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Mechanisms ● Mortality ● Therapeutics 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 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 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 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 strategies for risk-directed prophylaxis against VTE in at risk patients with cancer. ► Learn how to assess and manage special needs of cancer patients atrisk for VTE, with a focus on protecting against recurrent DVT. Program Faculty Craig M. Kessler, MD—Program 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 Faculty COI Financial Disclosures Craig M. Kessler, MD - Co-Chairman Grant/Research Support: GlaxoSmithKline Consultant: sanofi-aventis, Eisai Pharmaceuticals Speaker’s Bureau: sanofi-aventis, GlaxoSmithKline Frederick R. Rickles, MD Consultant: Eisai Pharmaceuticals, Genmab, Pharmacyclics Speaker’s 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. Innovation ● Investigation ● Application 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 VTE and Cancer—A Looming National Healthcare Crisis 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. Comorbidity Connection COMORBIDITY CONNECTION SUBSPECIALIST STAKEHOLDERS CAP UTI Cancer Heart Failure ABE/COPD Respiratory Failure Myeloproliferative Disorder Thrombophilia Surgery History of DVT Other Infectious diseases Oncology PHARMACISTS Cardiology Pulmonary medicine Hematology Oncology/hematology Interventional Radiology Hospitalist Surgeons EM PCP Epidemiology of First-Time VTE Variable Finding Seasonal Variation Possibly more common in winter and less common in summer Risk Factors 25% to 50% “idiopathic” 15%-25% associated with cancer 20% following surgery (3 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 White R. Circulation. 2003;107:I-4 –I-8.) Epidemiology of VTE ►One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders. ►Overall, about 25% to 50% of patient with firsttime VTE have an idiopathic condition, without a readily identifiable risk factor. ►Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease. White R. Circulation. 2003;107:I-4–I-8.) Thrombophilia Enhances Risks of Thrombosis in Cancer Patients Risk of thrombosis in cancer patients within the previous five years according to the presence of factor V Leiden or G20210A prothrombin gene mutation Mutation Patients with first venous thrombosis Control without venous thrombosis (n=2706) (n=1757) Yes 2125 1635 1.00 Yes 162 26 5.1 (3.3-7.7) No 403 95 3.3 (2.6-4.1) Yes 16 1 12.1 (1.6-88.1) No 2410 1693 1.00 Yes 164 27 4.5 (3.0-6.8) No 118 36 2.3 (1.6-3.3) Yes 14 0 Not determined Cancer Age- and sexadjusted odds ratio (95% CI) Factor V Leiden No Yes Prothombin 20210A No Yes H. Decousus et al. Thrombosis Research 120 Suppl. 2 (2007) S51-S61 Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds Ratio (95% CI) X2 Age > 75 years Cancer Previous VTE 1.03 (1.00-1.06) 1.62 (0.93-2.75) 2.06 (1.10-3.69) 0.0001 0.08 0.02 Acute infectious disease 1.74 (1.12-2.75) 0.02 Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968 VTE Recurrence Predictors of First VTE/ Recurrence Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 (1.11-1.24) Body Mass Index 1.24 (1.04-1.7) Neurologic disease with extremity paresis 1.87 (1.28-2.73) Malignant neoplasm With chemotherapy Without chemotherapy Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768 4.24 (2.58-6.95) 2.21 (1.60-3.06) Progression of Chronic Venous Insufficiency From UpToDate 2006 Rising VTE Incidence in Hospitalized Patients 2 VTE 1.5 DVT % 1 0.5 PE 0 79 81 83 85 87 89 Year Stein PD et al. Am J Cardiol 2005; 95: 1525-1526 91 93 95 97 99 DVT Registry (N=5,451) Top 5 Medical Comorbidities 1. Hypertension 2. Immobility 3. Cancer 4. Obesity (BMI > 30) 5. Cigarette Smoking Am J Cardiol 2004; 93: 259-262 Implementation of Guidelines in Cancer Patients Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines. Symposium Themes—Cancer/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 Clotting, Cancer, and Controversies 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 Cancer and Venous Thromboembolism The Legacy of Armand Trousseau (1801–1867) Professor Armand Trousseau Lectures in Clinical Medicine “ I have always been struck with the frequency with which cancerous patients are affected with painful oedema of the superior or inferior extremities….” New Syndenham Society – 1865 Professor Armand Trousseau More Observations About Cancer and Thrombosis “In other cases, in which the absence of appreciable 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.” Lectures in Clinical Medicine, 1865 Trousseau’s 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” Trousseau’s Syndrome ► Occult cancer in patients with idiopathic venous thromboembolism ► Thrombophlebitis in patients with cancer Effect of Malignancy on Risk of Venous Thromboembolism (VTE) • Population-based MEGA study • N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects • CA patients = OR 7x VTE risk vs. non-CA patients 40 30 28 22.2 20.3 19.8 20 14.3 10 3.6 2.6 5 to 10 years 4.9 1 to 3 years Adjusted odds ratio 50 53.5 1.1 Type of cancer > 15 years 3 to 12 months 0 to 3 months Distant metastases Breast Gastrointestinal Lung Hematological 0 Time since cancer diagnosis Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715 Cancer, Mortality, and VTE Epidemiology and Risk ► Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patients ► Patients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patients ► Cancer patients undergoing surgery have a 2-fold increased risk for postoperative VTE ► Death rate from cancer is four-fold higher if patient has concurrent VTE ► VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection) Heit et al Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et