VIEWS: 10 PAGES: 149 POSTED ON: 12/12/2011
Welcome to this Science-to-Strategy Summit Clotting, Cancer, and Clinical Strategies Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Oncology Practice Program Chairman Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Lombardi Comprehensive Cancer Center Washington, DC Welcome and Program Overview CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Program Educational Objectives As a result of this session, physicians will be able to: ► Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer, using FDA-indicated and approved agents ► Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT. ► Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis. ► Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer. ► Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy. Program Faculty Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Washington, DC John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Samuel Z. Goldhaber, MD Professor of Medicine Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Unit Brigham and Women’s Hospital Boston, MA Faculty COI Financial Disclosures Craig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, Octapharma Consultant: sanofi-aventis, Eisai, NovoNordisk John Fanikos, RPh, MBA Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Company Samuel Z. Goldhaber, MD Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK; Sanofi-Aventis; Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; Sanofi- Aventis Clots and Cancer—A Looming National Healthcare Crisis MISSION AND CHALLENGES Recognizing cancer patients at risk for DVT and identifying patients who are appropriate candidates for long-term prophylaxis and/or treatment with approved and indicated therapies are among the most important and difficult challenges encountered in contemporary oncology practice. Introduction and Chairman’s Overview Clotting, Cancer, And Controversies: What The Cascade Of Evidence And Current Thinking Tell Us The Evolving Science, Epidemiology, and Foundation Role of Low Molecular Weight Heparin in the Setting of Cancer Program Chairman Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Lombardi Comprehensive Cancer Center Washington, DC Comorbidity Connection COMORBIDITY SUBSPECIALIST CONNECTION STAKEHOLDERS CAP Infectious diseases UTI Oncology Cancer Cardiology Heart Failure Pulmonary medicine ABE/COPD Hematology Respiratory Failure Oncology/hematology Myeloproliferative Disorder Interventional Radiology Thrombophilia Hospitalist Surgery Surgeons History of DVT EM Other PCP Epidemiology of First-Time VTE Variable Finding Possibly more common in winter and less Seasonal Variation common in summer 25% to 50% ―idiopathic‖ Risk Factors 15%–25% associated with cancer; 20% following surgery (3 mo.) 6-month incidence: 7%; higher rate in patients with cancer Recurrent VTE Recurrent PE more likely after PE than after DVT 30 day incidence 6% after incident DVT 30 day incidence 12% after PE Death After Treated VTE Death strongly associated with cancer, age, and cardiovascular disease White R. Circulation. 2003;107:I-4 –I-8.) Epidemiology of VTE ► One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders. ► Overall, about 25% to 50% of patient with first-time VTE have an idiopathic condition, without a readily identifiable risk factor. ► Early mortality after VTE is strongly associated with presentation as PE, advanced age, cancer, and underlying cardiovascular disease. White R. Circulation. 2003;107:I-4 –I-8.) Comorbidity Connection Overview Comorbidity Connection Acute Medical Illness and VTE Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Acute Medical Illness Relative Risk X2 P value Heart failure 1.08 (0.72-1.62) 0.05 .82 NYHA class III 0.89 (0.55-1.43) 0.12 .72 NYHA class IV 1.48 (0.84-2.60) 1.23 .27 Acute respiratory disease 1.26 (0.85-1.87) 1.03 .31 Acute infectious disease 1.50 (1.00-2.26) 3.54 .06 Acute rheumatic disease 1.45 (0.84-2.50) 1.20 .27 Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968 Acute Medical Illness and VTE Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds Ratio X2 (95% CI) Age > 75y 1.03 (1.00-1.06) 0.0001 Cancer 1.26 (0.93-2.75) 0.08 Previous VTE 2.06 (1.10-3.69) 0.02 Acute infectious disease 1.74 (1.12-2.75) 0.02 Chronic respiratory disease 0.60 (0.38-0.92) 0.02 Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968 Comorbid Condition and DVT Risk ► Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursing home residence accounted for 13%. ► The individual attributable risk estimates for malignant neoplasm, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis were 18%, 12%, 10%, 9%, 7%, and 5%, respectively. ► Together, the 8 risk factors accounted for 74% of disease occurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study VTE Recurrence Predictors of First Overall VTE Recurrence Baseline Characteristic Hazard Ratio (95% CI) Age 1.17 (1.11-1.24) Body Mass Index 1.24 (1.04-1.47) Neurologic disease with extremity 1.87 (1.28-2.73) paresis Malignant neoplasm None 1.00 With chemotherapy 4.24 (2.58-6.95) Withot chemotherapy 2.21 (1.60-3.06) Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768 Clotting, Cancer, and Clinical Strategies Cancer, Thrombosis, and the Biology of Malignancy Scientific Foundations for the Role of Low-Molecular-Weight Heparin John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Professor Armand Trousseau Lectures in Clinical Medicine ― I have always been struck with the frequency with which cancerous patients are affected with painful oedema of the superior or inferior extremities….