Welcome to this Science-to-Strategy Summit

Welcome to this Science-to-Strategy Summit

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

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

Program Educational Objectives
As a result of this session, physicians will be able to: Review recent trials, research, and expert analysis of issues focused on thrombosis and cancer. Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer. Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT. Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis. Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer. Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy.

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

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

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 Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Mary’s School of Medicine and Dentistry The Thrombosis Research Institute London, UK

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

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

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

Comorbidity Connection
Overview Comorbidity Connection

Acute Medical Illness and VTE
Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Acute Medical Relative Risk Illness Risk X2 P Value Heart failure ( ) NYHA class III ( ) NYHA class IV ( ) Acute respiratory disease ( ) infectious disease ( ) rheumatic disease ( ) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

Acute Medical Illness and VTE
Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) Risk Factor Odds Ratio X2 (95% CI) Age >75 y ( ) Cancer ( ) 0.08 Previous VTE ( ) 0.02 Acute infectious disease ( ) 0.02 Chronic respiratory disease ( ) 0.02 Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:

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): Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

Predictors of First Overall VTE Recurrence
Baseline Hazard Ratio Characteristic (95% CI) Age 1.17 ( ) Body Mass Index 1.24 ( ) Neurologic disease with 1.87 ( ) extremity paresis Malignant neoplasm None With chemotherapy 4.24 ( ) Without chemotherapy 2.21 ( ) Heit J, Mohr D, et al. Arch Intern Med. 2000;160:

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

Meta-analysis of DVT Treatment Studies
Author Year No. of studies Cancer mortality UFH LMWH Green 1992 2 21/67 (31%) 7/62 (11%) Siragusa 1995 13 23/81 (28%) 10/74 (14%)

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

Kaplan–Meier survival curves for all ITT patients in dalteparin and placebo groups
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Dalteparin Placebo Kaplan–Meier survival distribution function estimate Time from randomisation (months) No. at risk: Dalteparin Placebo Kakkar AK, et al. J Clin Oncol. 2004;22:

Survival Analysis: Good Prognosis Patients
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.0 Dalteparin Placebo Kaplan–Meier survival distribution estimate Time from randomisation (months) No. at risk: Placebo Dalteparin Kakkar AK, et al. J Clin Oncol. 2004;22:

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

SCLC Study Survival Curves
1.0 0.8 0.6 0.4 0.2 0.0 5 10 15 20 25 30 35 40 Months after randomization Probability of survival Overall population p=0.01 Good prognosis population limited disease 1.0 0.8 0.6 0.4 0.2 0.0 5 10 15 20 25 30 35 40 Months after randomization Probability of survival p=0.007 Dalteparin Dalteparin Placebo Placebo Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.

CLOT Survival Curves Overall population Good prognosis population
without metastases 100 10 20 30 40 50 60 70 80 90 100 120 150 180 210 240 270 300 330 360 390 90 Dalteparin 80 p=0.62 70 OAC 60 Dalteparin Probability of survival (%) Probability of survival (%) 50 OAC 40 p=0.03 30 20 10 30 60 90 120 150 180 210 240 270 300 330 360 390 Days after randomization Days after randomization Lee, et.al. N Engl J Med, 2003;349:146

MALT Survival Curves Overall population Good prognosis population
>6 months survival 1.0 1.0 0.8 0.8 p=0.021 p=0.010 0.6 0.6 Probability of Survival Probability of Survival 0.4 0.4 Nadroparin 0.2 0.2 Nadroparin Placebo Placebo 0.0 0.0 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96 Months after randomization Months after randomization Klerk CPW, et al. J Clin Oncol. 2005;23:

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

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

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

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

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

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

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

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

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

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

Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor The cytoplasmic tail of TF, which contains three serine residues, appears to play a role in regulating VEGF expression in human cancer cells, perhaps by mediating signal transduction 4. Data consistent with new mechanism(s) by which TF signals VEGF synthesis in human cancer cells; may provide insight into the relationship between clotting and cancer Abe et.al. Proc Nat Acad Sci 1999;96:

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

“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:

