortality, and therapeutic issues focused on thrombosis and cancer. Learn about relationships among the clotting cascade, agents affecting the coagulation system, and mortality outcomes in cancer patients.Learn about relationships among the clotting cascade, agents affecting the coagulation system, and mortality outcomes in cancer patients. Learn about strategies for risk-directed prophylaxis against VTE in at risk patients with cancer.Learn about strategies for risk-directed prophylaxis against VTE in at risk patients with cancer. Learn how to assess and manage special needs of cancer patients at- risk for VTE, with a focus on protecting against recurrent DVT.Learn how to assess and manage special needs of cancer patients at- risk for VTE, with a focus on protecting against recurrent DVT.

5 Program Faculty Craig M. Kessler, MDProgram Chairman Professor of Medicine and Pathology Georgetown University Medical Center Lombardi Comprehensive Cancer Center Chief, Division of Coagulation Washington, DC Frederick R. Rickles, MD, FACP Center for Health Innovation Public Sector Healthcare, Noblis Professor of Medicine, Pediatrics and Pharmacology and Physiology The George Washington University Washington, DC Edith Nutescu, Pharm.D., FCCP Clinical Associate Professor, Pharmacy Practice Affiliate Faculty, Center for Pharmacoeconomic Research Director, Antithrombosis Center The University of Illinois at Chicago College of Pharmacy & Medical Center Chicago, Illinois

6 Faculty COI Financial Disclosures Craig M. Kessler, MD - Co-Chairman Grant/Research Support: GlaxoSmithKline Consultant: sanofi-aventis, Eisai Pharmaceuticals Speakers Bureau: sanofi-aventis, GlaxoSmithKline Frederick R. Rickles, MD Consultant: Eisai Pharmaceuticals, Genmab, Pharmacyclics Speakers Bureau: Eisai Pharmaceuticals Edith Nutescu, PharmD Speakers Bureau: Eisai Inc., GlaxoSmithKline, sanofi-aventis U.S. Advisory Committees or Review Panels, Board Membership, etc.: Boehringer Ingelheim Pharmaceuticals, Inc., Scios Inc.

7 Clotting, Cancer, and Controversies What the Trials, Emerging Science, and Current Thinking Tell Us About The Evolving Science and Foundation Role of Anticoagulation in the Setting of Cancer Clotting, Cancer, and Controversies What the Trials, Emerging Science, and Current Thinking Tell Us About The Evolving Science and Foundation Role of Anticoagulation in the Setting of Cancer Program Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Program Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Innovation Investigation Application

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

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

10 Epidemiology of First-Time VTE White R. Circulation. 2003;107:I-4 –I-8.) VariableFinding Seasonal Variation Possibly more common in winter and less common in summer Risk Factors 25% to 50% idiopathic 15%-25% associated with cancer 20% following surgery (3 months) Recurrent VTE 6-month incidence, 7%; Higher rate in patients with cancer Recurrent PE more likely after PE than after DVT Death After Treated VTE 30-day incidence 6% after incident DVT 30-day incidence 12% after PE Death strongly associated with cancer, age, and cardiovascular disease

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

12 Thrombophilia Enhances Risks of Thrombosis in Cancer Patients H. Decousus et al. Thrombosis Research 120 Suppl. 2 (2007) S51-S61 Risk of thrombosis in cancer patients within the previous five years according to the presence of factor V Leiden or G20210A prothrombin gene mutation MutationCancer Patients with first venous thrombosis (n=2706) Control without venous thrombosis (n=1757) Age- and sex- adjusted odds ratio (95% CI) Factor V Leiden NoYes Yes ( ) YesNo ( ) Yes ( ) Prothombin 20210A NoNo Yes ( ) YesNo ( ) Yes140 Not determined

13 Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164: Risk Factor Odds Ratio (95% CI) X2X2X2X2 Age > 75 years Cancer Previous VTE 1.03 ( ) 1.62 ( ) 2.06 ( ) Acute infectious disease 1.74 ( ) 0.02

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

15 Progression of Chronic Venous Insufficiency From UpToDate 2006

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

17 DVT Registry (N=5,451) Top 5 Medical Comorbidities Am J Cardiol 2004; 93: Hypertension 2.Immobility 3.Cancer 4.Obesity (BMI > 30) 5.Cigarette Smoking

18 Implementation of Guidelines in Cancer Patients Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines.

19 Symposium ThemesCancer/DVT 1.Cancer rates are increasing as treatment for heart disease and cancer improve 2.Cancer increases VTE risk 3.VTE is preventable (immunize!) 4.VTE prophylaxis may slow cancer 5.Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATF 6.Facilitate prophylaxis with alerts

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

21 (1801–1867) Cancer and Venous Thromboembolism The Legacy of Armand Trousseau

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

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

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

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

26 Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715 Population-based MEGA study N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects CA patients = OR 7x VTE risk vs. non-CA patients Population-based MEGA study N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects CA patients = OR 7x VTE risk vs. non-CA patients Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 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 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 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 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 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 Death rate from cancer is four-fold higher if patient has concurrent VTE VTE 2 nd most common cause of death in ambulatory cancer patients (tied with infection) VTE 2 nd most common cause of death in ambulatory cancer patients (tied with infection) Heit et al Arch Int Med 2000;160: and 2002;162: ; Prandoni et al Blood 2002;100: ; White et al Thromb Haemost 2003;90: ; Sorensen et al New Engl J Med 2000;343: ); Levitan et al Medicine 1999;78: ; Khorana et al Heit et al Arch Int Med 2000;160: and 2002;162: ; Prandoni et al Blood 2002;100: ; White et al Thromb Haemost 2003;90: ; Sorensen et al New Engl J Med 2000;343: ); Levitan et al Medicine 1999;78: ; Khorana et al J Thromb Haemost 2007;5:632-4

28 Mechanisms of Cancer-Induced Thrombosis Critical Interfaces and Questions 1.Pathogenesis? 2.Biological significance? 3.Potential importance for cancer therapy?