‖ New Syndenham Society – 1865 Professor Armand Trousseau More Observations About Cancer and Thrombosis ―In other cases, in which the absence of appreciable tumor made me hesitate as to the nature of the disease of the stomach, my doubts were removed, and I knew the disease to be cancerous when phlegmasia alba dolens appeared in one of the limbs.‖ Lectures in Clinical Medicine, 1865 Trousseau’s Syndrome Ironically, Trousseau died of gastric carcinoma 6 months after writing to his student, Peter, on January 1st, 1867: ―I am lost . . . the phlebitis that has just appeared tonight leaves me no doubt as to the nature of my illness‖ Trousseau’s Syndrome ► Occult cancer in patients with idiopathic venous thromboembolism ► Thrombophlebitis in patients with cancer Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 53.5 50 • Population-based case-control (MEGA) study • N=3220 consecutive patients with 1st 40 VTE vs. n=2131 control subjects Adjusted odds ratio • CA patients = OR 7x VTE risk vs. non- CA patients 30 28 22.2 20.3 19.8 20 14.3 10 4.9 3.6 2.6 1.1 0 > 15 years Lung Breast Distant 1 to 3 years 5 to 10 years Gastrointestinal metastases 0 to 3 months 3 to 12 months Hematological Type of cancer Time since cancer diagnosis Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715 Cancer, Mortality, and VTE Epidemiology and Risk ► Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patients ► Patients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patients ► Cancer patients undergoing surgery have a 2-fold increased risk for postoperative VTE ► Death rate from cancer is four-fold higher if patient has concurrent VTE ► VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection) Heit et.al. Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. Blood 2002;100:3484-3488; White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al. Medicine 1999;78:285-291; Khorana et.al. J Thromb Haemost 2007;5:632-4 Mechanisms of Cancer-Induced Thrombosis The Interface 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 Interface of Biology and Cancer Tumor cells Angiogenesis, Fibrinolytic Procoagulant Activities Basement matrix activities: degradation. t-PA, u-PA, u-PAR, PAI-1, PAI-2 IL-1, Activation of TNF-a, coagulation VEGF PMN leukocyte 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 Interface 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 Tumor Blood Coagulation TF Activation Cell VEGF THROMBIN FIBRIN Angiogenesis IL-8 PAR-2 TF Endothelial cells Angiogenesis Falanga and Rickles, New Oncology:Thrombosis, 2005 Coagulation Cascade and Tumor Biology Clotting- Clotting- dependent dependent TF Thrombin Fibrin VIIa Xa Clotting- independent Clotting- Clotting- independent dependent 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 Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic Cancer Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter, Jennifer Harvey and Mark B.Taubman (U Rochester, U Pitt, Johns Hopkins, Translational Genomics) Clin Cancer Res 2007;13:2870 ► Retrospective IH and microarray study of TF, VEGF and MVD in: ● Normal pancreas (10) ● Intraductal papillary mucinous neoplasms (IPMN; 70) ● Pancreatic intrepithelial neoplasia (PanIN; 40) ● Resected or metastatic pancreatic adenoca(130) ► Survival ► VTE Rate Correlation of Tissue Factor Expression with the Expression of Other Angiogenesis Cariables in Resected Pancreatic Cancer High TF Low TF P Expression Expression VEGF expression Negative 13 41 <0.0001 Positive 53 15 Microvessel density V6 per tissue core 27 33 0.47 >6 per tissue core 39 23 Median 8 6 0.01 Khorana et.al. Clin CA Res 2007:13:2870 Symptomatic VTE in Pancreatic Cancer 30% 5/19 26.3% 25% Rate of VTE 20% 15% 10% 1/22 4.5% 5% 0% Low TF High TF Khorana et.al. Clin CA Res 2007;13:2872 Activation of Blood Coagulation in Cancer: Malignant Transformation ► Epiphenomenon? ► Linked to malignant transformation? 