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

Blood Coagulation Parameters in Mice Transduced with the MET Oncogene
Transgene Parameter Time after Transduction (days) GFP _________ MET Platelets (x103) D-dimer (µg/ml) PT (s) ________________ < < <0.05 _______________________________ <

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:

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

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

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:

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

“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:

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

“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:

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

A Systematic Overview of VTE Prophylaxis In The Setting of Cancer
Clotting, Cancer, and Controversies 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 Let’s continue examining the association between DVT/PE and cancer. Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE. As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer. Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer. Ambrus JL et al. J Med. 1975;6:61-64 Donati MB. Haemostasis. 1994;24: Johnson MJ et al. Clin Lab Haem. 1999;21:51-54 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
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
0.00 0.20 0.40 1.00 0.80 0.60 DVT/PE and Malignant Disease Malignant Disease DVT/PE Only Nonmalignant Disease Number of Days Probability of Death Levitan N, et al. Medicine 1999;78:285

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

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

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

Prevention and Management of VTE in Cancer
Sparse data specifically related to cancer patients was available until recently Cancer patients are a small subset (< 20%) in most of the largest trials of antithrombotic therapy Therefore, until the last two or three years, we needed to extrapolate from non-cancer patients, bearing in mind that cancer patients are in the highest risk groups

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

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 N=16,954 Cancer N=6124 P-value Post-op VTE 0.61% 1.26% <0.0001 Non-fatal PE 0.27% 0.54% <0.0003 Autopsy PE 0.11% 0.41% Death 0.71% 3.14% Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732

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, 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) ( ) .85 Female Sex No Transfusion (n = 5565) 0.9 Referent Transfusion (n = 1610) 2.1 < ( ) .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 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 DVT Prophylaxis 2 475 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:

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

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

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 II 332 Double-blind Enoxaparin vs. placebo FAME (subgroup) 198 Open-label Dalteparin vs. no prophylaxis 1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346: 2. Rasmussen M, et al (FAME) Blood 2003;102:56a

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

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 Nov;4(11): 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 Small studies have suggested prophylaxis with either LDUH or LMWH is effective and safe Possible increased risk of pelvic hematoma and lymphocele formation DVT PE Fatal PE Radical retropubic prostatectomy 1–3% 0.6% Cystectomy 8% 2–4% 2% Radiological studies 51% 22% Kibel, Loughlin. J Urol. 1995;153:

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 One major bleeding event observed for every 7 proximal DVTs prevented with LMWH ES LMWH RR NNT/NNH P VTE 28.3% 17.5% 0.6 9 0.001 Proximal DVT 12.5% 6.2% 0.5 16 <0.01 Total bleeding 3.0% 6.1% 2.0 33 0.02 Major bleeding 1.3% 2.2% 1.7 115 0.30 Iorio A, Agnelli G. Arch Intern Med. 2000;160:

7th ACCP Consensus Guidelines
Grade Recommendations for Cancer Patients 1A Patients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U daily 2A Patients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Patients hospitalized with an acute medical illness should receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S

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

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– % 3.0– % > % Masci et al. J Clin Oncol. 2003;21:

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 1A Patients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U daily 2A Patients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) Patients hospitalized with an acute medical illness should receive LDUH or LMWH Geerts W, et al. Chest 2004; 126: 338S-400S

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 Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study. This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data. Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included. What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE. Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE. Heit JA et al. Thromb Haemost. 2001;86:

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

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

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

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

Thrombotic Outcomes from rEPO or Darbopoietin Use in Cancer Patients
Among 6,769 pts with cancer, RR for DVT with rEPO/Darbepo was increased by 67% (RR=1.67; 95% CI 1.35 to 2.06) Bohlius: The Cochrane Library, Volume (4).2006

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

Events per 100 patient years
Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies (UH/VKA vs. LMWH/VKA) Recurrent VTE Events per 100 patient years P value Malignant Non- Malignant 27.1 9.0 0.003 Hutten et.al. J Clin Oncol 2000;18:3078

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

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 ACUTE DVT or PE Randomization Dalteparin Oral 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
5 10 15 20 25 Days Post Randomization 30 60 90 120 150 180 210 Probability of Recurrent VTE, % Risk reduction = 52% p-value = Dalteparin OAC Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