al Blood 2002;100:3484-3488; White et al Thromb Haemost 2003;90:446-455; Sorensen et al New Engl J Med 2000;343:1846-1850); Levitan et al Medicine 1999;78:285-291; Khorana et al J Thromb Haemost 2007;5:632-4 Mechanisms of Cancer-Induced Thrombosis Critical Interfaces and Questions 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy? Trousseau’s Observations (continued) “There appears in the cachexiae…a particular condition of the blood that predisposes it to spontaneous coagulation.” Lectures in Clinical Medicine, 1865 Multiple Mechanisms in Trousseau's Syndrome Tissue Factor microparticles Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Varki, A. Blood 2007;110:1723-1729 Interface of Biology and Cancer Tumor Cells Angiogenesis, Basement matrix degradation Fibrinolytic activities: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities IL-1, TNF-a, VEGF PMN leukocyte Activation of coagulation FIBRIN Platelets Monocyte Endothelial cells Falanga and Rickles, New Oncology: Thrombosis, 2005; Hematology, 2007 Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s Triad 1. Stasis Prolonged bed rest Extrinsic compression of blood vessels by tumor 2. Vascular Injury Direct invasion by tumor Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium 3. Hypercoagulability Tumor-associated procoagulants and cytokines (tissue factor, CP, TNFa, IL-1, VEGF, etc.) Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S) Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages Mechanisms of Cancer-Induced Thrombosis Clot and Cancer Interfaces 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy? Activation of Blood Coagulation in Cancer Biological Significance? ► Epiphenomenon? Is this a generic secondary event where thrombosis is an incidental finding or, is clotting activation . . . ► A Primary Event? Linked to malignant transformation Interface of Clotting Activation and Tumor Biology FVII/FVIIa TF Tumor Cell Blood Coagulation Activation VEGF THROMBIN FIBRIN Angiogenesis IL-8 PAR-2 Angiogenesis TF Endothelial cells Falanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16 Coagulation Cascade and Tumor Biology TF Clottingdependent VIIa Clottingindependent Thrombin Xa Clottingindependent Clottingdependent Fibrin Clottingdependent PARs Angiogenesis, Tumor Growth and Metastasis Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584 Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor 1. TF regulates VEGF expression in human cancer cell lines 2. Human cancer cells with increased TF are more angiogenic (and, therefore, more “metastatic’) in vivo due to high VEGF production Abe et al Proc Nat Acad Sci 1999;96:8663-8668; Ruf et al Nature Med 2004;10:502-509 Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor 3. The cytoplasmic tail of TF, which contains three serine residues, appears to play a role in regulating VEGF expression in human cancer cells, perhaps by mediating signal transduction 4. Data consistent with new mechanism(s) by which TF signals VEGF synthesis in human cancer cells may provide insight into the relationship between clotting and cancer Abe et al Proc Nat Acad Sci 1999;96:8663-8668; Ruf et.al. Nature Med 2004;10:502-509 Activation of Blood Coagulation in Cancer and Malignant Transformation ► Epiphenomenon vs. Linked to Malignant Transformation? 1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio lab) (Boccaccio et al Nature 2005;434:396-400) 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 Ca Res 2005;65:1406-1413; 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 Blood 2005;105:1734-1741; Milson et al Ca Res 2008;68:10068-76) Activation of Blood Coagulation in Cancer: Malignant Transformation “1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” ► MET encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) Drives physiological cellular program of “invasive growth” (tissue morphogenesis, angiogenesis and repair) Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transformation, invasion, and metastasis Boccaccio et al Nature 2005;434:396-400 “MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” ► Mouse model of Trousseau’s Syndrome Targeted activated human MET to the mouse liver with lentiviral vector and liver-specific promoter slowly, progressive hepatocarcinogenesis Preceded and accompanied by a thrombohemorrhagic syndrome Thrombosis in tail vein occurs early and is followed by fatal internal hemorrhage Syndrome characterized by d-dimer and PT and platelet count (DIC) Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Time after Transduction (days) Transgene GFP MET Parameter 0 30 90 656 800 Platelets (x103) 968 D-dimer (µg/ml) <0.05 <0.05 <0.05 PT (s) 12.4 11.6 11.4 Platelets (x103) 974 350 150 D-dimer (µg/ml) <0.05 0.11 0.22 PT (s) 12.9 11.8 25.1 “MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” Mouse model of Trousseau’s Syndrome ● Genome-wide expression profiling of hepatocytes expressing MET - upregulation of PAI-1 and COX-2 genes with 2-3x circulating protein levels ● Using either XR5118 (PAI-1 inhibitor) or rofecoxib (Vioxx; COX-2 inhibitor) resulted in inhibition of clinical and laboratory evidence for DIC in mice Activation of Blood Coagulation in Cancer: Malignant Transformation 2. “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” ► Pten = tumor suppressor with lipid and protein phosphatase activity ► Loss or inactivation of Pten (70-80% of glioblastomas) leads to Akt activation and upregulation of Ras/MEK/ERK signaling cascade Rong et al Ca Res 2005;65:1406-1413 “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” ► Glioblastomas characterized histologically by “pseudopalisading necrosis” ► Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis ► Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growth ► TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2) “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” Results: 