1. MET oncogene induction produces DIC in human liver carcinoma (Boccaccio et. al. Nature 2005;434:396-400) 2. Pten loss produces TF activation and pseudopalisading necrosis in human glioblastoma (Rong et.al. Ca Res 2005;65:1406-1413) 3. K-ras oncogene, p53 inactivation and TF induction in human colorectal carcinoma (Yu et.al. Blood 2005;105:1734-1741) Activation of Blood Coagulation in Cancer: Malignant Transformation ―1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis‖ ► MET encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) ● Drives physiological cellular program of ―invasive growth‖ (tissue morphogenesis, angiogenesis and repair) ● Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transformation, invasion, and metastasis Boccaccio et al Nature 2005;434:396-400 ―MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis‖ ► Mouse model of Trousseau’s Syndrome ● Targeted activated human MET to the mouse liver with lentiviral vector and liver-specific promoter slowly, progressive hepatocarcinogenesis ● Preceded and accompanied by a thrombohemorrhagic syndrome ● Venous thrombosis in tail vein occurred early and was followed by fatal internal hemorrhage ● Syndrome characterized by d-dimer and PT and platelet count (DIC) Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Time after Transduction (days) Transgene Parameter 0 30 90 GFP Platelets (x103) 968 656 800 D-dimer (µg/ml) <0.05 <0.05 <0.05 PT (s) 12.4 11.6 11.4 _________ ________________ _______________________________ MET 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, Brat et.al. Ca Res 2005;65:1406-1413 ―Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma‖ ► Glioblastomas characterized histologically by ―pseudopalisading necrosis‖ ► Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by thrombosis ► Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growth ► TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2) ―Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma‖ Results: 1. Hypoxia and PTEN loss TF (mRNA, Ag and procoagulant activity); partially reversed with induction of PTEN 2. Both Akt and Ras pathways modulated TF in sequentially transformed astrocytes. 3. Ex vivo data: TF (by immunohistochemical staining) in pseudopalisades of # 7 human glioblastoma specimens Both Akt and Ras Pathways Modulate TF Expression By Transformed Astrocytes N=Normoxia H=hypoxia Rong, Brat et.al. Ca Res 2005;65:1406-1413 ―Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma‖ pseudopalisading necrosis H&E Vascular Endothelium TF Immuno- histochemistry Rong, Brat et.al. Ca Res 2005;65:1406-1413 Activation of Blood Coagulation in Cancer: Malignant Transformation 3. ―Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis‖ ► Activation of K-ras oncogene and inactivation of p53 tumor suppressor TF expression in human colorectal cancer cells ► Transforming events dependent on MEK/MAPK and PI3K ► Cell-associated and MP-associated TF activity linked to genetic status of cancer cells ► TF siRNA reduced cell surface TF expression, tumor growth and angiogenesis ► TF may be required for K-ras-driven phenotype Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Activation of Blood Coagulation in Cancer: Malignant Transformation ―Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis‖ TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status Mean Channel TF Flourescence 450 160 TF Activity (U/106 cells) 400 140 350 120 300 100 250 80 200 60 150 100 40 50 20 0 0 HKh-2 HCT116 379.2 HKh-2 HCT116 379.2 del/+ mut/+ mut/+ +/+ +/+ del/del Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Activation of Blood Coagulation in Cancer: Malignant Transformation ―Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis‖ Effect of TF si mRNA on tumor growth in vitro and in vivo Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 ―Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells‖ Effect of TF si mRNA on new vessel formation in colon cancer 14 %VWF-Positive Area 12 10 8 6 4 2 0 HCT116 SI-2 SI-3 MG only Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Activation of Blood Coagulation in Cancer: Malignant Transformation ―Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis‖ Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Mechanisms of Cancer-Induced Thrombosis: Implications 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy? Cancer and Thrombosis Year 2008 State-of-the-Science Update Key Questions 1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer? Cancer and Thrombosis Year 2008 State-of-the-Science Update Tentative Answers 1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWH in cancer patients indicate superiority in preventing recurrent VTE and suggest increased survival (not due to just preventing VTE)— “Titillating” Coagulation Cascade and Tumor Biology Clotting- Clotting- dependent dependent TF Thrombin Fibrin VIIa Xa Clotting- independent Clotting- Clotting- independent dependent ? PARs Angiogenesis, Tumor Growth and Metastasis LMWH (e.g. FRAGMIN) Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584 Clotting, Cancer, and Clinical Strategies A Systematic Overview of VTE Prophylaxis In The Setting of Cancer Linking Science to Clinical Practice Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Lombardi Comprehensive Cancer Center Washington, DC VTE and Cancer: Epidemiology ► Of all cases of VTE: ● About 20% occur in cancer patients ● Annual incidence of VTE in cancer patients ≈ 1/250 ► Of all cancer patients: ● 15% will have symptomatic VTE ● As many as 50% have VTE at autopsy ► Compared to patients without cancer: ● Higher risk of first and recurrent VTE ● Higher risk of bleeding on anticoagulants ● Higher risk of dying Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21 DVT and PE in Cancer