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

Treatment of Cancer-Associated VTE
Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding (%) Death CLOT Trial (Lee 2003) Dalteparin OAC 6 336 9 17 4 39 41 CANTHENOX (Meyer 2002) Enoxaparin 3 67 71 11 21 7 16 23 LITE (Hull ISTH 2003) Tinzaparin 80 87 8 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) 32 36 34 3.4 3.1 6.7 NS 0.002 NS 0.09 0.09 0.03 0.03 NS NS 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) 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
10 20 30 40 50 60 70 80 90 100 120 180 240 300 360 Dalteparin OAC HR 0.94 P-value = 0.40 Days Post Randomization Probability of Survival, % Lee A, et al. ASCO. 2003

Anti-Tumor Effects of LMWH
CLOT 12-month Mortality Patients Without Metastases (N=150) 10 20 30 40 50 60 70 80 90 100 Dalteparin OAC Probability of Survival, % HR = P-value = 0.03 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 + Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 Median survival, m 13.0 8.0 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266.

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

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

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

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

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

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

Extended Thromboprophylaxis in Cancer Surgery
NNT=14 P<0.03 NNT= 9 FAME ENOXACAN II Berquvist D et al NEJM 2002;346:975-80 Rasmusan M et al Blood 2003;102;52a

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

Thromboprophylaxis for CVC
Prior studies with ~ 5% incidence of symptomatic catheter-related thrombosis Regimen N Cath Thrombosis (%) Kathaus 2006 dalteparin 5000U qd placebo 285 140 11 (3.7) 5 (3.4) Couban 2005 warfarin 1mg QD Placebo 130 125 6 (4.6) 5 (4.0) Verso 2005 enoxaparin 40mg qd 155 22 (14.2) 28 (18.1) Karthaus et al Oncol 2006;17: Couban et al JCO 2006: 23:4063-8 Verso et al JCO 2006;23:

Thromboprophylaxis in Hospitalized Medical Cancer Patients
There are no randomized trials in hospitalzed medical oncology patients Randomized, placebo controlled trials in acutely ill hospitalized medical patients (of which cancer patients area percentage) Pt no 866 2991 644 Cancer (%) 14 5

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

Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t?
Meta-analysis: 12 RCTs DVT, PE, all VTE events, Bleeding Proximal DVT plus PE BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: 0.86 events per 1,000 patient days P=0.05 NNT 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing King CS et al. CHEST 2007;131:

Incidence and Economic Implications of HIT
3/27/2017 9:32 PM Incidence and Economic Implications of HIT N = 10,121 P = 0.037 P < 0.001 Retrospective analysis with a nested case-control Performed at a University-affiliated tertiary-care center Doses were defined as 10, ,000 units/day for UFH and mg /day for LMWH (enoxaparin was the only LMWH on formulary) Assumed equal efficacy and bleed rates among the agents Note: $ values reported on this slide are hospital costs (not charges!) Creekmore FM, et al. Pharmacotherapy. 2006;26: 114