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

30 Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Varki, A. Blood 2007;110: Multiple Mechanisms in Trousseau's Syndrome Tissue Factor microparticles

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

32 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

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

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

35 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;1:9-16 Interface of Clotting Activation and Tumor Biology

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

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

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

39 Activation of Blood Coagulation in Cancer and Malignant Transformation Epiphenomenon vs. Linked to Malignant Transformation? Epiphenomenon vs. Linked to Malignant Transformation? 1.MET oncogene induction produces DIC in human liver carcinoma (Boccaccio lab) (Boccaccio et al 2005;434: ) (Boccaccio et al Nature 2005;434: ) 2.Pten loss and EGFR amplification produce TF activation and pseudopalisading necrosis through JunD/Activator Protein-1 in human glioblastoma (Bratt lab) (Rong et al 2005;65: ; 2009;69:2540-9) (Rong et al Ca Res 2005;65: ; Ca Res 2009;69:2540-9) 3.K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma; TF and angiogenesis regulation in epithelial tumors by EGFR (ErbB1) – relationship to EMTs (Rak lab) (Yu et al 2005;105: ; Milson et al 2008;68: ) (Yu et al Blood 2005;105: ; Milson et al Ca Res 2008;68: )

40 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 2005;434: 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

41 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 thrombo- hemorrhagic syndrome l Thrombosis in tail vein occurs early and is 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

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

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

44 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 et al Ca Res 2005;65:

45 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

46 Results: 1.Hypoxia and PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTEN 2.Both Akt and Ras pathways modulated TF in sequentially transformed astrocytes 3.Ex vivo data: TF (by IH-chemical 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

47 Both Akt and Ras Pathways Modulate TF Expression By Transformed Astrocytes N = Normoxia H = Hypoxia H = Hypoxia Similar data for EGFR – upregulation of TF via JunD/ AP-1 transcription (CA Res 2009;69:2540-9)

48 H&E TF IHC Pten and Hypoxia Regulate Tissue Factor ExpressionPten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma Vascular Endothelium Pseudopalisading necrosis

49 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 et al 2005;105: Yu et al Blood 2005;105:

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

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

52 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 %VWF-Positive Area

53 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 Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung cancer cells, accompanied by epithelial-to-mesenchymal transition (EMT) Milsom et al 2008;68: Milsom et al CA Res 2008;68:

54 Kalluri and Kansaki Nature 2008;452:543 ( 21 nucleotides)* * Kleinman et al Nature 2008;452: ;452:591 Class Effect of siRNA for Angiogenesis Inhibition via Toll-Like Receptior 3 (TLR 3)

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

56 Activation of Blood Coagulation in Cancer: Malignant Transformation Q: What do all of these experiments in mice have to do with real patients with cancer? Q: What do all of these experiments in mice have to do with real patients with cancer? A: They suggest two things: A: They suggest two things: Tumor cell-derived, TF-rich microparticles (MPs) may be important as a predictive test for VTE Tumor cell-derived, TF-rich microparticles (MPs) may be important as a predictive test for VTE All patients with oncogene-driven cancer may need prophylactic anticoagulation All patients with oncogene-driven cancer may need prophylactic anticoagulation

57 Retrospective study Retrospective study Immunohistologic (IH) and microarray data on expression of TF and VEGF, as well as microvascular density (MVD) in: Immunohistologic (IH) and microarray data on expression of TF and VEGF, as well as microvascular density (MVD) in: l Normal pancreas (10) l Pre-malignant pancreatic lesions: Intraductal papillary mucinous neoplasms (IPMN; 70)Intraductal papillary mucinous neoplasms (IPMN; 70) Pancreatic intrepithelial neoplasia (PanIN; 40)Pancreatic intrepithelial neoplasia (PanIN; 40) l Resected or metastatic pancreatic adenoca (130) Survival Survival VTE Rate VTE Rate Tissue Factor Expression, Angiogenesis, and Thrombosis in Human Pancreatic Cancer Khorana et al Clin Cancer Res 2007;13:2870

58 Immunohistologic Correlation of TF with the Expression of Other Angiogenesis Variables in Resected Pancreatic Cancer Khorana et.al. Clin CA Res 2007:13:2870 High TF Expression Low TF Expression P Value VEGF Expression Negative1341< Positive5315 Microvessel Density V6 per tissue core >6 per tissue core 3923 Median860.01

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

60 Median Survival of 122 Resected Pancreatic Cancer Patients Months P = 0.16 (HR 2.06; ) Khorana et al Clin CA Res 2007;13:2872

61 1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer? Cancer and Thrombosis Year 2009 State-of-the-Science Update Key Questions Key Questions

62 1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWHs in cancer patients indicate superiority to oral agents in preventing recurrent VTE, as well as increasing survival (not due to prevention of VTE) Cancer and Thrombosis Year 2009 State-of-the-Science Update Tentative Answers

63 LMWH and Prolongation of Cancer Survival Mechanistic Explanations Coagulation Proteases Direct Heparin Other VTE

64 Heparins and Tumour Biology Multiple Potential Modes of Action Angiogenesis Apoptosis Heparanase Adhesion

65 Ex Vivo Angiogenesis: Embryonic Chick Aortic Rings Control Aortic Ring: Day 5 10U/ml Dalteparin-Treated Aortic Ring: Day 5 Fernandez, Patierno and Rickles. Proc AACR 2003;44:698 (Abstr. #3055)