Facts, Findings, and Natural History ► VTE is the second leading cause of death in hospitalized cancer patients1,2 ► The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2 ► Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3 ► Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4 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 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 ● Systemic ● Central venous catheters (~4% generate clinically relevant VTE) Thrombosis and Survival: Likelihood of Death After Hospitalization 1.00 DVT/PE and Malignant Disease 0.80 Probability of Death 0.60 Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120 140 160 180 Number of Days Levitan N, et al. Medicine 1999;78:285 As Number Of Cancer Survivors Increases, VTE Rates Increase 4 3.5 Cancer Patients And Noncancer Patients (%) VTE in Hospitalized Cancer 3 2.5 2 1.5 1 Noncancer Patients 0.5 0 79 81 83 85 87 89 91 93 95 97 99 Year Stein PD, et al. Am J Med 2006; 119: 60-68 Relative Risk of VTE in Cancer Patients 2 3 4 1 0.5 1.5 2.5 3.5 4.5 Pancreas Stein PD, et al. Am J Med 2006; 119: 60-68 Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney ―Solid And Liquid‖ Colon Ovary VTE Risk And Cancer Type: Liver Leukemia Relative Risk of VTE Ranged From 1.02 to 4.34 Breast Cervix Bladder Thrombosis Risk In Cancer Primary Prophylaxis ► Surgery ► Chemotherapy ► Radiotherapy ► Central Venous Catheters ► Acute Illness (immobilization) Prevention and Management of VTE in Cancer ► Sparse data specifically related to cancer patients was available until recently ► Cancer patients are a small subset (< 20%) in most of the largest trials of antithrombotic therapy ► Therefore, until the last two or three years, we needed to extrapolate from non-cancer patients, bearing in mind that cancer patients are in the highest risk groups Antithrombotic Therapy: Choices Nonpharmacologic Pharmacologic (Prophylaxis) (Prophylaxis & Treatment) Intermittent Elastic Unfractionated Low Molecular Pneumatic Stockings Heparin (UH) Weight Heparin Compression (LMWH) Inferior Vena Cava Oral Filter Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.? 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 Outcome P-value 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 Natural History of VTE in Cancer Surgery: The @RISTOS Registry ► Web-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patients Type of surgery • 52% General • 29% Urological • 19% Gynecologic 82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis Findings ► 2.1% incidence of clinically overt VTE (0.8% fatal) ► Most events occur after hospital discharge ► Most common cause of 30-day post-op death Agnelli, abstract OC191, ISTH 2003 Colorectal Cancer Resection Overall, 1% incidence of VTE with 3.8 fold mortality Transfused women 1.8-fold more likely to develop VTE than non-transfused women Association Between Transfusion and Venous Thromboembolism Stratified by Sex in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000 Variable Incidence of VTE, % P Value Stratified OR Adjusted (95% CI)* P Value Male Sex No Transfusion (n = 5683) 0.7 Referent Transfusion (n = 1156) 0.8 .84 0.9 (0.5-1.9) .85 Female Sex No Transfusion (n = 5565) 0.9 Referent Transfusion (n = 1610) 2.1 <.001 1.8 (1.2-2.6) .004 Nilsson: Arch Surg, 142;2007:126–132 VTE Risk Factors in Surgical Oncology Patients ► Age >40 years ► Cancer procoagulants ► Thrombophilias ► Adjuvant chemotherapy or hormonal treatment ► Complicated, lengthy surgery (tissue trauma, immobilization) ► Debilitation and slower recovery ► Indwelling venous access Surgical Prophylaxis LMWH better UFH better Asymptomatic DVT Clinical PE Clinical thromboembolism Cancer Death Non-cancer Major hemorrhage Total hemorrhage Wound hematoma Transfusion 0 1.0 2.0 3.0 4.0 Mismetti P et al. Br J Surg 2001;88:913–30 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 475 double-blind enoxaparin vs. UFH DVT Prophylaxis 2 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 20% 18.2% P>0.05 ENOXACAN Incidence of Outcome Event 14.7% 15% UFH 5000 U tid 10% N=319 enoxaparin 40 mg 2.9% 4.1% N=312 5% 0% VTE Major Bleeding ENOXACAN Study Group. Br J Surg 1997;84:1099–103 Prophylaxis in Surgical Patients 20% Canadian Colorectal 16.9% DVT Prophylaxis Incidence of Outcome Event 13.9% P=0.052 Trial 15% UFH 5000 U tid N=234 10% enoxaparin 40 mg N=241 5% 1.5% 2.7% 0% VTE Major Bleeding (Cancer) (All) McLeod R, et al. Ann Surg 2001;233:438-444 Prophylaxis in Surgical Patients Extended prophylaxis ► Abdominal or pelvic surgery for cancer ► LMWH for ~ 7 days vs. 28 days post-op ► Routine bilateral venography at ~day 28 Study N Design Regimens ENOXACAN 1 332 double-blind Enoxaparin vs. placebo Dalteparin vs. no FAME 198 Open-label prophylaxis 1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 2. Rasmussen M, et al (FAME) Blood 2003;102:56a Extended Prophylaxis in Surgical Patients 15% Incidence of Outcome Event 12.0% ENOXACAN II 10% P=0.02 placebo N=167 4.8% 5.1% enoxaparin 40 mg 5% 3.6% N=165 1.8% 0.6% 0% 0.4% NNT = 14 0% VTE Prox Any Major DVT 