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  • 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.
  • 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)
  • 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 4.05. 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.
  • Slide #6
  • 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 site 1 Data from 3891 completed questionnaires were available for analysis 1 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 patients 1 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 patients 2 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 patients 3 A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients 4 In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis 5 [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] [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, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist . 2003;8:381-388. 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;160:334-340. 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;158:1909-1912. 4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res . 2003;111:215-219. 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;93:259-262.
  • 10/29/10 12:01 Retrospective analysis with a nested case-control Performed at a University-affiliated tertiary-care center Doses were defined as 10,000 -15,000 units/day for UFH and 40-60 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!)
  • 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 conditions 1 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+ ___________________________________________________________________________________ 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. [Geerts. Chest.Sept.2004/ p371S/c1/line 1-8] [Geerts/ p338S/c1/Abstract/ line 4-8] [1/Geerts. Chest.Sept.2004/ p371S/c1/line 1-8] [1/Geerts/ p338S/c1/Abstract/ line 4-8]
  • 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 2005 1 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%, respectively 1 Overall, only 23.4% of patients received some form of prophylaxis and only 13.3% of patients received guideline-recommended prophylaxis 1 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 condition 1 [Yu.AHA.May.2006 [poster]p1/Fig 1, Fig 2] [1/Yu.AHA.May.2006 [poster]p1/Fig 1, Fig 2] _______________________________________________________________________________ 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.

slides slides Presentation Transcript

  • Welcome to this Science-to-Strategy Summit
  • Critical Challenges and Landmark Advances in Thrombosis Management The Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Oncology Practice Clotting, Cancer, and Controversies Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Mary’s School of Medicine and Dentistry The Thrombosis Research Institute London, UK
  • CME-accredited symposium jointly sponsored by the Postgraduate Institute of Medicine and CMEducation Resources Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview
  • 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
    • 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 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 White R. Circulation . 2003;107:I-4 –I-8.) Variable Finding Seasonal Variation Possibly more common in winter and less common in summer Risk Factors 25% to 50% “idiopathic” 15%–25% associated with cancer ; 20% following surgery (3 mo.) Recurrent VTE 6-month incidence: 7%; higher rate in patients with cancer Recurrent PE more likely after PE than after DVT Death After Treated VTE 30 day incidence 6% after incident DVT 30 day incidence 12% after PE Death strongly associated with cancer , age, and cardiovascular disease
  • Epidemiology of VTE White R. Circulation . 2003;107:I-4 –I-8.)
    • One major risk factor for VTE is ethnicity, with a significantly higher incidence among Caucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders.
    • 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.
  • Comorbidity Connection Comorbidity Connection Overview
  • Acute Medical Illness and VTE Acute Medical Relative Risk Illness Risk X 2 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 (0.84-2.6) 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 Among Patients Receiving Placebo or Ineffective Antithrombotic Therapy Alikhan R, Cohen A, et al. Arch Intern Med . 2004;164:963-968