66 Effects of Low-Molecular Weight Heparin on Lung Cancer Cell Apoptosis P<0.05 Chen et al Cancer Invest 2008;26: G1 arrest G1 arrest Decrease in Decrease in S phase S phase 3-fold in p21 WAF1 3-fold in p21 WAF1 and p27 KIP1 (p <0.01) and p27 KIP1 (p <0.01) Reversed apoptosis Reversed apoptosis and G1 arrest with and G1 arrest with p21 or p27 siRNA p21 or p27 siRNA

67 VEGFFGF-2 TNF- TNF- * * * * * * Cytokine+enoxaparin +dalteparin+UFH § § § Control * * * Marchetti et al. Thromb Res 2008;121: Heparins Inhibit Cytokine–Induced Capillary Tube Formation § = p<0.05 vs control, * = p<0.05 vs cytokine Tube Length (mm/cm 2 )

68 LMWH and VEGF Antisense Oligonucleotides Inhibit Growth and Metastasis of 3LL Tumors in Mice 40 mice with Lewis Lung Cancer (3LL) 40 mice with Lewis Lung Cancer (3LL) Rx qod x 15 with: Rx qod x 15 with: Control (saline) Control (saline) VEGF antisense oligos (ASODN) VEGF antisense oligos (ASODN) VEGF mismatch sense oligo (MSODN) VEGF mismatch sense oligo (MSODN) LMWH (dalteparin) LMWH (dalteparin) LMWH + ASODN LMWH + ASODN RESULTS: Growth Inhibit * Lung Mets * RESULTS: Growth Inhibit * Lung Mets * ASODN47%38% ASODN47%38% LMWH27%38% LMWH27%38% Combined59%25% Combined59%25% * P < 0.05 Zhang YH et al Chinese Med J 2006;86:749-52

69 Inhibition of Binding of Selectins to Human Colon Carcinoma by Heparins Stevenson et al Clin Ca Res 2005;11:

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

71 Coagulation Cascade and Tumor Biology Clotting- dependent Clotting- independent Clotting- dependent Clotting- independent Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584; Varki Blood 2007;110: VIIa Xa Angiogenesis, Tumor Growth and Metastasis ? LMWHs (e.g. dalteparin); Non-anticoagulant heparins or inhibitors ? TF Thrombin Fibrin PARs

72 A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice What Do Trials Teach? A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice What Do Trials Teach? Program Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Program Chairman Craig Kessler, MD MACP Director, Division of Coagulation Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Innovation Investigation Application

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

74 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

75 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

76 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

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

78 R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40 Cancer type Hazard ratio (95% CI) for death within one year, cases with VTE diagnosed in year 1 vs. no VTE, by stage LocalRegionalRemote Prostate 5.6 ( ) 5.6 ( ) 4.7 ( ) 4.7 ( ) 2.8 ( ) 2.8 ( ) Breast 6.6 ( ) 6.6 ( ) 2.4 ( ) 2.4 ( ) 1.8 ( )* Lung 3.1 ( ) 3.1 ( ) 2.9 ( ) 2.9 ( ) 2.5 ( ) 2.5 ( ) Colon/rectum 3.2 ( ) 3.2 ( ) 2.2 ( ) 2.2 ( ) 2.0 ( ) 2.0 ( ) Melanoma 14.4 ( ) 14.4 ( ) N/A 2.8 ( ) 2.8 ( ) Non-Hodgkins lymphoma 3.2 ( ) 3.2 ( ) 2.0 ( ) 2.0 ( ) 2.3 ( ) 2.3 ( ) Uterus 7.0 ( ) 7.0 ( ) 9.1 ( ) 9.1 ( ) 1.7 ( )* Bladder 3.2 ( ) 3.2 ( ) 3.3 ( ) 3.3 ( ) 3.3 ( ) 3.3 ( ) Pancreas 2.3 ( )* 3.8 ( ) 3.8 ( ) 2.3 ( ) 2.3 ( ) Stomach 2.4 ( )* 1.5 ( )* 1.8 ( ) 1.8 ( ) Ovary 11.3 ( ) 11.3 ( ) 4.8 ( )* 2.3 ( ) 2.3 ( ) Kidney 3.2 ( )* 1.4 ( ) 1.3 ( ) * p<0.05; p<0.01); p<0.001) Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Local Stage Disease

79 VTE Associated with Accelerated Death in Breast Cancer Does Symptomatic VTE Reflect Presence or Emergence of Metastatic, Aggressive Cancer? White, et al. Thromb Res,120 suppl. 2 (2007)

80 Recurrent Ovarian Cancer Fotopoulou C et al. Thromb Res % symptomatic VTE ( % in primary ovarian Cancer) 78% of VTE in ROC occur within 2 months of second line chemo regimen: cisplatin-related Ascites is the only independent risk factor for VTE (HR=2.2) 7% symptomatic VTE ( % in primary ovarian Cancer) 78% of VTE in ROC occur within 2 months of second line chemo regimen: cisplatin-related Ascites is the only independent risk factor for VTE (HR=2.2)

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

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

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

84 Medical Inpatients Cancer and Thrombosis

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

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

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

88 Surgical Patients Cancer and Thrombosis

89 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

90 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, Ann Surg 2006; 243: 89-95

91 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

92 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 Incidence of Outcome Event VTEMajor Bleeding VTEMajor Bleeding (Cancer) (All) Prophylaxis in Surgical Patients

93 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

94 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.