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 Both Akt and Ras Pathways Modulate TF Expression By Transformed Astrocytes N = Normoxia H = Hypoxia Similar data for EGFR – upregulation of TF via JunD/ AP-1 transcription (CA Res 2009;69:2540-9) “Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma” Pseudopalisading necrosis H&E TF IHC Vascular Endothelium Activation of Blood Coagulation in Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” ► ► ► ► ► Activation of K-ras oncogene and inactivation of p53 tumor suppressor TF expression in human colorectal cancer cells Transforming events dependent on MEK/MAPK and PI3K Cell-associated and MP-associated TF activity linked to genetic status of cancer cells TF siRNA reduced cell surface TF expression, tumor growth and angiogenesis TF may be required for K-ras-driven phenotype Yu et al Blood 2005;105:1734-41 Activation of Blood Coagulation in Cancer: Malignant Transformation TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status 450 400 350 160 TF Activity (U/106 cells) Mean Channel TF Flourescence “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” 300 250 200 150 100 50 0 HKh-2 HCT116 del/+ +/+ mut/+ +/+ 379.2 mut/+ del/del 140 120 100 80 60 40 20 0 HKh-2 HCT116 379.2 Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” Effect of TF si mRNA on tumor growth in vitro and in vivo “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells” %VWF-Positive Area Effect of TF si mRNA on new vessel formation in colon cancer 14 12 10 8 6 4 2 0 HCT116 SI-2 SI-3 MG only Activation of Blood Coagulation in Cancer: Malignant Transformation “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis” Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology 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 CA Res 2008;68:10068-76 Class Effect of siRNA for Angiogenesis Inhibition via Toll-Like Receptior 3 (TLR 3) (21 nucleotides)* * Kleinman et al Nature 2008;452:591 Kalluri and Kansaki Nature 2008;452:543 Mechanisms of Cancer-Induced Thrombosis Clinical Implications 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy? 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? ► A: They suggest two things: ● 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 Tissue Factor Expression, Angiogenesis, and Thrombosis in Human Pancreatic Cancer ► Retrospective study ► Immunohistologic (IH) and microarray data on expression of TF and VEGF, as well as microvascular density (MVD) in: Normal pancreas (10) Pre-malignant pancreatic lesions: • Intraductal papillary mucinous neoplasms (IPMN; 70) • Pancreatic intrepithelial neoplasia (PanIN; 40) Resected or metastatic pancreatic adenoca (130) ► Survival ► VTE Rate Khorana et al Clin Cancer Res 2007;13:2870 Immunohistologic Correlation of TF with the Expression of Other Angiogenesis Variables in Resected Pancreatic Cancer High TF Expression Low TF Expression P Value Negative 13 41 <0.0001 Positive 53 15 V6 per tissue core 27 33 >6 per tissue core 39 23 Median 8 6 VEGF Expression Microvessel Density Khorana et.al. Clin CA Res 2007:13:2870 0.047 0.01 Symptomatic VTE in Pancreatic Cancer 5/19; 26.3% 1/22; 4.5% Khorana et al Clin CA Res 2007;13:2872 Median Survival of 122 Resected Pancreatic Cancer Patients Months 17.9 Khorana et al Clin CA Res 2007;13:2872 P = 0.16 (HR 2.06; 0.74-5.7) 12.6 Cancer and Thrombosis Year 2009 State-of-the-Science Update Key Questions 1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer? Cancer and Thrombosis Year 2009 State-of-the-Science Update Tentative Answers 1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWHs in cancer patients indicate superiority to oral agents in preventing recurrent VTE, as well as increasing survival (not due to prevention of VTE) LMWH and Prolongation of Cancer Survival Mechanistic Explanations VTE Coagulation Proteases Direct Heparin Other Heparins and Tumour Biology Multiple Potential Modes of Action Angiogenesis Apoptosis Heparanase Adhesion 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) Effects of Low-Molecular Weight Heparin on Lung Cancer Cell Apoptosis P<0.05 • G1 arrest • Decrease in S phase • 3-fold in p21WAF1 and p27KIP1 (p <0.01) • Reversed apoptosis and G1 arrest with p21 or p27 siRNA Chen et al Cancer Invest 2008;26:718-24 Heparins Inhibit Cytokine–Induced Capillary Tube Formation Tube Length (mm/cm ) 500 § § 400 300 § * * * * * * * * Control * 200 100 2 0 VEGF Cytokine Marchetti et al. Thromb Res 2008;121:637-645 FGF-2 +UFH TNF-a +enoxaparin +dalteparin § = p<0.05 vs control, * = p<0.05 vs cytokine LMWH and VEGF Antisense Oligonucleotides Inhibit Growth and Metastasis of 3LL Tumors in Mice ► ► 40 mice with Lewis Lung Cancer (3LL) Rx qod x 15 with: ● ● ● ● ● ► Control (saline) VEGF antisense oligos (ASODN) VEGF mismatch sense oligo (MSODN) LMWH (dalteparin) LMWH + ASODN RESULTS: Growth Inhibit* Lung Mets* ● ASODN LMWH 47% 27% 38% 38% ● Combined 59% 25% ● * P < 0.05 Zhang YH et al Chinese Med J 2006;86:749-52 Inhibition of Binding of Selectins to Human Colon Carcinoma by Heparins Stevenson et al Clin Ca Res 2005;11:7003-11 Heparin Inhibition of B16 Melanoma Lung Metastasis in Mice Stevenson et al Clin Ca Res 2005;11:7003-11 Coagulation Cascade and Tumor Biology Clottingdependent TF VIIa Clottingindependent Thrombin Xa Clottingdependent Clottingindependent ? PARs ? Angiogenesis, Tumor Growth and Metastasis LMWHs (e.g. dalteparin); Non-anticoagulant heparins or inhibitors Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584; Varki Blood 2007;110:1723-1729 Fibrin Clottingdependent Innovation ● Investigation ● Application 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 VTE and Cancer: Epidemiology ► Of all cases of VTE: ● ● ► Of all cancer patients: ● ● ► About 20% occur in cancer patients Annual incidence of VTE in cancer patients ≈ 1/250 15% will have symptomatic VTE As many as 50% have VTE at autopsy Compared to patients without cancer: ● ● ● Higher risk of first and recurrent VTE Higher risk of bleeding on anticoagulants Higher risk of dying Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21 DVT and PE in Cancer Facts, Findings, and Natural History ► VTE is the second leading cause of death in hospitalized cancer patients1,2 ► The risk of VTE in cancer patients undergoing surgery is 3to 5-fold higher than those without cancer2 ► Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 ► Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 1. Ambrus JL et al. J Med. 1975;6:61-64 2. Donati MB. Haemostasis. 