  • Acute Medical Illness and VTE Risk Factor Odds Ratio X 2 (95% CI) Age >75 y 1.03 (1.00-1.06) 0.0001 Cancer 1.62 (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 Multivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE) 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 Baseline Hazard Ratio Characteristic (95% CI) Age 1.17 (1.11-1.24) Body Mass Index 1.24 (1.04-1.47) Neurologic disease with 1.87 (1.28-2.73) extremity paresis Malignant neoplasm None 1.00 With chemotherapy 4.24 (2.58-6.95) Without chemotherapy 2.21 (1.60-3.06) Predictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med . 2000;160:761-768
  • 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 Clotting, Cancer, and Controversies
  • 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%)
  • Famous: Trial Design Treatment for 1 year or until death 1º Endpoint: 1 year mortality (50%  35%) 2º Endpoints: VTE and bleeding R Advanced solid tumour malignancy N/Saline placebo Dalteparin 5000 IU od Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
  • Kaplan–Meier survival curves for all ITT patients in dalteparin and placebo groups Kaplan–Meier survival distribution function estimate 0 12 24 36 48 60 72 84 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time from randomisation (months) No. at risk: Dalteparin Placebo 190 85 30 22 12 5 4 Dalteparin 184 72 15 9 8 5 2 Placebo Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
  • Survival Analysis: Good Prognosis Patients Kaplan–Meier survival distribution estimate 17 23 29 35 41 47 53 59 65 71 77 83 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.0 47 17 10 9 9 8 8 5 3 2 0 Placebo 55 31 26 22 20 13 8 5 5 5 3 Dalteparin Time from randomisation (months) No. at risk: Dalteparin Placebo Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
  • LMWH and Survival: Further Studies (2003) Klerk CPW, et al. J Clin Oncol . 2005;23:2130-2135. Altinbas M, et al. J Thromb Haemost . 2004;2:1-6. Lee, et.al. N Engl J Med, 2003;349:146 Solid tumor malignancy and acute VTE All patients received dalteparin 200 IU/kg od 5–7 days R Dalteparin 1 month 200 IU/kg od 5 months  160 IU/kg od Oral anticoagulant 6 months Small cell lung cancer (SCLC) Patients with responsive limited disease received thoracic radiotherapy Chemotherapy plus dalteparin 5000 IU od 18 weeks Chemotherapy (cyclophosphamide, epirubicin, vincristine) 18 weeks Solid tumor malignancy Nadroparin 2 weeks therapeutic dose 4 weeks 1/2 therapeutic dose Placebo 6 weeks CLOT SCLC study MALT R R
  • SCLC Study Survival Curves Good prognosis population limited disease p=0.007 Dalteparin Dalteparin Placebo Placebo Altinbas M, et al. J Thromb Haemost. 2004;2:1-6. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 Months after randomization Probability of survival 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 Months after randomization Probability of survival Overall population p=0.01
  • CLOT Survival Curves Probability of survival (%) Dalteparin OAC Days after randomization 0 10 20 30 40 50 60 70 80 90 100 0 30 60 90 120 150 180 210 240 270 300 330 360 390 OAC Dalteparin Probability of survival (%) Overall population Good prognosis population without metastases p=0.62 p=0.03 Days after randomization Lee, et.al. N Engl J Med, 2003;349:146 0 10 20 30 40 50 60 70 80 90 100 0 30 60 90 120 150 180 210 240 270 300 330 360 390
  • MALT Survival Curves Probability of Survival 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 Months after randomization Placebo Nadroparin p=0.010 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 Months after randomization Probability of Survival Placebo Nadroparin p=0.021 Overall population Good prognosis population >6 months survival Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.
  • LMWH and Prolonged Cancer Survival Mechanistic explanations VTE Coagulation Protease Direct Heparin Other
  • Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
    • Population-based case-control (MEGA) study
    • N=3220 consecutive patients with 1 st VTE vs. n=2131 control subjects
    • CA patients = 7x OR for VTE vs. non-CA patients
    Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 0 10 20 30 40 50 Hematological Lung Gastrointestinal Breast Distant metastases 0 to 3 months 3 to 12 months 1 to 3 years 5 to 10 years > 15 years Adjusted odds ratio Type of cancer Time since cancer diagnosis 28 22.2 20.3 4.9 19.8 53.5 14.3 2.6 1.1 3.6
  • Mechanisms of Cancer-Induced Thrombosis: The Interface
    • Pathogenesis?
    • Biological significance?
    • 3 . Potential importance for cancer therapy?
  • Falanga and Rickles, New Oncology:Thrombosis , 2005 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-  VEGF Tumor cells Monocyte PMN leukocyte Activation of coagulation Platelets Angiogenesis, Basement matrix degradation.
  • 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 sign ifican ce?