2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A) General, Gynecologic, Urologic Surgery Low Dose Unfractionated Heparin 5,000 units TID LMWH > 3,400 units Daily Dalteparin 5,000 units Enoxaparin 40 mg Tinzaparin 4,500 units GCS and/or IPC Surgical patients may receive post-discharge prophylaxis with LMWH (Grade 2A) No routine prophylaxis for central venous catheters, including LMWH (Grade 2B) and fixed-dose warfarin (Grade 1B) Cancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A) Low Dose Unfractionated Heparin LMWH Contraindication to anticoagulant prophylaxis (Grade 1C+) GCS or IPC [Geerts. Chest.Sept.2004/ p371S/c1/line 1-8] [Geerts/ p338S/c1/Abstract/ line 4-8] In the 2004 guidelines on venous thromboembolism prophylaxis endorsed by the ACCP, Geerts and coworkers reviewed evidence from 11 studies on the use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in patients with general medical conditions1 ACCP Grade 1A treatment options for deep vein thrombosis (DVT) prophylaxis in general medical patients with clinical risk factors for DVT/PE (including active cancer, bed rest, heart failure, severe lung disease, prior DVT/PE, sepsis, acute neurologic disease, or IBD)1 LMWH Low-dose UFH The investigators assigned a Grade of 1A to 2 for treatment options, defined as follows:1 Grade 1: Benefits of a given intervention are certain to outweigh the risks, burdens, and costs of the intervention Grade 2: Less certainty that the benefits outweigh the risks, burdens, and costs Methodological quality of evidence subcategorized by letters A-C A: Randomized clinical trials (RCTs) with consistent results B: RCTs with inconsistent results C: Observational studies, generalizations from single patient group in an RCT compared to a similar patient group not in the RCT. More compelling evidence in this category is graded C+ [1/Geerts. Chest.Sept.2004/ p371S/c1/line 1-8] [1/Geerts/ p338S/c1/Abstract/ line 4-8] Geerts WH et al. Chest. 2004;126(suppl):338S-400S ___________________________________________________________________________________ Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl):338S-400S. 115

NCCN Practice Guidelines in VTE Disease
At Risk Population Initial Prophylaxis Prophylactic anticoagulation therapy (category 1) + sequential compression device (SCD) Adult patient Diagnosis or clinical suspicion of cancer Inpatient NO Relative contra-indication to anticoagulation treatment Mechanical prophylaxis (options) - SCD - Graduated compression stockings YES Modifiable risk factors: Lifestyle, smoking, tobacco, obesity, activity level/exercise RISK FACTOR ASSESSMENT Age Prior VTE Familial thrombophilia Active cancer Trauma Major surgical procedures Acute or chronic medical illness requiring hospitalization or prolonged bed rest Central venous catheter/IV catheter Congestive heart failure Pregnancy Regional bulky lymphadenopathy with extrinsic vascular compression AGENTS ASSOCIATED WITH INCREASED RISK Chemotherapy Exogenous estrogen compounds - HRT - Oral contraceptives - Tamoxifen/Raloxifene - Diethystilbestrol Thalidomide/lenalidomide

Inpatient Prophylactic Anticoagulation Therapy LMWH - Dalteparin 5,000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily or units/kg cubcutaneous daily Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily Unfractioned heparin 5,000 units subcutaneous 3 times daily

Relative Contraindications to Prophylactic or Therapeutic Anticoagulation Recent CNS bleed, intracranial or spinal lesion at high risk for bleeding Active bleeding (major): more than 2 units transfused in 24 hours Chronic, clinically significant measurable bleeding > 48 hours Thrombocytopenia (platelets < 50,000/mcL) Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) Recent major operation at high risk for bleeding Underlying coagulopathy Clotting factor abnormalities - Elevated PT or aPTT (excluding lupus inhibitors) - Spinal anesthesia/lumbar puncture High risk for falls

Compliance With ACCP VTE Prophylaxis Guidelines Is Poor
Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group 9.9% 6.7% 35,124 62,012 5,000 10,000 70,000 Number of patients At risk for DVT/PE Received compliant care 15.3% 12.7% 52.4% 2324 9175 1388 Orthopedic Surgery At-risk Medical Conditions General Surgery Urologic Surgery Gynecologic Surgery [Yu.AHA.May [poster]p1/Fig 1, Fig 2] [1/Yu.AHA.May [poster]p1/Fig 1, Fig 2] A study by Yu and colleagues showed that even when risk is recognized, the thromboprophylactic strategy chosen may be inadequate The study assessed compliance with the 2001 ACCP guidelines for prophylaxis for DVT and PE. The authors looked at records from more than 120,000 adult hospital admissions between January 2001 and March 20051 Orthopedic surgery patients (n=2324) had the highest rate of compliance, 52.4%1 The rate of compliance for patients with at-risk medical conditions (n=62,012) was 15.3%. For general surgery patients (n=35,124), the rate of compliance was 12.7%1 For urologic (n=1338) and gynecologic (n=9175) surgery patients, the rates of compliance were 9.9% and 6.7%, respectively1 Overall, only 23.4% of patients received some form of prophylaxis and only 13.3% of patients received guideline-recommended prophylaxis1 Thus, only about a quarter of patients received prophylaxis at all, and of those only about half received the prophylaxis recommended by ACCP guidelines for patients with their condition1 Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 _______________________________________________________________________________ Yu H-T, Dylan ML, Lin J, Dubois RW. Prophylaxis of venous thromboembolism: do providers follow guidelines [poster]? Presented at the American Heart Association 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, May 7-9, 2006; Washington, DC. 119