1994;24:128-131 3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 4. Prandoni P et al. Ann Intern Med. 1996;125:1-7 Clinical Features of VTE in Cancer ► VTE has significant negative impact on quality of life ► VTE may be the presenting sign of occult malignancy ● ● ● 10% with idiopathic VTE develop cancer within 2 years 20% have recurrent idiopathic VTE 25% have bilateral DVT Bura et. al., J Thromb Haemost 2004;2:445-51 Thrombosis and Survival Likelihood of Death After Hospitalization 1.00 Probability of Death DVT/PE and Malignant Disease 0.80 0.60 Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120140 160 180 Number of Days Levitan N, et al. Medicine 1999;78:285 Incidence of VTE and Colon Cancer Stage 7% Local Regional Remote Incidence of VTE (%) 6% 5% 4% 3% 2% 1% 0% 0 50 100 150 200 250 300 Days after Cancer Diagnosis White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40 350 400 Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Local Stage Disease Cancer type Hazard ratio (95% CI) for death within one year, cases with VTE diagnosed in year 1 vs. no VTE, by stage Local Regional Remote Prostate 5.6 (3.8-8.5)‡ 4.7 (1.9-11.5) ‡ 2.8 (1.5-5.0) † Breast 6.6 (3.7-11.8) ‡ 2.4 (1.3-4.5) ‡ 1.8 (1.1-2.9)* Lung 3.1 (2.1-4.5) ‡ 2.9 (2.3-3.5) ‡ 2.5 (2.3-2.7) ‡ Colon/rectum 3.2 (1.8-5.5) ‡ 2.2 (1.7-3.0) ‡ 2.0 (1.7-2.4) ‡ Melanoma 14.4 (4.6-45.2) ‡ N/A 2.8 (1.5-5.3) † Non-Hodgkin’s lymphoma 3.2 (1.9-5.3) ‡ 2.0 (1.3-3.2) † 2.3 (1.7-3.1) ‡ Uterus 7.0 (3.4-14.2) ‡ 9.1 (4.8-17.2) ‡ 1.7 (1.0-3.0)* Bladder 3.2 (1.7-6.2) ‡ 3.3 (1.7-6.4) ‡ 3.3 (1.8-6.2) ‡ Pancreas 2.3 (1.2-4.6)* 3.8 (2.8-5.1) ‡ 2.3 (1.9-2.7) ‡ Stomach 2.4 (1.1-5.1)* 1.5 (1.0-2.1)* 1.8 (1.4-2.3) ‡ Ovary 11.3 (2.5-51.7) † 4.8 (1.1-20.4)* 2.3 (1.7-3.0) ‡ Kidney 3.2 (1.2-8.8)* 1.4 (0.6-3.2) 1.3 (0.9-2.0) R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40 * p<0.05; †p<0.01); ‡ p<0.001) 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) Recurrent Ovarian Cancer • 7% symptomatic VTE (2.8-6.1% 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) Fotopoulou C et al. Thromb Res 2009 Mortality (%) Hospital Mortality With or Without VTE N=66,016 Khorana, JCO, 2006 N=20,591 N=17,360 Thrombosis Risk In Cancer Primary Prophylaxis ► Medical Inpatients ► Surgery ► Radiotherapy ► Central Venous Catheters Risk Factors for Cancer-Associated VTE ► Cancer ● Type • Men: prostate, colon, brain, lung • Women: breast, ovary, lung ● ► Stage Treatments ● Surgery • 10-20% proximal DVT • 4-10% clinically evident PE • 0.2-5% fatal PE ● ● Chemotherapy Central venous catheters (~4% generate clinically relevant VTE) ► Patient ● ● ● Prior VTE Comorbidities Genetic background Cancer and Thrombosis Medical Inpatients Antithrombotic Therapy: Choices Nonpharmacologic (Prophylaxis) Intermittent Pneumatic Compression Elastic Stockings Inferior Vena Cava Filter Pharmacologic (Prophylaxis & Treatment) Unfractionated Heparin (UH) Low Molecular Weight Heparin (LMWH) Oral Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.? Rate of VTE (%) Prophylaxis Studies in Medical Patients Relative risk reduction 63% Relative risk reduction 44% Placebo Enoxaparin Placebo Dalteparin MEDENOX Trial PREVENT Francis, NEJM, 2007 Relative risk reduction 47% Placebo Fondaparinux ARTEMIS 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: 5490-5505. Cancer and Thrombosis Surgical Patients Incidence of VTE in Surgical Patients ► Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: No Cancer Cancer N=16,954 N=6124 Post-op VTE 0.61% 1.26% <0.0001 Non-fatal PE 0.27% 0.54% <0.0003 Autopsy PE 0.11% 0.41% <0.0001 Death 0.71% 3.14% <0.0001 Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 P-value Natural History of VTE in Cancer Surgery: The @RISTOS Registry ► Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings ► 2.1% incidence of clinically overt VTE (0.8% fatal) ► Most events occur after hospital discharge ► Most common cause of 30-day post-op death Agnelli, Ann Surg 2006; 243: 89-95 Prophylaxis in Surgical Patients LMWH vs. UFH ► Abdominal or pelvic surgery for cancer (mostly colorectal) ► LMWH once daily vs. UFH tid for 7–10 days post-op ► DVT on venography at day 7–10 and symptomatic VTE Study N Design Regimens ENOXACAN 1 631 double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475 double-blind enoxaparin vs. UFH 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:438-444 Prophylaxis in Surgical Patients Incidence of Outcome Event 16.9% P=0.052 13.9% Canadian Colorectal DVT Prophylaxis Trial N=234 N=241 1.5% 2.7% VTE (Cancer) McLeod R, et al. Ann Surg 2001;233:438-444 Major Bleeding (All) Incidence of Outcome Event Extended Prophylaxis in Surgical Patients 12.0% ENOXACAN II P=0.02 N=167 5.1% 4.8% N=165 3.6% 1.8% 0.6% VTE Prox DVT 0% 0.4% NNT = 14 Any Major Bleeding Bleeding Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 Major Abdominal Surgery: FAME Investigators—Dalteparin Extended ► A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment ► RESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012). ► CONCLUSIONS: 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis. Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1. ASCO Guidelines: VTE Prophylaxis ► All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis. ► Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis. ► Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features. Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505. Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these events: –Fibrin sheath formation –Superficial phlebitis –Ball-valve clot –Deep vein thrombosis (DVT) Geerts W, et al. Chest Jun 2008: 381S–453S Prophylaxis for Venous Catheters Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* 2002 Dalteparin 5000 U daily placebo 285 140 11 (3.7) 5 (3.4) Couban* 2002 Warfarin 1mg daily placebo 130 125 6 (4.6) 5 (4.0) ETHICS† 2004 Enoxaparin 40 mg daily placebo 155 155 22 (14.2) 28 (18.1) *symptomatic outcomes; †routine venography at 6 weeks Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730 WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Warfarin evaluation Dose evaluation Relative risk (95% CI, p value) Fixeddose warfarin (n=471) Doseadjusted warfarin (n=473) Relative risk (95% CI, p value) 24 (6%) 0.99 (0.57-1.72, 0.98) 34 (7%) 13 (3%) 0.38 (0.20-0.71,0.002) 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%) 37 (8%) 26 (6%) Thrombotic Events No warfarin (n=404) Warfarin (n=408) Catheterrelated thrombotic events 24 (6%) No catheterrelated event Young AM et al. Lancet 2009;373:567 0.78 (0.50-1.24), 0.30 0.70 (0.43-1.14, 0.15) WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Warfarin evaluation Bleeding and Raised INR Dose evaluation Relative risk (95% CI, p value) Fixeddose warfarin (n=471) Doseadjusted warfarin (n=473) Relative risk (95% CI, p value) 3 (<1%) - 5 (1%) 7 (1%) - 0 4 (<1%) - 2 (<1%) 9 (2%) - Total major bleeding 1 (<1%) 7 (2%) 6.93 (0.85-56.08, 0.07) 7 (1%) 16 (3%) 2.28 (0.95-5.48, 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%) - No warfarin (n=404) Warfarin (n=408) Major bleeding and no reported raised INR 1 (<1%) Major bleeding and raised INR Young AM et al. Lancet 2009;373:567 WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CA Combined thrombosis and major bleeding events Warfarin evaluation Dose evaluation Relative risk (95% CI, p value) Fixeddose warfarin (n=471) Doseadjusted warfarin (n=473) Relative risk (95% CI, p value) 31 (8%) 1.23 (0.83-1.52, 0.51) 41 (9%) 29 (6%) 0.84 (0.74-2.04, 0.17) 37 (9%) 0.94 (0.61-1.44, 0.87) 44 (9%) 42 (9%) 0.95 (0.64-1.42, 0.89) No warfarin (n=404) Warfarin (n=408) Total catheterrelated thrombosis and major bleeding events 25 (6%) All thrombotic and major bleeding events 39 (10%) Young AM et al. Lancet 2009;373:567 Central Venous Catheters: Warfarin Tolerability of Low-Dose Warfarin ► 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily ► INR measured at baseline and four time points ► 10% of all recorded INRs >1.5 ► Patients with elevated INR 2.0–2.9 6% 3.0–4.9 19% >5.0 7% Masci et al. J Clin Oncol. 2003;21:736-739 Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls: CA + FVL OR=5.18 (95% confidence interval: 3.0-8.8) CA + G20210A OR=3.95 (95% confidence interval: 1.5-10.6) The attributable risk of catheter associated thrombosis conferred by: FVL 13.5% G20210A 3.6% Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564 8th 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 Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient ► No recommendations from ACCP ► No data from randomized trials (RCTs) ► Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian) ► Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.) Risk Factors for VTE in Medical Oncology Patients ► Tumor ● Ovary, brain, pancreas, lung, colon ► Stage, ● ► grade, and extent of cancer Metastatic disease, venous stasis due to bulky disease Type of antineoplastic treatment ● ► type Multiagent regimens, hormones, anti-VEGF, radiation Miscellaneous VTE risk factors ● Previous VTE, hospitalization, immobility, infection, thrombophilia Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery with institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 Heit JA et al. Thromb Haemost. 2001;86:452-463 VTE Incidence In Various Tumors Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further treatment 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Non-Hodgkin’s lymphomas w/ chemo 3% Hodgkin’s disease w/ chemo 6% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-VEGF + chemo) 47% Wilms tumor (cavoatrial extension) 4% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Primary VTE Prophylaxis ►Recommended for hospitalized cancer patients ►Not universally recommended for outpatients, but there are exceptions ● ● New data for certain agents Heterogeneous population Need for risk stratification VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Myeloma All-Grade Venous Thromboembolism, No./Total No. No. of Studies Bevacizumab Control Incidence (95% CI), % RR (95% CI) Overall 6 155/1196 107/1083 11.9 (6.8-19.9) 1.29 (1.03-1.63) Colorectal cancer 3 108/564 85/532 19.1 (16.1-22.6) 1.19 (0.92-1.55) NSCLC 1 10/66 3/32 14.9 (8.2-25.5) 1.59 (0.47-5.37) Breast cancer 1 17/229 12/215 7.3 (4.6-11.5) 1.30 (0.64-2.67) Renal cell carcinoma 1 20/337 6/304 3.0 (1.6-5.5) 3.00 (1.23-7.33) Tumor Type Naluri SR et al. JAMA. 2008;300:2277 Bevacizumab Increases Risk of Symptomatic VTE by 33% vs Controls Naluri SR et al. JAMA. 2008;300:2277 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 Treatment Odds Ratio (95% CI) P Value Lenalidomide plus High-dose dexamethasone 3.51 (1.77-6.97) <0.001 Concomitant erythropoietin 3.21 (1.72-6.01) <0.001 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 Oral Anticoagulant Therapy in Cancer Patients: Problematic ► Warfarin ● ● ● ● ► therapy is complicated by: Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Increased risk of both recurrence and