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. Gynecological Cancer Surgery ► Paucity of level I/II studies in this population ► Based on small historical studies: ● Postoperative risk of DVT/PE varies 12%–35% ● LDUH (5000 u bid) ineffective ● LDUH 5000 u tid reduces risk by 50%–60% ● Once-daily LMWH comparable to LDUH for efficacy and safety Gynecological Surgery Cochrane Systematic Review ► Meta-analysis of 8 randomized controlled trials ► Heparin reduces risk of DVT by 70% (95% CI 0.10–0.89) ► No evidence that anticoagulation reduces risk of PE ► No statistical difference between LDUH and LMWH in efficacy and bleeding Oates-Whitehead et al. Cochrane Database Syst Rev 2003;4:CD003679 Urological Cancer Surgery Poorly studied population Risk of VTE varies with type of surgery and diagnosis DVT PE Fatal PE Radical retropubic prostatectomy 1–3% 1–3% 0.6% Cystectomy 8% 2–4% 2% Radiological studies 51% 22% ► Small studies have suggested prophylaxis with either LDUH or LMWH is effective and safe ► Possible increased risk of pelvic hematoma and lymphocele formation Kibel, Loughlin. J Urol. 1995;153:1763-1774 Neurosurgery and VTE OBSERVATIONS ► Majority of patients undergoing neurosurgery for malignancy ► Risk of venographic VTE ~30%-40% ► High risk of intracranial or intraspinal hemorrhage ► Mechanical prophylaxis preferred method ► Use of anticoagulant prophylaxis remains controversial in this setting Neurosurgery and VTE Prophylaxis Meta-analysis of three (3) RCTs evaluating LMWH prophylaxis ES LMWH RR NNT/NNH P VTE 28.3% 17.5% 0.6 9 0.001 Proximal DVT 12.5% 6.2% 0.5 16 <0.01 Total bleeding 3.0% 6.1% 2.0 33 0.02 Major bleeding 1.3% 2.2% 1.7 115 0.30 ► One major bleeding event observed for every 7 proximal DVTs prevented with LMWH Iorio A, Agnelli G. Arch Intern Med. 2000;160:2327-2332 7th ACCP Consensus Guidelines Grade Recommendations for Cancer Patients Patients undergoing surgery should receive LDUH 5000 U tid 1A or LMWH > 3400 U daily Patients undergoing surgery may receive post-hospital 2A discharge prophylaxis with LMWH No routine prophylaxis to prevent thrombosis secondary to 2A central venous catheters, including LMWH (2B) and fixed- dose warfarin (1B) Patients hospitalized with an acute medical illness should 1A receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S Central Venous Catheters Thrombosis is a potential complication of central venous catheters, including these events: –Fibrin sheath formation –Superficial phlebitis –Ball-valve clot –Deep vein thrombosis (DVT) • Incidence up to 60% from historical data • ACCP guidelines recommended routine prophylaxis with low dose warfarin or LMWH Geerts W, et al. Chest 2001;119:132S-175S Prophylaxis for Venous Catheters Placebo-Controlled Trials Study Regimen N CRT (%) Reichardt* Dalteparin 5000 U od 285 11 (3.7) 2002 placebo 140 5 (3.4) Couban* Warfarin 1mg od 130 6 (4.6) 2002 placebo 125 5 (4.0) ETHICS† Enoxaparin 40 mg od 155 22 (14.2) 2004 placebo 155 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 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 Prophylaxis for Central Venous Access Devices Summary ► Recent studies demonstrate a low incidence of symptomatic catheter-related thrombosis (~4%) ► Routine prophylaxis is not warranted to prevent catheter-related thrombosis, but catheter patency rates/infections have not been studied ► Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for preventing symptomatic and asymptomatic thrombosis 7th ACCP Consensus Guidelines Grade Recommendations for Cancer Patients Patients undergoing surgery should receive LDUH 5000 U tid or 1A LMWH > 3400 U daily Patients undergoing surgery may receive post-hospital discharge 2A prophylaxis with LMWH No routine prophylaxis to prevent thrombosis secondary to 2A central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Patients hospitalized with an acute medical illness should receive 1A LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S Primary Prophylaxis in Cancer Radiotherapy in the Ambulatory Patient ► No recommendations from ACCP ► No data from randomized trials (RCTs) ► Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin- secreting adenocarcinomas-colorectal, pancreatic, lung, renal cell, ovarian) ► Recommendations extrapolated from other groups of patients if additional risk factors present (e.g. hemiparesis in brain tumors, etc.) Risk Factors for VTE in Medical Oncology Patients ► Tumor type ● Ovary, brain, pancreas, lung, colon ► Stage, grade, and extent of cancer ● Metastatic disease, venous stasis due to bulky disease ► Type of antineoplastic treatment ● Multiagent regimens, hormones, anti-VEGF, radiation ► Miscellaneous VTE risk factors ● Previous VTE, hospitalization, immobility, infection, thrombophilia Independent Risk Factors for DVT/PE Risk Factor/Characteristic O.R. Recent surgery w/ institutionalization 21.72 Trauma 12.69 Institutionalization without recent surgery 7.98 Malignancy with chemotherapy 6.53 Prior CVAD or pacemaker 5.55 Prior superficial vein thrombosis 4.32 Malignancy without chemotherapy 4.05 Neurologic disease w/ extremity paresis 3.04 Serious