    • 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
  • VEGF Angiogenesis Endothelial cells IL-8 Blood Coagulation Activation PAR-2 Angiogenesis FVII/FVIIa THROMBIN Tumor C ell Falanga and Rickles, New Oncology:Thrombosis , 2005 Interface of Biology and Cancer TF FIBRIN TF
  • Coagulation Cascade and Tumors TF Thrombin Clotting-dependent Clotting-dependent Clotting-independent Clotting-dependent Clotting-independent Tumor Growth And Metastasis Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31 ANGIOGENESIS Fibrin PARs
  • 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;96:8663-8668
    • 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
    Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668
  • 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)
    • 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 “ 1. MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis” Activation of Blood Coagulation in Cancer: Malignant Transformation
    • 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)
    “ MET Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”
  • Blood Coagulation Parameters in Mice Transduced with the MET Oncogene Transgene Parameter Time after Transduction (days) 0 30 90 GFP _________ MET Platelets (x10 3 ) D-dimer ( µg/ml) PT (s) ________________ Platelets (x10 3 ) D-dimer (µg/ml) PT (s) 968 656 800 <0.05 <0.05 <0.05 12.4 11.6 11.4 _______________________________ 974 350 150 <0.05 0.11 0.22 12.9 11.8 25.1
  • 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
    • 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
    “ Pten and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”
  • 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 Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 Mean Channel TF Flourescence TF Activity (U/10 6 cells) del/+ mut/+ mut/+ +/+ +/+ del/del
  • 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 Yu, Mackman, Rak et.al. Blood 2005;105:1734-41 %VWF-Positive Area
  • 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
    • Pathogenesis?
    • Biological significance?
    • Potential importance for cancer therapy?
  • 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 Clotting, Cancer, and Controversies
  • 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 patients 1,2
    • The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer 2
    • Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE 3
    • Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years 4
    • Ambrus JL et al. J Med . 1975;6:61-64
    • Donati MB. Haemostasis . 1994;24:128-131
    • 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
    • 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 Levitan N, et al. Medicine 1999;78:285 0 20 40 60 80 100 120 140 160 180 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
  • As Number Of Cancer Survivors Increases, VTE Rates Increase YEAR VTE in Hospitalized Cancer And Noncancer Patients (%) Stein PD, et al. Am J Med 2006; 119: 60-68 Cancer Patients Noncancer Patients
  • VTE Risk And Cancer Type: “Solid And Liquid” Stein PD, et al. Am J Med 2006; 119: 60-68 Relative Risk of VTE in Cancer Patients Pancreas Brain Myeloprol Stomach Lymphoma Uterus Lung Esophagus Prostate Rectal Kidney Colon Ovary Liver Leukemia Breast Cervix Bladder 4.5 4 3.5 3 2.5 2 1.5 1 0.5 Relative Risk of VTE Ranged From 1.02 to 4.34
  • 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) Low Molecular Weight Heparin (LMWH) Nonpharmacologic (Prophylaxis) Unfractionated Heparin (UH) Oral Anticoagulants Elastic Stockings Inferior Vena Cava Filter Intermittent Pneumatic Compression New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?
    • Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis :
    Incidence of VTE in Surgical Patients Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732 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% <0.0001 Death 0.71% 3.14% <0.0001
  • 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
  • Nilsson: Arch Surg, 142;2007:126–132 Colorectal Cancer Resection Association Between Transfusion and Venous Thromboembolism Stratified by Sex in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 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 Overall, 1% incidence of VTE with 3.8 fold mortality Transfused women 1.8-fold more likely to develop VTE than non-transfused women
    • Age >40 years
    • Cancer procoagulants
    • Thrombophilias
    • Adjuvant chemotherapy or hormonal treatment
    • Complicated, lengthy surgery (tissue trauma, immobilization)
    • Debilitation and slower recovery
    • Indwelling venous access
    VTE Risk Factors in Surgical Oncology Patients
  • Clinical thromboembolism Cancer 0 1.0 2.0 3.0 4.0 Major hemorrhage Asymptomatic DVT Clinical PE Death Total hemorrhage Wound hematoma Transfusion Non-cancer Mismetti P et al. Br J Surg 2001;88:913–30 Surgical Prophylaxis LMWH better UFH better
    • 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
    Prophylaxis in Surgical Patients 1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103 2. McLeod R, et al. Ann Surg 2001;233:438-444 Study N Design Regimens ENOXACAN 1 631 double-blind enoxaparin vs. UFH Canadian Colorectal DVT Prophylaxis 2 475 double-blind enoxaparin vs. UFH
  • Prophylaxis in Surgical Patients VTE Major Bleeding Incidence of Outcome Event ENOXACAN 14.7% 2.9% 4.1% 18.2% N=319 N=312 ENOXACAN Study Group. Br J Surg 1997;84:1099–103 P>0.05
  • Prophylaxis in Surgical Patients Canadian Colorectal DVT Prophylaxis Trial 13.9% 1.5% 2.7% 16.9% N=234 N=241 McLeod R, et al. Ann Surg 2001;233:438-444 P=0.052 Incidence of Outcome Event VTE Major Bleeding (Cancer) (All)
    • Extended prophylaxis
    • Abdominal or pelvic surgery for cancer
    • LMWH for ~ 7 days vs. 28 days post-op
    • Routine bilateral venography at ~day 28
    Prophylaxis in Surgical Patients 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 Study N Design Regimens ENOXACAN II 332 Double-blind Enoxaparin vs. placebo FAME (subgroup) 198 Open-label Dalteparin vs. no prophylaxis
  • VTE Prox Any Major DVT Bleeding Bleeding P=0.02 5.1% 1.8% Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980 ENOXACAN II Incidence of Outcome Event N=167 N=165 0% 0.4% 12.0% 4.8% NNT = 14 0.6% 3.6% Extended Prophylaxis in Surgical Patients
    • 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.
    Major Abdominal Surgery: FAME Investigators—Dalteparin Extended Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
    • 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 Cancer 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
    Gynecological Surgery 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
    Kibel, Loughlin. J Urol . 1995;153:1763-1774 DVT PE Fatal PE Radical retropubic prostatectomy 1 – 3% 1 – 3% 0.6% Cystectomy 8% 2 – 4% 2% Radiological studies 51% 22%
    • 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 OBSERVATIONS
    • Meta-analysis of three (3) RCTs evaluating LMWH prophylaxis
    • One major bleeding event observed for every 7 proximal DVTs prevented with LMWH
    Neurosurgery and VTE Prophylaxis Iorio A, Agnell i G . Arch Intern Med. 2000;160:2327 - 2332 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