95 ASCO Guidelines: VTE Prophylaxis All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. Lyman GH et al. J Clin Oncol (25) 2007; 34:

96 Thrombosis is a potential complication of central venous catheters, including these events: –Fibrin sheath formation –Superficial phlebitis –Ball-valve clot –Deep vein thrombosis (DVT) Central Venous Catheters Geerts W, et al. Chest Jun 2008: 381S–453S

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

98 Young AM et al. Lancet 2009;373:567 Thrombotic Events Warfarin evaluation Dose evaluation No warfarin (n=404) Warfarin (n=408) Relative risk (95% CI, p value) Fixed- dose warfarin (n=471) Dose- adjusted warfarin (n=473) Relative risk (95% CI, p value) Catheter- related thrombotic events 24(6%)24(6%)0.99 ( , 0.98) 34(7%)13(3%)0.38( ,0.002) No catheter- related event 370(92%)372(91%)- 433 (92%) 448 (95%) - Not known 10(2%)12(3%)4(<1%)12(3%) All thrombotic events 38(9%)30(7%)0.78 ( ), (8%)26(6%)0.70 ( , 0.15) WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA

99 Young AM et al. Lancet 2009;373:567 WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Bleeding and Raised INR Warfarin evaluation Dose evaluation No warfarin (n=404) Warfarin (n=408) Relative risk (95% CI, p value) Fixed- dose warfarin (n=471) Dose- adjusted warfarin (n=473) Relative risk (95% CI, p value) Major bleeding and no reported raised INR 1 (<1%) 3 (<1%) - 5 (1%) 7 (1%) - Major bleeding and raised INR 0 4 (<1%) - 2 (<1%) 9 (2%) - Total major bleeding 1 (<1%) 7 (2%) 6.93 ( , 0.07) 7 (1%) 16 (3%) 2.28 ( , 0.09) Moderate and severe raised INR and no major bleeding 0 3 (<1%) - 1 (<1%) 12 (3%) - Minor bleeding 1 (<1%) 14 (3%) - 21 (4%) 24 (5%) -

100 Young AM et al. Lancet 2009;373:567 WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Combined thrombosis and major bleeding events Warfarin evaluation Dose evaluation No warfarin (n=404) Warfarin (n=408) Relative risk (95% CI, p value) Fixed- dose warfarin (n=471) Dose- adjusted warfarin (n=473) Relative risk (95% CI, p value) Total catheter- related thrombosis and major bleeding events 25 (6%) 31 (8%) 1.23 ( , 0.51) 41 (9%) 29 (6%) 0.84 ( , 0.17) All thrombotic and major bleeding events 39 (10%) 37 (9%) 0.94 ( , 0.87) 44 (9%) 42 (9%) 0.95 ( , 0.89)

101 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:

102 In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls: The attributable risk of catheter associated thrombosis conferred by: Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564 Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer CA + FVL OR=5.18 (95% confidence interval: ) CA + G20210A OR=3.95 (95% confidence interval: ) FVL 13.5% G20210A 3.6%

103 8 th ACCP Consensus Guidelines No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Revised 2009 NCCN guidelines diverge from this philosophy Chest Jun 2008: 454S–545S

104 Primary Prophylaxis in Cancer Radiotherapy 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.)

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

106 Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery with 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:

107 VTE Incidence In Various Tumors 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 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-Hodgkins lymphomas w/ chemo 3% Hodgkins 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%

108 Primary VTE Prophylaxis Recommended for hospitalized cancer patients Recommended for hospitalized cancer patients Not universally recommended for outpatients, but there are exceptions Not universally recommended for outpatients, but there are exceptions New data for certain agents New data for certain agents Heterogeneous population Heterogeneous population Need for risk stratification

109 Naluri SR et al. JAMA. 2008;300:2277 VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Myeloma All-Grade Venous Thromboembolism, No./Total No. Tumor Type No. of Studies BevacizumabControl Incidence (95% CI), % RR (95% CI) Overall6155/ / ( )1.29( ) Colorectal cancer 3108/56485/ ( )1.19( ) NSCLC110/663/3214.9( )1.59( ) Breast cancer 117/22912/2157.3( )1.30( ) Renal cell carcinoma 120/3376/3043.0( )3.00( )

110 Naluri SR et al. JAMA. 2008;300:2277 Bevacizumab Increases Risk of Symptomatic VTE by 33% vs Controls

111 Knight: N Engl J Med.2006,354:2079 rEPO used more in USA and Canada rEPO used more in USA and Canada L+Dex: 23% VTE with EPO vs 5% w/o EPO L+Dex: 23% VTE with EPO vs 5% w/o EPO Placebo + Dex: 7% VTE with EPO vs 1% without EPO Placebo + Dex: 7% VTE with EPO vs 1% without EPO Incidence of VTE: USA and Canada Greater than 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

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

113 CLOT: Landmark Cancer/VTE Trial [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 Dalteparin Oral Anticoagulant CANCER PATIENTS WITH ACUTE DVT or PE Randomization

114 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

115 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

116 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

117 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) NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer (NCCN preferred agent) NOTE: Dalteparin is only LMWH approved (May, 2007) for both the treatment and secondary prevention of VTE in cancer (NCCN preferred agent) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendationACCP) Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendationACCP) Chest Jun 2008: 454S–545S New Development New Development

118 CLOT 12-month Mortality All Patients Lee AY et al. J Clin Oncol. 2005; 23:

119 Days Post Randomization Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Patients Without Metastases (N=150) Lee AY et al. J Clin Oncol. 2005; 23:

120 LMWH Influences Survival of Patients with Advanced Solid Tumor Malignancies <6 mos anticipated survival >6 mos anticipated survival 6 wks LMWH immediately post diagnosis of CA-no initial chemo Klerk, C. P.W. et al. J Clin Oncol; 23:

121 84 patients randomized: Chemo +/- LMWH (18 weeks) 84 patients randomized: Chemo +/- 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. Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % y overall survival, % Median survival, m CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily

122 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:

123 Conclusions and Summary Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniaRisk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopenia Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinLong-term secondary prevention with LMWH has been shown to produce better outcomes than warfarin Guidelines and landmark trials support administration of LMWH in at risk patientsGuidelines and landmark trials support administration of LMWH in at risk patients Cancer patients are under-prophylaxed for VTECancer patients are under-prophylaxed for VTE Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient populationHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population