liver disease 0.10 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 0.2% treatment Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Non-Hodgkin’s lymphomas w/ chemo 3% Hodgkin’s disease w/ chemo 6% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-VEGF + chemo) 47% Wilms tumor (cavoatrial extension) 4% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Strategies for Thromboprophylaxis in Thalidomide Treated MM Patients Aspirin Warfarin Warfarin Therapy No prophylaxis LMWH (81 1mg/daily (INR 2 – 3) mg/d) 25% Weber, 2002 26% Cavo, 2002 T+ D in newly (24 pts) 7% Weber, (19 pts) diagnosed 2002 18% Rajkumar, 2004 patients 13% Cavo, 2004 (46 pts) (102 pts) (52 pts) 14.7% T+ dox in Zangari, 2004 newly 34.5% Zangari, 2004 31.4% Zangari, (68pts) diagnosed (87 pts) 2004 (35 pts) 17.8% 7% Minnema, patients Baz, 2004 (412 pts) 2004 (103 pts) T+dox at 16% Zangari, 2002 relapse (192 pts) MM-009/010: Thromboembolic Events 16 14 12 10 DVT 8 6 PE 4 2 0 Len + D(%) D (%) Len + D(%) D (%) MM-009 MM-010 Weber D. ASCO 2005 Annual Meeting Incidence of VTE: USA and Canada >Israel, Australia, and Europe ► rEPO used Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant more in USA Erythropoietin for the Treatment of Multiple Myeloma and Canada ► L+Dex: 23% Treatment Odds Ratio P Value VTE with EPO (95% CI) vs 5% w/o EPO Lenalidomide plus 3.51 (1.77-6.97) <0.001 ► Placebo + Dex: High-dose dexamethasone 7% VTE with EPO vs 1% Concomitant erythropoietin 3.21 (1.72-6.01) <0.001 without EPO Knight: N Engl J Med.2006,354:2079 Thrombotic Outcomes from rEPO or Darbopoietin Use in Cancer Patients Among 6,769 pts with cancer, RR for DVT with rEPO/Darbepo was increased by 67% (RR=1.67; 95% CI 1.35 to 2.06) Bohlius: The Cochrane Library, Volume (4).2006 Standard Treatment of VTE Can We Do Better Than This? Initial treatment 5 to 7 days LMWH or UFH Long-term therapy > 3 months Vitamin K antagonist (INR 2.0 - 3.0) Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies (UH/VKA vs. LMWH/VKA) Recurrent VTE Events per 100 patient years P value Malignant Non- Malignant 27.1 9.0 0.003 Hutten et.al. J Clin Oncol 2000;18:3078 Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies Major Bleeding Events per 100 patient years P-value Non- Malignant malignant 13.3 2.1 0.002 Hutten et.al. J Clin Oncol 2000;18:3078 Oral Anticoagulant Therapy in Cancer Patients: Problematic ► Warfarin (Coumadin®) therapy is complicated by: ● Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. ● Frequent interruptions for thrombocytopenia and procedures ● Difficulty in venous access for monitoring ● Increased risk of both recurrence and bleeding ► Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why? CLOT: Landmark Cancer/VTE Trial Dalteparin Dalteparin CANCER PATIENTS WITH Randomization ACUTE DVT or PE Oral Dalteparin Anticoagulant [N = 677] ► Primary Endpoints: Recurrent VTE and Bleeding ► Secondary Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 Landmark CLOT Cancer Trial Reduction in Recurrent VTE Probability of Recurrent VTE, % 25 Risk reduction = 52% Recurrent VTE p-value = 0.0017 20 15 OAC 10 Dalteparin 5 0 0 30 60 90 120 150 180 210 Lee, Levine, Kakkar, Rickles et.al. N Engl Days Post Randomization J Med, 2003;349:146 Bleeding Events in CLOT Dalteparin OAC N=335 P-value* N=338 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 Treatment of Cancer-Associated VTE Length Major of Recurrent Death Study Design N Bleeding Therapy VTE (%) (%) (%) (Months) CLOT Trial Dalteparin 336 9 0.002 6 NS 39 NS (Lee 2003) OAC 6 336 17 4 41 CANTHENOX Enoxaparin 67 11 0.09 7 0.09 11 0.03 (Meyer 2002) OAC 3 71 21 16 23 LITE Tinzaparin 80 6 0.03 6 NS 23 NS (Hull ISTH 2003) OAC 3 87 11 8 22 ONCENOX Enox (Low) 32 3.4 NS NS NR (Deitcher ISTH Enox (High) 6 36 3.1 2003) OAC 34 6.7 Treatment and 2° Prevention of VTE in Cancer – Bottom Line New Development ► New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendation—ACCP) ► Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP) Buller et.al. Chest Suppl 2004;126:401S-428S CLOT 12-month Mortality All Patients 100 90 Probability of Survival, % 80 70 Dalteparin 60 50 OAC 40 30 20 10 HR 0.94 P-value = 0.40 0 0 30 60 90 120 180 240 300 360 Days Post Randomization Lee A, et al. ASCO. 2003 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Patients Without Metastases (N=150) 100 90 Dalteparin Probability of Survival, % 80 70 60 OAC 50 40 30 20 10 HR = 0.50 P-value = 0.03 0 0 30 60 90 120 150 180 240 300 360 Days Post Randomization Lee A, et al. ASCO. 2003 LMWH for Small Cell Lung Cancer Turkish Study ► 84 patients randomized: CEV +/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemo + Chemo alone P-value Dalteparin 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. VTE Prophylaxis Is Underused in Patients With Cancer Cancer: Major 100 FRONTLINE Survey1— Surgery2 Rate of Appropriate Prophylaxis, % 3891 Clinician 89 90 Respondents 80 Cancer: 70 Surgical Major Confirmed DVT 60 52 Abdominothoracic (Inpatients)5 Surgery (Elderly)3 Medical 50 Inpatients4 42 38 40 33 Cancer: 30 Medical 20 10 5 0 FRONTLINE FRONTLINE: Stratton Bratzler Rahim DVT FREE Surgical Medical 1. Kakkar AK et al. Oncologist. 