  • 7 th ACCP Consensus Guidelines Geerts W, et al. Chest 2004; 126: 338S-400S Grade Recommendations for Cancer Patients 1A Patients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U daily 2A Patients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH 2A No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) 1A Patients hospitalized with an acute medical illness should receive LDUH or LMWH
    • 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
    Central Venous Catheters Geerts W, et al. Chest 2001;119:132S-175S
    • Placebo-Controlled Trials
    Prophylaxis for Venous Catheters Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO 2004;23:730 Study Regimen N CRT (%) Reichardt* 2002 Dalteparin 5000 U od placebo 285 140 11 (3.7) 5 (3.4) Couban* 2002 Warfarin 1mg od placebo 130 125 6 (4.6) 5 (4.0) ETHICS † 2004 Enoxaparin 40 mg od placebo 155 155 22 (14.2) 28 (18.1) * symptomatic outcomes ; † routine venography at 6 weeks
    • 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%
    Central Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:736-739
    • 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
    Prophylaxis for Central Venous Access Devices
  • 7 th ACCP Consensus Guidelines Geerts W, et al. Chest 2004; 126: 338S-400S Grade Recommendations for Cancer Patients 1A Patients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U daily 2A Patients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH 2A No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B) 1A Patients hospitalized with an acute medical illness should receive LDUH or LMWH
  • 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 Heit JA et al. Thromb Haemost . 2001;86:452-463 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
  • VTE Incidence In Various Tumors 47% Solid tumors (anti-VEGF + chemo) 43% Renal cell carcinoma 28% Multiple myeloma (thalidomide + chemo) 9% Advanced cancer (1-year survival=12%) 6% Hodgkin’s disease w/ chemo 3% Non-Hodgkin’s lymphomas w/ chemo 8% Breast cancer (Stage IV) w/ chemo 26% High-grade glioma 2% Breast cancer (Stage I & II) w/ chemo 0.2% Breast cancer (Stage I & II) w/o further treatment VTE Incidence Oncology Setting 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 16% Zangari, 2002 (192 pts) T+dox at relapse 17.8% Baz, 2004 (103 pts) 14.7% Zangari, 2004 (68pts) 7% Minnema, 2004 (412 pts) 31.4% Z angari, 2004 (35 pts) 34.5% Zangari, 2004 (87 pts) T+ dox in newly diagnosed patients 7% Weber, 2002 (46 pts) 25% Weber, 2002 (24 pts) 13% Cavo, 2004 (52 pts) 26% Cavo, 2002 (19 pts) 18% Rajkumar, 2004 (102 pts) T+ D in newly diagnosed patients Aspirin (81 mg/d) LMWH Warfarin (INR 2 – 3) Warfarin 1mg/daily No prophylaxis Therapy
  • MM-009/010: Thromboembolic Events DVT Len + D(%) D (%) Len + D(%) D (%) MM-009 MM-010 0 2 4 6 8 10 12 14 16 PE Weber D. ASCO 2005 Annual Meeting
  • Knight: N Engl J Med.2006,354:2079
    • rEPO used more in USA and Canada
    • L+Dex: 23% VTE with EPO vs 5% w/o EPO
    • Placebo + Dex: 7% VTE with EPO vs 1% without EPO
    Incidence of VTE: USA and Canada >Israel, Australia, and Europe Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma Treatment Odds Ratio P Value (95% CI) Lenalidomide plus 3.51 (1.77-6.97) <0.001 High-dose dexamethasone Concomitant erythropoietin 3.21 (1.72-6.01) <0.001
  • Thrombotic Outcomes from rEPO or Darbopoietin Use in Cancer Patients Bohlius: The Cochrane Library, Volume (4).2006 Among 6,769 pts with cancer, RR for DVT with rEPO/Darbepo was increased by 67% (RR=1.67; 95% CI 1.35 to 2.06)
  • Vitamin K antagonist (INR 2.0 - 3.0) > 3 months LMWH or UFH 5 to 7 days Initial treatment Long-term therapy Standard Treatment of VTE Can We Do Better Than This?
  • Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies (UH/VKA vs. LMWH/VKA) Hutten et.al. J Clin Oncol 2000;18:3078 Recurrent VTE Events per 100 patient years P value Malignant Non- Malignant 27.1 9.0 0.003
  • Recurrent VTE in Cancer – Subset Analysis of the Home Rx Studies Hutten et.al. J Clin Oncol 2000;18:3078 Major Bleeding Events per 100 patient years P-value Malignant Non-malignant 13.3 2.1 0.002
  • 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 CANCER PATIENTS WITH ACUTE DVT or PE Randomization Dalteparin Dalteparin Oral Anticoagulant Dalteparin [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 Recurrent VTE Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 0 5 10 15 20 25 Days Post Randomization 0 30 60 90 120 150 180 210 Probability of Recurrent VTE, % Risk reduction = 52% p -value = 0.0017 Dalteparin OAC
  • * Fisher’s exact test Bleeding Events in CLOT Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 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
  • Treatment of Cancer-Associated VTE NS NS 0.03 NS NS 0.002 NS NS NR 0.09 0.03 0.09 Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding (%) Death (%) CLOT Trial (Lee 2003) Dalteparin OAC 6 336 336 9 17 6 4 39 41 CANTHENOX (Meyer 2002) Enoxaparin OAC 3 67 71 11 21 7 16 11 23 LITE (Hull ISTH 2003) Tinzaparin OAC 3 80 87 6 11 6 8 23 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC 6 32 36 34 3.4 3.1 6.7
  • Treatment and 2 ° Prevention of VTE in Cancer – Bottom Line
    • New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A 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 New Development
  • CLOT 12-month Mortality All Patients
    • Lee A, et al. ASCO. 2003
    0 10 20 30 40 50 60 70 80 90 100 0 30 60 90 120 180 240 300 360 Dalteparin OAC HR 0.94 P-value = 0.40 Days Post Randomization Probability of Survival, %
  • Days Post Randomization 0 30 60 90 120 150 180 240 300 360 Probability of Survival, % OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Lee A, et al. ASCO. 2003 Patients Without Metastases (N=150) 0 10 20 30 40 50 60 70 80 90 100
    • 84 patients randomized: CEV +/- LMWH (18 weeks)
    • Patients balanced for age, gender, stage, smoking history, ECOG performance status
    LMWH for Small Cell Lung Cancer Turkish Study Altinbas et al. J Thromb Haemost 2004;2:1266. CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Chemo + Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 0.01 Median survival, m 13.0 8.0 0.01
  • VTE Prophylaxis Is Underused in Patients With Cancer 1. Kakkar AK et al. Oncologist . 2003;8:381-388 2. Stratton MA et al. Arch Intern Med . 2000;160:334-340 3. Bratzler DW et al. Arch Intern Med . 1998;158:1909-1912 Cancer: FRONTLINE Survey 1 — 3891 Clinician Respondents Rate of Appropriate Prophylaxis, % Major Surgery 2 Major Abdominothoracic Surgery (Elderly) 3 Medical Inpatients 4 Confirmed DVT (Inpatients) 5 Cancer: Surgical Cancer: Medical 4. Rahim SA et al. Thromb Res . 2003;111:215-219 5. Goldhaber SZ et al. Am J Cardiol . 2004;93:259-262
  • 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 Clotting, Cancer, and Controversies
  • 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 Haas S et al Thromb Haemost 2005;94:814-819 Kakkar AJ et al Thromb Haemost 2005;94:867-71 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 0.0001
  • 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 ENOXACAN Canadian Colorectal Study P=NS NNT=29 P=0.05 NNT=33 ENOXACAN Study Group Br J Surg 1997;84:1099-1103 Mcleod R et al Ann Surg 2001;233:436-44
  • Extended Thromboprophylaxis in Cancer Surgery ENOXACAN II FAME P= 0.02 NNT=14 P<0.03 NNT= 9 Berquvist D et al NEJM 2002;346:975-80 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 - 12.7% 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
    Karthaus et al Oncol 2006;17:286-296 Couban et al JCO 2006: 23:4063-8 Verso et al JCO 2006;23:4057-62 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 placebo 155 155 22 (14.2) 28 (18.1)
  • 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 5