124 Pharmacologic Prophylaxis of DVT in Special Populations Edith Nutescu, PharmD, FCCP Clinical Associate Professor Pharmacy Practice Affiliate Faculty, Center for Pharmacoeconomic Research Director, Antithrombosis Center The University of Illinois at Chicago College of Pharmacy & Medical Center Chicago, IL Edith Nutescu, PharmD, FCCP Clinical Associate Professor Pharmacy Practice Affiliate Faculty, Center for Pharmacoeconomic Research Director, Antithrombosis Center The University of Illinois at Chicago College of Pharmacy & Medical Center Chicago, IL Mechanisms Mortality Therapeutics

125 Objectives 1.Differentiate data with various LMWHs in special populations 2.Review appropriate dosing and monitoring of LMWHs in patients with obesity and renal failure

126 Risk of Inadequate Therapy in High Risk Patients 524 VTE Patients 524 VTE Patients Active Cancer in 26% Active Cancer in 26% Only 1/3 rd on LMWH monotherapy Only 1/3 rd on LMWH monotherapy Weight > 100Kg in 15% Weight > 100Kg in 15% Under-dosing of LMWH by > 10% Under-dosing of LMWH by > 10% –36% of > pts 100Kg –8% of pts < 100Kg (p < 0.001) CrCL < 30mL/min in 5% CrCL < 30mL/min in 5% LMWH tx in 67% LMWH tx in 67% Cook LM, et.al. J Thromb Hemost 2007;5;

127 8 th ACCP Conference on Antithrombotic Therapy In obese patients given LMWH prophylaxis or treatment, we suggest weight-based dosing (Grade 2C). What is this weight-based dosing and how does it differ from typical dosing? What is this weight-based dosing and how does it differ from typical dosing? At what weight do we move away from standard dosing and move to weight-based dosing? At what weight do we move away from standard dosing and move to weight-based dosing? Hirsh J et al. Chest. 2008;133(suppl):141S-159S. Obese Patients

128 Pharmacokinetic Characteristics of Low Molecular Weight Heparins Lipid solubilityLOW Plasma protein bindingHIGH Tissue bindingLOW Volume of distribution5-7 L Logical conclusion: IBW may be a better predictor of LMWH dosing than TBW

129 LMWH: Maximum Weights Studied * max dose 18, ,000 IU/day Duplaga BA et al. Pharmacotherapy 2001; 21: Synergy Trial: Data on File Davidson, et al. J Thromb Haem 2007;5: Kinetic Studies Clinical Trials Dalteparin 190 kg 128 kg* Enoxaparin 144 kg 194 kg Tinzaparin 165 kg 88 kg Fondaparinux kg

130 LMWH Pharmacokinetics in Obesity Actual body weight correlates best with anticoagulant response to LMWHs as measured by anti-factor Xa levels Clin Pharmacol Ther 2002;72: Thromb Haemost 2002;87:

131 Dalteparin Pharmacokinetics in Obesity Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56: Dose: 200 U/kg qd Duration: routine Obese (BMI > 30) Normal (BMI < 30) N1010 TBW (mean +/- SD) / /- 9.3 LBW (mean +/- SD) / /- 8.7 Mean Vd (l) Mean CI (l/hr)

132 Dalteparin Pharmacokinetics In Obesity Correlation Coefficient Between Vd and: LBW0.05 ABW0.52 TBW0.55 Correlation Coefficient Between Cl and: LBW0.01 ABW0.32 TBW0.39 Conclusion: TBW may be a better predictor of LMWH dose than IBW Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7.

133 Conclusion: Body mass does not appear to have an important effect on the response to LMWH up to a weight of 190kg in patients with normal renal function. Dalteparin Pharmacokinetics In Obesity Dose: 200 U/kg qd Duration: 5 Days Max TBW: 190kg <20% of IBW 20-40% of IBW > 40% of IBWN Mean Dose (U) 14,03017,64623,565 Ant-Xa Activity (u/ml) Day 3 Peak NS Day 3 Trough NS Wilson SJ et al. Hemostasis 2001; 31:42-8.

134 LMWH Safety and Effectiveness Using TBW Enoxaparin In ACS (ESSENCE/TIMI IIb) 14.3% 16.1% P=0.39 P=0.13 Obese: BMI > 30mg/m2 Enoxaparin max weight 158 kg Spinler SA et al. Am Heart J 2003; 146: % 1.6%

135 Safety Of TBW-based Dosing of Dalteparin for Treatment of Acute VTE in Obese Patients Al-Yaseen E et al. J Thromb Haemost 2004; 3: N = 193 patients 3 month outcomes: major bleeding = 1.0% (n=2) > 90 kg recurrent VTE = 1.6% (n=3) > 90 kg recurrent VTE = 1.6% (n=3)WEIGHT(kg)NMeanDose Full dose +/- 5% QD Dosing BIDDosing , , , , , , > ,280664

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

137 Body Weight and Anti-Xa Activity for Prophylactic Doses of LMWH N = 17 patients and 2 volunteers Enoxaparin 40mg SQ x1 dose AntiXa levels hourly x10 hours Frederiksen SG et al. Br J Surgery 2003; 90: Body Weight (kg) Area under the curve for 10 h Regression line 95% CI for line 95% CI for data points Regression line 95% CI for line 95% CI for data points

138 Kucher N et al. Arch Int Med 2005;165: Favors Dalteparin Favor Placebo Relative Risk < > Overall Prevent Trial Dalteparin Fixed Dosing For VTE Prevention Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill) BMI (kg/m2) Patients % Dalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except patients with BMI>40) with no observed difference in mortality or major bleeding

139 Enoxaparin VTE Prophylaxis in TKA/THA/Trauma Samama MM et al. Thromb Haemost 1995; 73:977. N: 807 Dose: 40 mg qd Obese : BMI>32kg/m % 16.7% p<0.001