2003;8:381-388 2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 4. Rahim SA et al. Thromb Res. 2003;111:215-219 3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262 Cancer and Venous Thrombosis VTE Prophylaxis in the Cancer Patient and Beyond Guidelines and Implications for Day-to-day Practice Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Learning Objectives ► Scope of the problem ► Tools in the toolkit: drugs, devices ► Guidelines: ASCO, NCCN, ACCP ► Implementation: voluntary or mandatory Scope of the Problem ► Epidemiology ► Long-term sequelae ► Failure to prophylax Medical Service patients, especially Medical Oncology patients Annual Patients At-Risk For VTE U.S. Hospitals ► 7.7 million Medical Service inpatients ► 4.3 million Surgical Service inpatients ► Based upon ACCP guidelines for VTE prophylaxis Anderson FA Jr, et al. Am J Hematol 2007; 82: 777-782 Patients At-Risk For VTE An 86-year-old man underwent successful gastrectomy for newly diagnosed stomach cancer. He was recovering uneventfully. On POD #4, he had a witnessed cardiac arrest while transferring from commode to bed. ACLS yielded repeated PEA. After 35 minutes, the code was ―called.‖ An autopsy was obtained. ICOPER Cumulative Mortality 25 20 17.5% Mortality (%) 15 10 5 0 7 14 30 60 90 Days From Diagnosis Lancet 1999; 353: 1386-1389 Progression Of Chronic Venous Insufficiency VTE Prophylaxis: Underused Implementation of VTE prophylaxis continues to be problematic, despite detailed North American and European Consensus guidelines. The Amin Report VTE Prophylaxis Rates in USA ► Studied 196,104 Medical Service discharges from 227 hospitals. ► VTE prophylaxis rate was 62%. ► ACCP-deemed appropriate prophylaxis rate was 34%. J Thromb Haemostas 2007; 5: 1610-6) The Amin Report Medical Oncology Patients ► Of 196,104 Medical Service discharges, 30,708 were medical oncology patients. ► Only 56% received any VTE prophylaxis. ► Only 28% received ACCP-deemed appropriate prophylaxis J Thromb Haemostas 2007; 5: 1610-6 Medical Patient Prophylaxis In Canada ► Studied 1,894 Medical Service discharges from 29 hospitals. ► VTE prophylaxis was indicated in 90% of patients. ► ACCP-deemed appropriate prophylaxis rate was 16%. Thrombosis Research 2007; 119: 145-155 Cancer: Medical Patient Prophylaxis In Canada ► 19% of the 1,894 Medical Service patients had cancer, either as the admission diagnosis (9%) or an active comorbid condition (19%). ► The most common cancers were: lung, breast, prostate, and colon. Thrombosis Research 2007; 119: 145-155 Cancer: Decreased Likelihood Of VTE Prophylaxis In Canada ► Multivariable analysis: 60% less likely to prescribe VTE prophylaxis (95% CI: 32% to 76% less likely; p=0.0007). ► Perhaps MDs fear an increased risk of bleeding in cancer patients? Thrombosis Research 2007; 119: 145-155 VTE in Cancer Patients ► Prospective registry of 5,451 consecutive ultrasound-confirmed DVT patients at 183 U.S. institutions. (Am J Cardiol 2004; 93:259-262 ) ► Cancer occurred in 1,768 (39%), of whom 1,096 (62%) had active cancer, of whom 599 (55%) were receiving chemotherapy. Thromb Haemost 2007; 98: 656-661 VTE in Cancer Patients ► Lung, colorectal, and breast cancer were the most common cancers. ► Cancer patients less often received VTE prophylaxis (28%) compared with the other DVT Registry patients (35%) (p<0.0001). ► Cancer patients were more likely to receive IVC filters (22% vs. 14%; p<0.0001) than non-cancer patients. Thromb Haemost 2007; 98: 656-661 Tools in the Toolkit ► LMWH, Unfractionated Heparin, Fondaparinux, Warfarin ► IVC Filters ► Graduated Compression Stockings and Intermittent Pneumatic Compression Devices VTE Prophylaxis In 19,958 Medical Patients/ 9 Studies (Meta-analysis) ► 62% reduction in fatal PE ► 57% reduction in fatal or nonfatal PE ► 53% reduction in DVT Dentali F, et al. Ann Intern Med 2007; 146: 278-288 Dalteparin Prophylaxis in 3,706 Medical Patients Cancer Subgroup ► Dalteparin 5,000 U/d vs. placebo ► 6 of 72 placebo patients (8.3%) developed VTE, compared with 2 of 65 dalteparin patients (3.1%) ► Dalteparin was effective in all subgroups. Vascular Medicine 2007; 12: 123-128 Filters Filter insertion has increased, especially retrievable filters. Filters prevent PE but increase DVT rate (and do not halt the thrombotic process). Main indications: 1) Severe bleeding that precludes anticoagulation 2) Recurrent PE despite therapeutic anticoagulation 3) Prophylaxis Retrievable Filters Prospective Series (N=228) ► Retrieval attempted in only 25% ► Filter tilting: 5.7% ► Puncture site hematoma: 4.2% ► Filter migration: 1.4% ► Infection: 0.9% ► DVT: 15% ► Fatal PE: 2.3% Mismetti P et al. Chest 2007; 131: 223-229 Intermittent Pneumatic Compression Meta-analysis In Postop Patients ► 2,270 patients in 15 randomized trials ► IPC devices reduced DVT risk by 60% (Relative Risk 0.40, 95% CI 0.29-0.56, p< 0.001) Urbankova J. Thromb Haemost 2005; 94: 1181-5 Guidelines ► ASCO ► NCCN ► ACCP National Comprehensive Cancer Network (NCCN) ► The NCCN ―recommends prophylactic anticoagulation for all inpatients with a diagnosis of active cancer who do not have a contraindication.