bleeding Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? CLOT: Landmark Cancer/VTE Trial Dalteparin CANCER PATIENTS WITH ACUTE DVT or PE [N = 677] ► ► Dalteparin Randomization Dalteparin Oral Anticoagulant Primary Endpoints: Recurrent VTE and Bleeding Secondary Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 Landmark CLOT Cancer Trial Probability of Recurrent VTE, % Reduction in Recurrent VTE 25 Risk reduction = 52% p-value = 0.0017 Recurrent VTE 20 OAC 15 10 Dalteparin 5 0 0 30 60 90 120 150 Days Post Randomization Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 180 210 Bleeding Events in CLOT Dalteparin OAC N=338 N=335 Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact test Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 P-value* Treatment of Cancer-Associated VTE Study Design Length of Therapy (Months) N Recurrent Major Death VTE Bleeding (%) (%) (%) 6 4 NS 39 41 0.09 7 16 0.09 11 0.03 23 0.03 6 8 CLOT Trial (Lee 2003) Dalteparin OAC 6 336 336 9 17 0.002 CANTHENOX (Meyer 2002) Enoxaparin OAC 3 67 71 11 21 LITE (Hull ISTH 2003) Tinzaparin OAC 3 80 87 6 11 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC 6 32 36 34 3.4 3.1 6.7 NS NS NS 23 22 NS NS NR Treatment and 2° Prevention of VTE in Cancer – Bottom Line New Development ► New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendation—ACCP) ► 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 recommendation—ACCP) Chest Jun 2008: 454S–545S CLOT 12-month Mortality All Patients Probability of Survival, % 100 90 80 70 Dalteparin 60 OAC 50 40 30 20 10 0 HR 0.94 P-value = 0.40 0 30 60 90 120 180 240 300 Days Post Randomization Lee AY et al. J Clin Oncol. 2005; 23:2123-9. 360 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Patients Without Metastases (N=150) Probability of Survival, % 100 Dalteparin 90 80 70 OAC 60 50 40 30 20 10 HR = 0.50 P-value = 0.03 0 0 30 60 90 120 150 180 240 300 Days Post Randomization Lee AY et al. J Clin Oncol. 2005; 23:2123-9. 360 LMWH Influences Survival of Patients with Advanced Solid Tumor Malignancies 6 wks LMWH immediately post diagnosis of CA-no initial chemo <6 mos anticipated survival Klerk, C. P.W. et al. J Clin Oncol; 23:2130-2135 2005 >6 mos anticipated survival LMWH for Small Cell Lung Cancer Turkish Study ► 84 patients randomized: Chemo +/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 0.01 Median survival, m 13.0 8.0 0.01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266. Rate of Appropriate Prophylaxis, % VTE Prophylaxis Is Underused in Patients With Cancer Cancer: FRONTLINE Survey1— 3891 Clinician Respondents Cancer: Surgical Major Surgery2 Major Abdominothoracic Surgery (Elderly)3 Medical Inpatients4 Confirmed DVT (Inpatients)5 Cancer: Medical 1. Kakkar AK et al. Oncologist. 2003;8:381-388 4. Rahim SA et al. Thromb Res. 2003;111:215-219 2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262 Conclusions and Summary ► Risk 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 warfarin ► Guidelines and landmark trials support administration of LMWH in at risk patients ► Cancer patients are under-prophylaxed for VTE ► Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient population Mechanisms ● Mortality ● Therapeutics 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 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 Risk of Inadequate Therapy in High Risk Patients ► 524 VTE Patients ● Active Cancer in 26% • Only 1/3rd on LMWH monotherapy ● Weight > 100Kg in 15% • Under-dosing of LMWH by > 10% – 36% of > pts 100Kg – 8% of pts < 100Kg (p < 0.001) ● CrCL < 30mL/min in 5% • LMWH tx in 67% Cook LM, et.al. J Thromb Hemost 2007;5;937-41. 8th ACCP Conference on Antithrombotic Therapy Obese Patients “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? ► 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. Pharmacokinetic Characteristics of Low Molecular Weight Heparins Lipid solubility LOW Plasma protein binding HIGH Tissue binding LOW Volume of distribution 5-7 L Logical conclusion: IBW may be a better predictor of LMWH dosing than TBW LMWH: Maximum Weights Studied Kinetic Studies Clinical Trials Dalteparin 190 kg 128 kg* Enoxaparin 144 kg 194 kg Tinzaparin 165 kg 88 kg Fondaparinux * max dose 18,000 - 20,000 IU/day Duplaga BA et al. Pharmacotherapy 2001; 21:218-34. Synergy Trial: Data on File Davidson, et al. J Thromb Haem 2007;5:1191-4 175.5 kg 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;72:308-18. Thromb Haemost 2002;87:817-23. Dalteparin Pharmacokinetics in Obesity Dose: 200 U/kg qd Duration: routine Obese (BMI > 30) Normal (BMI < 30) 10 10 TBW (mean +/- SD) 106.4 +/- 22.1 69.7 +/- 9.3 LBW (mean +/- SD) 64.1 +/- 12.3 66.1 +/- 8.7 Mean Vd (l) 12.39 8.36 Mean CI (l/hr) 1.30 1.11 N Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56:293-7. Dalteparin Pharmacokinetics In Obesity Correlation Coefficient Between Vd and: LBW 0.05 ABW 0.52 TBW 0.55 Correlation Coefficient Between Cl and: LBW 0.01 ABW 0.32 TBW 0.39 Conclusion: TBW may be a better predictor of LMWH dose than IBW Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7. Dalteparin Pharmacokinetics In Obesity Dose: 200 U/kg qd Duration: 5 Days Max TBW: 190kg <20% of IBW 20-40% of IBW > 40% of IBW N 13 14 10 Mean Dose (U) 14,030 17,646 23,565 Day 3 Peak 1.01 0.97 1.12 NS Day 3 Trough 0.12 0.11 0.11 NS Ant-Xa Activity (u/ml) 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. Wilson SJ et al. Hemostasis 2001; 31:42-8. LMWH Safety and Effectiveness Using TBW Enoxaparin In ACS (ESSENCE/TIMI IIb) P=0.39 16.1% 14.3% P=0.13 1.6% 0.4% Obese: BMI > 30mg/m2 Enoxaparin max weight 158 kg Spinler SA et al. Am Heart J 2003; 146:33-41 Safety Of TBW-based Dosing of Dalteparin for Treatment of Acute VTE in Obese Patients N = 193 patients > 90 kg 3 month outcomes: major bleeding = 1.0% (n=2) recurrent VTE = 1.6% (n=3) WEIGHT (kg) N