140 Enoxaparin: VTE Prophylaxis in Bariatric Surgery Scholten Obes Surg 2002; 12: mg bid: n=92 BMI 51.7kg/m 2 5.4% 0.6% p< mg bid: n=389 BMI 50.3kg/m 2

141 Anti-factor Xa level Number of patient (%) Body weight (kg) Below target value (<0.2 UI/ml) 41 (30.4%) ± 35.8 Target value (0.2–0.5 UI/ml) 81 (60.0%) ± 28.4 Above target value (>0.5 UI/ml) 13 (9.6%) ± 24.2 p value N=135 Bariatric Surgery Mean Weight: 148.8Kg Mean BMI: 53.7 Dalteparin: 7,500 IU daily Dalteparin in Morbid Obesity: Bariatric Surgery Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print] P=0.031 P=0.052 P=0.444 Under target value <0.2 IU/mL n-=41 Under target value <0.2 IU/mL n-=41 Target value < IU/mL n-=81 Target value < IU/mL n-=81 Over target value <>0.5 IU/mL n=13 Over target value <>0.5 IU/mL n= Body Weight (kg)

142 LMWH in Obesity: Summary Treatment: in controlled trials, LMWH dosing has been based on TBW (max kg) Treatment: in controlled trials, LMWH dosing has been based on TBW (max kg) Dalteparin Dalteparin Dose based on TBW Dose based on TBW PI recommends dose capping PI recommends dose capping Recent clinical data supports TBW dosing Recent clinical data supports TBW dosing –QD or BID dosing Enoxaparin Enoxaparin Dose based on TBW Dose based on TBW Dose capping NOT recommended Dose capping NOT recommended BID dosing preferred BID dosing preferred Tinzaparin Tinzaparin Dose based on TBW, NO dose adjustment or capping Dose based on TBW, NO dose adjustment or capping Anti-Xa monitoring not necessary for TBW < 190kg Anti-Xa monitoring not necessary for TBW < 190kg Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):

143 8 th ACCP Conference on Antithrombotic Therapy Renal Impairment For each of the antithrombotic agents, we recommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C) For each of the antithrombotic agents, we recommend that clinicians follow manufacturer-suggested dosing guidelines (Grade 1C) We recommend that renal function be considered when making decisions about the use of and/or dose of LMWH or fondaparinux (Grade 1A) We recommend that renal function be considered when making decisions about the use of and/or dose of LMWH or fondaparinux (Grade 1A) Options for patients with renal impairment (Grade 1B) Options for patients with renal impairment (Grade 1B) Avoid agents that renal accumulate Avoid agents that renal accumulate Use a lower dose Use a lower dose Monitor the drug level or anticoagulant effect Monitor the drug level or anticoagulant effect Geerts WH. Chest 2008;133(suppl):381S-453S.

144 LMWH in Renal Dysfunction Manufacturer Recommendations Dalteparin should be used with caution in patients with severe kidney insufficiency. should be used with caution in patients with severe kidney insufficiency. Monitor anti-Factor Xa for dose guiding with therapeutic doses Monitor anti-Factor Xa for dose guiding with therapeutic dosesEnoxaparin adjustment of dose is recommended for patients with severe renal impairment (CrCL < 30 mL/min). adjustment of dose is recommended for patients with severe renal impairment (CrCL < 30 mL/min).Tinzaparin patients with severe renal impairment should be dosed with caution. patients with severe renal impairment should be dosed with caution.Fondaparinux - Contraindicated in CrCL < 30mL/min

145 Study; year Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Peto OR (95%, CI) Weight (%) Peto OR (95%, CI) Collet, et al; /281/ (0.00 – 23.94) Paulas, et al; /513/ (0.02 – 3.50) Siguret, et al; /170/13 Not estimable Chow, et al; /50/13 Not estimable Khazan, et al. (adj.); /103/ (0.01 – 5.16) (Prophylactic) /363/ (0.25 – 7.05) (Therapeutic) /173/ (0.35 – 27.31) Spinler, et al; /6974/3, (2.02 – 49.98) Green, et al; /180/ (0.16 – ) Kruse & Lee; /501/ (0.00 – 17.90) Macie, et al; /76/ (19.61 – 48,752.07) Peng, et al; /70/43 Not estimable Thorevska, et al; /6511/ (0.63 – 5.40) Bazinet, et al; /362/ (0.15 – 51.73) Total (95%, CI) 21/416107/4, (1.19 – 4.27) Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal Dysfunction Lim W, et al. Ann Intern Med. 2006;144: Dosage adjustments for renal dysfunction Favors edFavors ed bleeding

146 Sanderink GJCM. Thromb Res 2002;105: Enoxaparin PK and PD in Renal Impairment Result: Tmax: 3-4 hours Amax: 10-35% higher in RI groups CI/F linearly correlated with CrCl Result: Tmax: 3-4 hours Amax: 10-35% higher in RI groups CI/F linearly correlated with CrCl Day 4 CL/F(L/h)Half-life(h) AUC (0-24) (hIU/mL) Normals Mild RI % 20% Moderate RI % 21% Severe RI % 65%

147 LMWH Renal Dosing in NSTE ACS Patients 56 UA pts with CrCl <60 ml/min 56 UA pts with CrCl <60 ml/min Enoxaparin dose empirically and anti-Xa level measured after 3 rd dose Enoxaparin dose empirically and anti-Xa level measured after 3 rd doseCrCl (ml/min) (ml/min)<30 (n = 28) (n = 28) >30 and 30 and <60 (n =28) (n =28)Age76+/-373+/-3 Enoxaparin (mg/kg/12h) Anti-Xa (IU/ml) Collet JP et al. International J Cardiol 2001;80:81-2. Dose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl ml/minDose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl ml/min Anti-Xa monitoringAnti-Xa monitoring Doses appeared safeDoses appeared safe Further prospective evaluation neededFurther prospective evaluation needed