‖ ► ―Anticoagulation should be administered throughout hospitalization.‖ ► ―VTE prophylaxis after hospital discharge should be strongly considered.‖ J NCCN 2006; 4: 838-869 American Society Of Clinical Oncology (ASCO) ► ―Consider all hospitalized cancer patients for VTE prophylaxis with anticoagulants, in absence of bleeding…‖ ► ―Give routine prophylaxis to outpatients receiving thalidomide or lenalidomide.‖ ► ―LMWH represents the preferred agent.‖ ► ―Impact of anticoagulants on cancer patient survival requires additional study.‖ JCO 2007; 25: 5490-5505 American College Of Chest Physicians (ACCP) ► VTE prophylaxis while hospitalized ► Treat acute DVT or PE with LMWH as monotherapy without warfarin for at least 3-6 months ► Continue anticoagulant therapy indefinitely or until the cancer resolves. CHEST 2004; 126: 338S-400S CHEST 2004; 126: 401S-428S Implementation ► Electronic (computerized) alerts to physicians ► Human Alerts ► JCAHO ► Medicare payments ► ―Opt out‖ strategies Implementation The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing ―sudden cardiac death‖ emphasize the need for improved preventive efforts. Failure to institute prophylaxis is a much bigger problem with Medical Service patients, especially medical oncology patients, than Surgical Service patients. Implementation We have initiated trials to change MD behavior and improve implementation of VTE prophylaxis—not trials of specific types of prophylaxis—eAlert RCT, eAlert cohort, human Alert, 3-screen eAlert. Quality Improvement Initiative to Improve Clinical Practice Randomized (―eAlert‖) controlled trial to issue or withhold electronic alerts to MDs whose high-risk patients were not receiving DVT prophylaxis. Kucher N, et al. NEJM 2005;352:969-977 Definition of ―High Risk‖ VTE risk score ≥ 4 points: ► Cancer 3 (ICD codes) ► Prior VTE 3 (ICD codes) ► Hypercoagulability 3 (Leiden, ACLA) ► Major surgery 2 (> 60 minutes) ► Bed rest 1 (―bed rest‖ order) ► Advanced age 1 (> 70 years) ► Obesity 1 (BMI > 29 kg/m2) ► HRT/OC 1 (order entry) DVT Prophylaxis at BWH ► There were 13,922 patients with a VTE risk score ≥ 4 from September 2000 to January 2004 ► 11,416 (82%) patients received DVT prophylaxis ► 2506 (18%) patients did not receive DVT prophylaxis Kucher N, et al. NEJM 2005;352:969-977 Randomization VTE risk score > 4 No prophylaxis N = 2506 INTERVENTION CONTROL Single alert No alert n = 1255 n = 1251 Kucher N, et al. NEJM 2005;352:969-977 Baseline Characteristics ► Median age = 62.5 years ► Medical services: 83% ► Surgical services: 17% ► Comorbidities ● Cancer: 80% ● Hypertension: 34% ● Infection: 30% ● Prior VTE: 20% Kucher N, et al. NEJM 2005;352:969-977 90-Day Primary Endpoint Intervent. Control Hazard Ratio p N=1255 N=1251 (95% CI) Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001 Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004 Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08 Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10 UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90 Kucher N, et al. NEJM 2005;352:969-977 Primary End Point %Freedom from DVT/ PE 100 98 Intervention 96 94 92 Control 90 0 30 60 90 Number at risk Time (days) Intervention 1255 977 900 853 Control 1251 976 893 839 Kucher N, et al. NEJM 2005;352:969-977 Conclusions Electronic alerts 1. Facilitated the detection of patients at high risk of DVT/PE 2. Increased the rate of DVT prophylaxis from 14.5% to 33.5% 3. Reduced the incidence of DVT/PE by 41%, without increasing bleeding Kucher N, et al. NEJM 2005;352:969-977 JCAHO Performance Measures Prophylaxis (Approved in May 2006) ► Surgery patients with recommended VTE prophylaxis ordered ► Surgery patients who received appropriate VTE prophylaxis within 24 hours preop to 24 hours after surgery Risk Assessment/Prophylaxis (Pending) ► VTE risk assessment/ prophylaxis within 24 hours of hospital admission ► VTE risk assessment/ prophylaxis within 24 hours of transfer to ICU Quality Measures ►2 measures are in current use ● SCIP VTE 1: Was DVT/PE prophylaxis ordered? ● SCIP VTE 2: Was DVT/PE prophylaxis received? ►Implementation by Medicare ● Hospitals must report on the 2 measures beginning January 2007 to receive full payment in 2008 ● Medicare adjusted rate increase will be reduced by 2.0% for noncompliance Default (―Opt Out‖) Options ► Flu, pneumonia vaccines. ► Remove urinary catheters within 72h. ► Head of bed at 30-45 angle in ICU. ► Interrupt sedatives daily: vented pts. ► Prophylax against VTE. Halpern SD et al. NEJM 2007; 357: 1340 Summary 1. Cancer and VTE is a disabling and at times deadly combination. 2. VTE prophylaxis is safe and effective. 3. ASCO, NCCN, and ACCP endorse VTE prophylaxis in cancer patients. 4. For unclear reasons, VTE prophylaxis is underutilized. 5. VTE prophylaxis of cancer patients will increase, through a combination of voluntary initiatives and regulatory mandates.
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