  • Dentali, F. et. al. Ann Intern Med 2007;146:278-288 Fatal Pulmonary Embolism During Anticoagulant Prophylaxis 0.001 0.01 0.1 1.0 10 100 1000 Favors Treatment Favors Placebo Study, Year (Reference) Prophylaxis n/n Placebo n/n RR Fixed (95% CI) RR Fixed (95% CI) Dahan et al, 1986 (41) 1/132 3/131 0.33 (0.03 to 3.14) Garlund at al, 1996 (35) 3/5776 12/5917 0.26 (0.07 to 0.91) Leizorovic et al, 2004 (23) 0/1829 2/1807 0.20 (0.01 to 4.11) Mahe et al, 2005 (22) 10/1230 17/1244 0.59 (0.27 to 1.29) Cohen at, 2006 (42) 0/321 5/323 0.09 (0.01 to 1.65) Total (95% CI) 0.38 (0.21 to 0.69) Total events 14 39
  • 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;131:507-516
  • Incidence and Economic Implications of HIT Creekmore FM, et al. Pharmacotherapy. 2006;26:1438-1445 . N = 10,121 P = 0.037 P < 0.001
  • 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 WH et al. Chest . 2004;126(suppl):338S-400S
  • NCCN Practice Guidelines in VTE Disease At Risk Population Initial Prophylaxis http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
    • Adult patient
    • Diagnosis or clinical suspicion of cancer
    • Inpatient
    Relative contra-indication to anticoagulation treatment Prophylactic anticoagulation therapy (category 1) + sequential compression device (SCD) Mechanical prophylaxis (options) - SCD - Graduated compression stockings NO YES
    • RISK FACTOR ASSESSMENT
    • Age
    • 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
    Modifiable risk factors: Lifestyle, smoking, tobacco, obesity, activity level/exercise
  • NCCN Practice Guidelines in VTE Disease http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
    • 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 75 units/kg cubcutaneous daily
    • Pentasaccharide
    • - Fondaparinux 2.5 mg subcutaneous daily
    • Unfractioned heparin 5,000 units subcutaneous 3 times daily
  • NCCN Practice Guidelines in VTE Disease http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
    • 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 Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group 9.9% 6.7% 35,124 62,012 0 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
  • 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)
  • Odds Ratio Malignancy 0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender 0.92 Hospital Size 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC 1.46 Duration of Immobility 1.60 VTE Risk Factors 1.78 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Effect Odds Ratio (95% CI) Predictors of the Use of Thromboprophylaxis Kahn SR et Al. Thromb Res 2007; 119:145-155
  • Independent factors present at admission for in-hospital bleeding – multivariate analysis (IMPROVE Registry)
    • Adjusted Odds Ratio (95% CI)
    • Bleeding disorder 5.11 (2.38, 10.98)
    • Active G-duodenal ulcer 4.93 (2.86, 8.50)
    • Adm platelets<50 x 10 9 3.00 (1.67, 5.41)
    • Hepatic failure 2.79 (1.57, 4.95)
    • ICU/CCU stay 2.41 (1.60, 3.63)
    • Current cancer 1.99 (1.39, 2.85)
    • Central venous catheter 1.98 (1.33, 2.95)
    • Age  85 years 1.91 (1.29, 2.85)
    • S. creatinine ≥2.5 mg/dL 1.88 (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
  • Electronic Alerts to Prevent VTE Freedom from DVT or PE (%) Number at risk Intervention group 1,255 977 900 853 Control group 1,251 876 893 839 Control group Intervention group P <0.001 Time (days) Kucher N, et al. N Engl J Med. 2005;352:969-77
  • Cohen A et al Thromb Haemost 2005;94(4):750-9 VTE Risk Assessment for Hospitalized Medical Patients All medical patients should be routinely assessed and considered for thromboprophylaxis Is the patient > 40 years old with acute medical illness and reduced mobility? Does the patient have one of the following acute medical illnesses/conditions? Evidence-based:
    • Acute 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
  • Cohen A et al Thromb Haemost 2005;94(4):750-9 . VTE Risk Assessment for Hospitalized Medical Patients Is pharmacological thromboprophylaxis contraindicated? YES Mechanical thromboprophylaxis with graduated compression stockings or intermittent pneumatic compression is recommended YES LMWH (enoxaparin 40 mg o.d. or dalteparin 5000 IU o.d.) or UFH (5000 IU t.i.d.) (LMWH preferred due to better safety profile) NO No evidence for the benefits of thromboprophylaxis. However, patients should be considered for thromboprophylaxis on a case-by-case basis NO
  • Conclusions
    • Current practices of VTE prophylaxis in the cancer pat ient
    • 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