148 Clinical Use Of Recommended Enoxaparin Dosage in Renal Impairment Lachish T et al. Pharmacotherapy 2007; 27: PEAK ANTI-Xa LEVELS TROUGH ANTI-Xa LEVELS N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h First dose Subsequent doses (second and third) Subsequent doses (second and third) Median 25-75% interquartile range Antifactor X1 Level (U/mL) Trough Antifactor Xa Level (U/mL) Number of Patients

149 Tinzaparin 175 U/kg Peak Anti-Xa Levels According to Renal Function Siguret V et al. Thromb Haemost 2000;84: No correlation between peak anti-Xa activity and Clcr No accumulation of Anti-Xa activity after 10 days of therapy

150 Pharmacokinetics of Prophylactic Enoxaparin vs Tinzaparin Mahe I et al. Thromb Haemost 2007; 97: Enoxaparin 40mg qd or or Tinazaparin 4500 IU qd N = 52 patients Mean age = 87.7 yrs Mean wt = 52.3kg Mean Clcr = 34.7ml/min

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

152 Pharmacokinetics of Prophylactic Doses of Dalteparin Tincani E et al. Haematologica 2006; 91: N = 115 elderly (age > 65) pts with acute medical illness and elevated SCr Tx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxis Renal Failure Mild(n=12)Moderate(n=73)Severe(n=24) CrCL (ml/min) <30 Day 6 peak anti-Xa Minor Bleeding 030 Major Bleeding 000 P=0.72P=0.72 No evidence of accumulation of anti-Xa activity No relationship between the degree of renal impairment and peak anti-Xa level on Day 6 No association between creatinine clearance and anti-Xa levels

153 Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct Study N=138 critically ill patientsN=138 critically ill patients CrCl < 30 ml/minCrCl < 30 ml/min Mean CrCL 18.9ml/min Mean CrCL 18.9ml/min Dalteparin 5000 IU sc dailyDalteparin 5000 IU sc daily Serial anti Xa levels measured on days 3, 10, and 17Serial anti Xa levels measured on days 3, 10, and 17 Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mLBioaccumulation defined as trough anti-Xa level > 0.40 IU/mL Results: The median duration of dalteparin exposure was 7 (4-12) daysThe median duration of dalteparin exposure was 7 (4-12) days No patient had a trough anti Xa level > 0.4 IU/mlNo patient had a trough anti Xa level > 0.4 IU/ml Based on serial measurementsBased on serial measurements peak anti-Xa levels were 0.29 to 0.34 IU/mL peak anti-Xa levels were 0.29 to 0.34 IU/mL trough levels were lower than 0.06 IU/mL trough levels were lower than 0.06 IU/mL Douketis, et al. Arch Intern Med Sep 8;168(16):

154 Dosing of LMWHs In Renal Impairment Recommendations FOR CrCL < 30 ml/min Enoxaparin: Enoxaparin: Prophylaxis doses: 30 mg sq QD Prophylaxis doses: 30 mg sq QD Treatment doses: 1mg/Kg sq QD Treatment doses: 1mg/Kg sq QD Dalteparin and Tinzaparin: Dalteparin and Tinzaparin: no specific dosing guidelines no specific dosing guidelines No or lower degree of accumulation expected No or lower degree of accumulation expected Anti-Factor Xa activity monitoring Anti-Factor Xa activity monitoring FOR CrCL mL/min No specific recommendations No specific recommendations Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) Monitoring anti-Xa ? Monitoring anti-Xa ? Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):

155 Unresolved Issues in Renal Dosing of LMWHs CrCl (mL/min) Recommendations < 30 Dose of enoxaparin should be adjusted; dalteparin and tinzaparin no short term accumulation expected. < LMWHs have not been adequately studied as repeated doses for prophylaxis and treatment indications; UFH is preferred in these patients. Issues with anti-factor Xa testing include: true therapeutic range, standardization, availability, recommendations for dose adjustment

156 Anti-Xa Activity Level Monitoring Enoxaparin 1mg/kg SQ pharmacokinetic profile Peak (goal ~ U/ml) at 3-4 hrs Trough (goal < 0.5 U/ml) at hrs Laposata et al. Arch Pathol Lab Med. 1998;122:

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

158 Applying National Guidelines to Clinical Practice Current Status of ASCO and NCCN Guidelines for VTE Prophylaxis in Cancer Patients Applying National Guidelines to Clinical Practice Current Status of ASCO and NCCN Guidelines for VTE Prophylaxis in Cancer Patients Program Chairman Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Lombardi Comprehensive Cancer Center Washington, DC Mechanisms Mortality Therapeutics

159 ASCO Guidelines Hospitalized Patients with Cancer Role of VTE Prophylaxis Evidence Patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in the absence of bleeding or other contraindications to anticoagulation Multiple RCTs of hospitalized medical patients with subgroups of patients with cancer. The 8th ACCP guidelines strongly recommend (1A) prophylaxis with either low- dose heparin or LMWH for bedridden patients with active cancer.