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

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

Predictors of the Use of Thromboprophylaxis
Effect Odds Ratio (95% CI) Malignancy 0.40 Others Infection Bleeding Risk Gender Hospital Size Age LOS Cardiovascular Disease Internal Medicine Respiratory AMC Duration of Immobility VTE Risk Factors Kahn SR et Al. Thromb Res 2007; 119: Odds Ratio

Adjusted Odds Ratio (95% CI) Bleeding disorder 5.11 (2.38, 10.98)
Independent factors present at admission for in-hospital bleeding – multivariate analysis (IMPROVE Registry) Adjusted Odds Ratio (95% CI) Bleeding disorder (2.38, 10.98) Active G-duodenal ulcer (2.86, 8.50) Adm platelets<50 x (1.67, 5.41) Hepatic failure (1.57, 4.95) ICU/CCU stay (1.60, 3.63) Current cancer (1.39, 2.85) Central venous catheter (1.33, 2.95) Age 85 years (1.29, 2.85) S. creatinine ≥2.5 mg/dL (1.26, 2.79) Decousus H et al Blood 2005

Computer Reminder System
Computer program linked to patient database to identify consecutive hospitalized patients at risk for VTE Patients randomized to intervention group or control group In the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxis Point scale for VTE risk Major risk: Cancer, prior VTE, hypercoagulability (3 points) Intermediate risk: Major surgery (2 points) Minor risk: Advanced age, obesity, bedrest, HRT, use of oral contraceptives (1 point) VTE prophylaxis (graduated elastic stockings, IPC, UFH, LMWH, warfarin) Kucher N, et al. N Engl J Med. 2005;352:969-77 124

Electronic Alerts to Prevent VTE
Intervention group Freedom from DVT or PE (%) Control group P<0.001 Time (days) Number at risk Intervention group 1, Control group 1, Kucher N, et al. N Engl J Med. 2005;352:969-77 125

VTE Risk Assessment for Hospitalized Medical Patients
Does the patient have one of the following acute medical illnesses/conditions? Evidence-based: Acute MI Acute heart failure—NYHA III/IV Active cancer requiring therapy Severe infection/sepsis Respiratory disease (respiratory failure with/without mechanical ventilation, exacerbations of chronic respiratory disease) Rheumatic disease (including acute arthritis of lower extremities and vertebral compression) Ischemic stroke Paraplegia Consensus view only: Inflammatory disorder with immobility Inflammatory bowel disease YES Does the patient have one of the following risk factors? Evidence-based in acutely ill medical patients: History of VTE History of malignancy Concurrent acute infectious disease Age > 75 years Consensus view only: Prolonged immobility Age > 60 years Varicose veins Obesity Hormone therapy Pregnancy/postpartum Nephrotic syndrome Dehydration Thrombopilia Thrombocytosis All medical patients should be routinely assessed and considered for thromboprophylaxis Is the patient > 40 years old with acute medical illness and reduced mobility? Cohen A et al Thromb Haemost 2005;94(4):750-9

VTE Risk Assessment for Hospitalized Medical Patients
Is pharmacological thromboprophylaxis contraindicated? YES No evidence for the benefits of thromboprophylaxis. However, patients should be considered for thromboprophylaxis on a case-by-case basis NO Mechanical thromboprophylaxis with graduated compression stockings or intermittent pneumatic compression is recommended YES LMWH (enoxaparin 40 mg o.d. or dalteparin 5000 IU o.d.) or UFH (5000 IU t.i.d.) (LMWH preferred due to better safety profile) NO Cohen A et al Thromb Haemost 2005;94(4):750-9.

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

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