Mean Dose Full dose +/- 5% QD Dosing BID Dosing 90-99 40 19,300 39 24 16 100-109 52 20,850 49 25 17 110-119 41 21,470 21 26 15 120-129 25 24,300 22 16 9 130-139 16 25,250 8 10 6 140-149 9 26,920 6 5 4 > 150 10 28,280 6 6 4 Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2. Fondaparinux In Obesity Results From the Matisse Trials Fondaparinux: < 50kg: 5mg qd 50-100kg: 7.5mg qd > 100kg: 10mg qd Enoxaparin: (Matisse DVT) 1mg/kg q12h Heparin: (Matisse PE) Adjusted per aPTT Davidson BL et al. J Thrombosis Haemost 2007; 5:1191-4. No weight-dependent difference in efficacy or safety Body Weight and Anti-Xa Activity for Prophylactic Doses of LMWH Area under the curve for 10 h N = 17 patients and 2 volunteers Enoxaparin 40mg SQ x1 dose AntiXa levels hourly x10 hours Regression line 95% CI for line 95% CI for data points 200 150 100 50 0 40 60 80 100 120 Body Weight (kg) Frederiksen SG et al. Br J Surgery 2003; 90:547-8 140 160 Dalteparin Fixed Dosing For VTE Prevention Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill) BMI (kg/m2) < 25 25-29.9 30-34.9 35-39.9 > 40 Patients % Favors Dalteparin Favor Placebo 37.5 33.1 18.9 7.1 3.3 Overall Prevent Trial 0.01 0.1 0.55 1.0 Relative Risk 10.0 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 Kucher N et al. Arch Int Med 2005;165:341-5. Enoxaparin VTE Prophylaxis in TKA/THA/Trauma 31.8% p<0.001 16.7% N: 807 Dose: 40 mg qd Samama MM et al. Thromb Haemost 1995; 73:977. Obese : BMI>32kg/m2 Enoxaparin: VTE Prophylaxis in Bariatric Surgery 5.4% p<0.01 0.6% 30mg bid: n=92 BMI 51.7kg/m2 Scholten Obes Surg 2002; 12:19-24. 40mg bid: n=389 BMI 50.3kg/m2 Dalteparin in Morbid Obesity: Bariatric Surgery N=135 Bariatric Surgery Mean Weight: 148.8Kg Mean BMI: 53.7 Dalteparin: 7,500 IU daily Body Weight (kg) 200 180 P=0.052 P=0.444 160 140 120 0 Anti-factor Xa level P=0.031 Under target value Target value Over target value <>0.5 IU/mL <0.2 IU/mL <0.2-0.5 IU/mL n=13 n-=41 n-=81 Number of patient (%) Body weight (kg) Below target value (<0.2 UI/ml) 41 (30.4%) 159.4 ± 35.8 Target value (0.2–0.5 UI/ml) 81 (60.0%) 145.7 ± 28.4 Above target value (>0.5 UI/ml) 13 (9.6%) 134.6 ± 24.2 p value Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print] 0.0152 LMWH in Obesity: Summary ► Treatment: in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg) ● Dalteparin • Dose based on TBW • PI recommends dose capping • Recent clinical data supports TBW dosing – QD or BID dosing ● Enoxaparin • Dose based on TBW • Dose capping NOT recommended • BID dosing preferred ● Tinzaparin • Dose based on TBW, NO dose adjustment or capping ● ► Anti-Xa monitoring not necessary for TBW < 190kg Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients) Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):1064-83. 8th ACCP Conference on Antithrombotic Therapy Renal Impairment ► 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) ► Options for patients with renal impairment (Grade 1B) ● ● ● Avoid agents that renal accumulate Use a lower dose Monitor the drug level or anticoagulant effect Geerts WH. Chest 2008;133(suppl):381S-453S. LMWH in Renal Dysfunction Manufacturer Recommendations Dalteparin ● “should be used with caution in patients with severe kidney insufficiency.” • Monitor anti-Factor Xa for dose guiding with therapeutic doses Enoxaparin ● “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.” Fondaparinux - Contraindicated in CrCL < 30mL/min Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal Dysfunction Patients w/ renal insuff. (n/n) Patients w/ no renal insuff. (n/n) Collet, et al; 2001 Paulas, et al; 2002 Siguret, et al; 2000 0/28 0/51 0/17 1/83 3/149 0/13 Chow, et al; 2003 0/5 0/13 Khazan, et al. (adj.); 2003 (Prophylactic) 2003 (Therapeutic) 2003 Spinler, et al; 2003 0/10 3/36 2/17 5/69 3/42 3/47 3/61 74/3,432 4.78 14.77 8.62 15.93 0.28 (0.01 – 5.16) 1.33 (0.25 – 7.05) 3.09 (0.35 – 27.31) 10.05 (2.02 – 49.98) Green, et al; 2005 1/18 0/20 2.66 8.26 (0.16 – 418.42) Kruse & Lee; 2004 0/50 1/120 2.22 0.24 (0.00 – 17.90) Macie, et al; 2004 2/7 6/201 2.68 977.78 (19.61 – 48,752.07) Peng, et al; 2004 0/7 0/43 Thorevska, et al; 2004 7/65 11/171 35.56 1.85 (0.63 – 5.40) Bazinet, et al; 2005 1/36 2/160 4.75 2.74 (0.15 – 51.73) 21/416 107/4,555 Study; year Total (95%, CI) Peto OR (95%, CI) 2.01 6.02 Peto OR (95%, CI) 0.26 (0.00 – 23.94) 0.26 (0.02 – 3.50) Not estimable Not estimable Not estimable 0.01 0.1 Favors ↓’ed Lim W, et al. Ann Intern Med. 2006;144:673-684. Weight (%) 100.00 1 10 100 Favors ↑’ed bleeding 2.25 (1.19 – 4.27) Dosage adjustments for renal dysfunction 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 CL/F (L/h) Half-life (h) Normals 0.98 6.87 Mild RI 0.87 9.94 20% ↑ Moderate RI 0.76 11.3 21% ↑ Severe RI 0.58 15.9 65% ↑ Day 4 Sanderink GJCM. Thromb Res 2002;105:225-31. AUC (0-24) (h●IU/mL) LMWH Renal Dosing in NSTE ACS Patients ► 56 UA pts with CrCl <60 ml/min ► Enoxaparin dose empirically and anti-Xa level measured after 3rd dose • • • • Dose may be to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl 30-60 ml/min Anti-Xa monitoring Doses “appeared safe” Further prospective evaluation needed CrCl (ml/min) <30 (n = 28) >30 and <60 (n =28) Age 76+/-3 73+/-3 Enoxaparin (mg/kg/12h) 0.64 0.84 Anti-Xa (IU/ml) 0.95 0.95 Collet JP et al. International J Cardiol 2001;80:81-2. Clinical Use Of Recommended Enoxaparin Dosage in Renal Impairment N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h 1.0. 6 0.9 TROUGH ANTI-Xa LEVELS 5 0.8 Number of Patients Antifactor X1 Level (U/mL) PEAK ANTI-Xa LEVELS 0.7 0.6 0.5 0.4 0.3 4 3 2 1 0.2 0.1 0 First dose Median Subsequent doses (second and third) 25-75% interquartile range Lachish T et al. Pharmacotherapy 2007; 27:1347-52. 