160 Ambulatory Patients with Cancer Without VTE Receiving Systemic Chemotherapy Role of VTE Prophylaxis Evidence Routine prophylaxis with an antithrombotic agents is not recommended except as noted below Routine prophylaxis in ambulatory patients receiving chemotherapy is not recommended due to conflicting trials, potential bleeding, the need for laboratory monitoring and dose adjustment, and the relatively low incidence of VTE. LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma patients on thalidomide or lenalidomide plus chemotherapy or dexamethasone This recommendation is based on nonrandomized trial data and extrapolation from studies of postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose warfarin in breast cancer

161 Patients with Cancer Undergoing Surgery Role of VTE Prophylaxis Evidence All patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis with low- dose UFH, LMWH, or fondaparinux starting as early as possible for at least 7-10 days unless contraindicated. RCTs of UFH and those comparing the effects of LMWH and UFH on DVT rates on patients with cancer indicate broadly similar prophylactic efficacies for these two agents Mechanical methods may be added to anticoagulation in very high risk patients but should not be used alone unless anticoagulation in contraindicated. A Cochrane review of 19 studies A Cochrane review of 19 studies

162 Patients with Cancer Undergoing Surgery (continued) Role of VTE Prophylaxis Evidence LMWH for up to 4 weeks may be considered after major abdominal/pelvic surgery with residual malignant disease, obesity, and a previous history of VTE Recent RCTs suggest that prolonging prophylaxis up to 4 weeks is more effective than short-course prophylaxis in reducing postoperative VTE.

163 Treatment of Patients with Established VTE to Prevent Recurrence Role of VTE Prophylaxis Evidence LMWH is the preferred approach for the initial 5-10 days in cancer patient with established VTE. LMWH for 3-6 months is more effective than vitamin K antagonists given for a similar duration for preventing recurrent VTE. LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable when LMWH is not available. The CLOT study demonstrated a relative risk reduction of 49% with LMWH vs. a vitamin K antagonist. Dalteparin sodium approved by the FDA for extended treatment of symptomatic VTE to reduce the risk of recurrence of VTE in patients with cancer (FDA 2007)

164 Treatment of Patients with Established VTE to Prevent Recurrence (continued) Role of VTE Prophylaxis Evidence Anticoagulation for an indefinite period should be considered for patients with active cancer (metastatic disease, continuing chemotherapy) In the absence of clinical trials, benefits and risks of continuing LMWH beyond 6 months is a clinical judgment in the individual patient. Caution is urged in elderly patients and those with intracranial malignancy. Inferior vena cava filters are reserved for those with contraindications to anticoagulation or PE despite adequate long-term LMWH. Consensus recommendations due to lack of date in cancer-specific populations

165 Anticoagulants in the Absence of Established VTE to Improve Survival Role of VTE Prophylaxis Evidence Anticoagulants are not currently recommended to improve survival in patients with cancer without VTE. RCTs and meta-analysis of warfarin, UFH and LMWH have reported encouraging but variable results generally showing clinical benefit only in subgroup analyses.

166 Summary of NCCN Guidelines Updates Summary of Major Changes in the Version of the NCCN Venous Thromboembolic Disease Guidelines

167 Changes in 2009 NCCN Guidelines Stage 1 Immediate: Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk assessment (heparin phase) changed to Stage 1 Immediate: At diagnosis or during diagnostic evaluation Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk assessment (heparin phase) changed to Stage 1 Immediate: At diagnosis or during diagnostic evaluation Low –molecular-weight-heparin: New footnote 6 was added that states, Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the FDA for this indication. Low –molecular-weight-heparin: New footnote 6 was added that states, Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the FDA for this indication. Unfractionated heparin (IV): target aPTT range changed from x control) to x control… (Also for VTE-H) in these patients. Unfractionated heparin (IV): target aPTT range changed from x control) to x control… (Also for VTE-H) in these patients.

168 Changes in 2009 NCCN Guidelines Stage 3 Chronic: Third bullet: Consider indefinite anticoagulation…. changed to Recommend indefinite anticoagulation…. Third bullet: Consider indefinite anticoagulation…. changed to Recommend indefinite anticoagulation…. Fourth bullet: For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at least 3 months after catheter removal. Fourth bullet: For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at least 3 months after catheter removal.

169 Changes in 2009 NCCN Guidelines 6 Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this indication. 6 Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparins efficacy in this population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this indication. Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism on patients with cancer. New Eng J Med 2003;349(2):

170 (VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered. The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered.

171 (VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Stage 1 Immediate: At diagnosis or during diagnostic evaluation: Low-molecular-weight heparin (LMWH) Low-molecular-weight heparin (LMWH) Dalteparin (200 units/kg subcutaneous daily)Dalteparin (200 units/kg subcutaneous daily) Enoxaparin (1 mg/kg subcutaneous every 12 hours)Enoxaparin (1 mg/kg subcutaneous every 12 hours) Tinzaparin (175 units/kg subcutaneous daily)Tinzaparin (175 units/kg subcutaneous daily) Fondaparinux (5 mg [ 100 kg] subcutaneous daily Fondaparinux (5 mg [ 100 kg] subcutaneous daily Unfractionated heparin (IV) (80 units/kg load, then 18 units/kg per hour, target aPTT of x control or per hospital SOP) Unfractionated heparin (IV) (80 units/kg load, then 18 units/kg per hour, target aPTT of x control or per hospital SOP)

172 (VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Additional VTE risk factors for surgical oncology patients with a previous episode of VTE include anesthesia times longer than 2 hours, advanced stage disease, bed rest, > 4 days and patients age 60 years or older. Extended prophylaxis out to 4 weeks post-surgery was associated with a greater than 50% reduction in venographic VTE Additional VTE risk factors for surgical oncology patients with a previous episode of VTE include anesthesia times longer than 2 hours, advanced stage disease, bed rest, > 4 days and patients age 60 years or older. Extended prophylaxis out to 4 weeks post-surgery was associated with a greater than 50% reduction in venographic VTE

173 (VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Stage 2 Acute: Short term, during transition to chronic phase: LMWH (category 1) is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer LMWH (category 1) is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer If UFH or factor Xa antagonist, transition to LMWH or warfarin If UFH or factor Xa antagonist, transition to LMWH or warfarin Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR ) Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR )

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

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

176 Thank You Questions? Mechanisms Mortality Therapeutics


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