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 Trough Antifactor Xa Level (U/mL) Tinzaparin 175 U/kg Peak Anti-Xa Levels According to Renal Function No correlation between peak anti-Xa activity and Clcr No accumulation of Anti-Xa activity after 10 days of therapy Siguret V et al. Thromb Haemost 2000;84:800-4. Pharmacokinetics of Prophylactic Enoxaparin vs Tinzaparin Enoxaparin 40mg qd or Tinazaparin 4500 IU qd N = 52 patients Mean age = 87.7 yrs Mean wt = 52.3kg Mean Clcr = 34.7ml/min Mahe I et al. Thromb Haemost 2007; 97:581-6. Pharmacokinetics of Prophylactic Doses of Dalteparin 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) 60-89 30-59 <30 Day 6 peak anti-Xa 0.030 0.033 0.048 Minor Bleeding 0 3 0 Major Bleeding 0 0 0 P=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 Tincani E et al. Haematologica 2006; 91:976-9. Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct Study ► N=138 critically ill patients ► CrCl < 30 ml/min • Mean CrCL 18.9ml/min ► Dalteparin 5000 IU sc daily ► Serial anti Xa levels measured on days 3, 10, and 17 ► Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL Results: ► The median duration of dalteparin exposure was 7 (4-12) days ► No patient had a trough anti Xa level > 0.4 IU/ml ► Based on serial measurements • peak anti-Xa levels were 0.29 to 0.34 IU/mL • trough levels were lower than 0.06 IU/mL Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12. Dosing of LMWHs In Renal Impairment Recommendations FOR CrCL < 30 ml/min ► Enoxaparin: ● ● ► Prophylaxis doses: 30 mg sq QD Treatment doses: 1mg/Kg sq QD Dalteparin and Tinzaparin: ● ● ● no specific dosing guidelines No or lower degree of accumulation expected Anti-Factor Xa activity monitoring FOR CrCL 30-50 mL/min ► No specific recommendations ► Concern with prolonged use > 10 days with enoxaparin (15-25% dose decrease ?) ► Monitoring anti-Xa ? Nutescu E, et.al. Ann Pharmacother; 2009; 43(6):1064-83. 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. < 20-15 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 Anti-Xa Activity Level Monitoring Enoxaparin 1mg/kg SQ pharmacokinetic profile Peak (goal ~ 0.5-1 U/ml) at 3-4 hrs Trough (goal < 0.5 U/ml) at 11-12 hrs Laposata et al. Arch Pathol Lab Med. 1998;122:799-807. Fondaparinux Use in Patients with Impaired Renal Function ► Total clearance lower than in patients with normal renal function Fondaparinux: PI ● Mild impairment ~25% ● Moderate impairment ~40% ● Severe impairment ~55% Mechanisms ● Mortality ● Therapeutics 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 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 lowdose heparin or LMWH for bedridden patients with active cancer. 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 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 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. Treatment of Patients with Established VTE to Prevent Recurrence Role of VTE Prophylaxis LMWH is the preferred approach for the initial 5-10 days in cancer patient with established 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) Evidence LMWH for 3-6 months is more effective than vitamin K antagonists given for a similar duration for preventing recurrent VTE. Treatment of Patients with Established VTE to Prevent Recurrence (continued) Role of VTE Prophylaxis Evidence In the absence of clinical trials, benefits and risks of continuing LMWH Anticoagulation for an indefinite period beyond 6 months is a clinical should be considered for patients with judgment in the individual patient. active cancer (metastatic disease, Caution is urged in elderly patients continuing chemotherapy) 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 Anticoagulants in the Absence of Established VTE to Improve Survival Role of VTE Prophylaxis Anticoagulants are not currently recommended to improve survival in patients with cancer without VTE. Evidence RCTs and meta-analysis of warfarin, UFH and LMWH have reported encouraging but variable results generally showing clinical benefit only in subgroup analyses. Summary of NCCN Guidelines Updates Summary of Major Changes in the 1.2009 Version of the NCCN Venous Thromboembolic Disease Guidelines 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” ► 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, dalteparin’s 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 “2.02.9 x control) to “2.0-2.5 x control…” (Also for VTE-H) in these patients. Changes in 2009 NCCN Guidelines Stage 3 Chronic: ► “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”. Changes in 2009 NCCN Guidelines ► 6Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparin’s 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): 146-153. (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. (VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism Stage 1 Immediate: At diagnosis or during diagnostic evaluation: ► Low-molecular-weight heparin (LMWH) • • • Dalteparin (200 units/kg subcutaneous daily) Enoxaparin (1 mg/kg subcutaneous every 12 hours) Tinzaparin (175 units/kg subcutaneous daily) ► Fondaparinux (5 mg [<50 kg]; 7.5 mg [50-100 kg]; 10 mg [> 100 kg] subcutaneous daily ► Unfractionated heparin (IV) (80 units/kg load, then 18 units/kg per hour, target aPTT of 2.0-2.5 x control or per hospital SOP) (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 (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 ► 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 2.0-3.0) Therapeutic Anticoagulation Failure Therapeutic INR Patient on warfarin Switch to heparin (LMWH preferred) or fondaparinux Check INR Subtherapeutic INR Increase warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinux Therapeutic Anticoagulation Failure Therapeutic aPTT Patient on heparin Increase dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HIT Check aPTT levels Subtherapeutic aPTT Increase dose of heparin to reach therapeutic level Mechanisms ● Mortality ● Therapeutics Thank You Questions?