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					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
                  Charles W. Francis, MD
            Professor of Medicine and Pathology and
                      Laboratory Medicine
                    Department of Medicine
                    University of Rochester
                School of Medicine and Dentistry
                      Rochester, New York
           Welcome and Program Overview

CME-accredited symposium jointly sponsored by University of
Massachusetts Medical Center, office of CME and CMEducation
Resources, LLC

Commercial Support: Sponsored by an independent educational grant
from Eisai, Inc.

Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management

Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies

COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
                   Program Educational Objectives

As a result of this session, physicians will:

►    Review recent trials, research, and expert analysis of issues focused on
    thrombosis and cancer.

►   Learn how national guidelines for thrombosis prevention should impact
    management of patients with cancer.

►   Be able to specify strategies for risk-directed prophylaxis against DVT in at risk
    patients with cancer.

►   Be able to explain how to assess and manage special needs of cancer patients
    at risk for DVT, with a focus on protecting against recurrent DVT.

►    Be able to describe how to risk stratify patients undergoing cancer surgery, and
    implement ACCP-mandated pharmacologic and non-pharmacologic measures
    aimed at DVT prophylaxis.
                              Program Faculty
Program Chairman
Charles W. Francis, MD
Professor of Medicine and Pathology and Laboratory Medicine
Department of Medicine
University of Rochester
School of Medicine and Dentistry
Rochester, NY

Frederick Rickles, MD
Professor of Medicine, Pediatrics, Pharmacology and Physiology
Department of Medicine
Division of Hematology-Oncology
The George Washington University
Washington, DC

John Fanikos, RPh, MBA
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA
               Faculty COI Financial Disclosures

Charles Francis, MD
Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai,
Amgen, Pfizer

Frederick Rickles, MD
Consultant: Pfizer, Eisai, sanofi-aventis, and Bristol-Myers Squibb
Speakers Bureau: Eisai

John Fanikos, RPh, MBA
Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai
Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines
Company
        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
                Charles W. Francis, MD
           Professor of Medicine and Pathology and
                     Laboratory Medicine
                   Department of Medicine
                   University of Rochester
               School of Medicine and Dentistry
                     Rochester, New York
            Comorbidity Connection


COMORBIDITY                   SUBSPECIALIST
CONNECTION                    STAKEHOLDERS
CAP                           Infectious diseases
UTI                           Oncology
Cancer                        Cardiology
Heart Failure                 Pulmonary medicine
ABE/COPD                      Hematology
Respiratory Failure           Oncology/hematology
Myeloproliferative Disorder   Interventional Radiology
Thrombophilia                 Hospitalist
Surgery                       Surgeons
History of DVT                EM
Other                         PCP
                                 Epidemiology of First-Time VTE

                    Variable                               Finding
                                            Possibly more common in winter and less
            Seasonal Variation
                                                      common in summer
                                                  25% to 50% “idiopathic”
                 Risk Factors                  15%-25% associated with cancer
                                               20% following surgery (3 months)
                                                    6-month incidence, 7%;
                                               Higher rate in patients with cancer
               Recurrent VTE
                                             Recurrent PE more likely after PE than
                                                            after DVT
                                            30-day incidence 6% after incident DVT
                                                30-day incidence 12% after PE
       Death After Treated VTE
                                            Death strongly associated with cancer,
                                               age, and cardiovascular disease

White R. Circulation. 2003;107:I-4 –I-8.)
                                            Epidemiology of VTE

            ► One major risk factor for VTE is ethnicity, with a
              significantly higher incidence among Caucasians
              and African Americans than among Hispanic
              persons and Asian-Pacific Islanders.

            ► Overall, about 25% to 50% of patient with first-time
              VTE have an idiopathic condition, without a readily
              identifiable risk factor.

            ► Early mortality after VTE is strongly associated with
              presentation as PE, advanced age, cancer, and
              underlying cardiovascular disease.


White R. Circulation. 2003;107:I-4 –I-8.)
   Comorbidity Connection




                       Overview




Comorbidity
Connection
                              Acute Medical Illness and VTE
                                  Among Patients Receiving Placebo or
                                   Ineffective Antithrombotic Therapy

     Acute Medical
                                    Relative Risk              X2       P Value
        Illness
       Heart failure                1.08 (0.72-1.62)           0.05       .82
      NYHA class III                0.89 (0.55-1.43)           0.12       .72
      NYHA class IV                 1.48 (0.84-2.60)           1.23       .27
     Acute respiratory
                                    1.26 (0.85-1.87)           1.03       .31
         disease
     Acute infectious
                                    1.50 (1.00-2.26)           3.54       .06
        disease
     Acute rheumatic
                                    1.45 (0.84-2.50)           1.20       .27
         disease


Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
                                 Acute Medical Illness and VTE
                                     Multivariate Logistic Regression Model
                                 for Definite Venous Thromboembolism (VTE)


                   Risk Factor                          Odds Ratio       X2
                                                           (95% CI)

                 Age > 75 years                      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
                                                     1.74 (1.12-2.75)    0.02
                    disease


              Chronic respiratory
                                                     0.60 (0.38-0.92)    0.02
                   disease


Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
                         Comorbid Condition and DVT Risk

       ► Hospitalization for surgery (24%) and for medical illness
         (22%) accounted for a similar proportion of the cases, while
         nursing home residence accounted for 13%.

       ► The individual attributable risk estimates for malignant
         neoplasm, trauma, congestive heart failure, central venous
         catheter or pacemaker placement, neurological disease with
         extremity paresis, and superficial vein thrombosis were 18%,
         12%, 10%, 9%, 7%, and 5%, respectively.

       ► Together, the 8 risk factors accounted for 74% of disease
         occurrence


Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern Med. 2002 Jun
10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study
                                                     VTE Recurrence
                                 Predictors of First Overall VTE Recurrence


              Baseline Characteristic                        Hazard Ratio
                                                                (95% CI)

                                Age                          1.17 (1.11-1.24)


                      Body Mass Index                        1.24 (1.04-1.7)

         Neurologic disease with extremity
                                                             1.87 (1.28-2.73)
                      paresis
                   Malignant neoplasm
                          None                                     1.00
                   With chemotherapy                         4.24 (2.58-6.95)
                  Without chemotherapy                       2.21 (1.60-3.06)


Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
 Clotting, Cancer, and Clinical Strategies


Cancer, Thrombosis, and the
   Biology of Malignancy
 Scientific Foundations for the Role of
    Low-Molecular-Weight Heparin


         Frederick R. Rickles, MD
         Professor of Medicine, Pediatrics,
           Pharmacology and Physiology
         The George Washington University
                 Washington, DC
           Professor Armand Trousseau
              Lectures in Clinical Medicine




“ I have always been struck with the
frequency with which cancerous patients
are affected with painful oedema of the
superior or inferior extremities….”

New Syndenham Society – 1865
            Professor Armand Trousseau
       More Observations About Cancer and Thrombosis




“In other cases, in which the absence of
appreciable tumor made me hesitate as to
the nature of the disease of the stomach, my
doubts were removed, and I knew the
disease to be cancerous when phlegmasia
alba dolens appeared in one of the limbs.”

Lectures in Clinical Medicine, 1865
             Trousseau’s Syndrome


Ironically, Trousseau died of gastric carcinoma 6
months after writing to his student, Peter, on January
1st, 1867:


“I am lost . . . the phlebitis that has just
appeared tonight leaves me no doubt as to
the nature of my illness”
          Trousseau’s Syndrome



► Occult cancer in patients with idiopathic
  venous thromboembolism


► Thrombophlebitis in patients
  with cancer
                                                       Effect of Malignancy on Risk of
                                                      Venous Thromboembolism (VTE)
                                                                                                            53.5
                                 50        • Population-based case-control
                                             (MEGA) study
                                           • N=3220 consecutive patients with 1st
                                 40          VTE vs. n=2131 control subjects
           Adjusted odds ratio




                                           • CA patients = OR 7x VTE risk vs. non-
                                             CA patients
                                 30      28
                                              22.2
                                                     20.3                 19.8
                                 20
                                                                                                                             14.3

                                 10                                                4.9
                                                                                                                                               3.6             2.6
                                                                                                                                                                                1.1
                                  0




                                                                                                                                                                                 > 15 years
                                                         Lung




                                                                                     Breast




                                                                                                  Distant




                                                                                                                                                1 to 3 years

                                                                                                                                                                5 to 10 years
                                                                                              metastases




                                                                                                             0 to 3 months

                                                                                                                              3 to 12 months
                                      Hematological




                                                                Gastrointestinal




                                                      Type of cancer                                        Time since cancer diagnosis
Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
                                        Cancer, Mortality, and VTE
                                                Epidemiology and Risk

           ►   Patients with cancer have a 4- to 6-fold increased risk
               for VTE vs. non-cancer patients
           ►   Patients with cancer have a 3-fold increased risk for
               recurrence of VTE vs. non-cancer patients
           ►   Cancer patients undergoing surgery have a 2-fold
               increased risk for postoperative VTE
           ►   Death rate from cancer is four-fold higher if patient has
               concurrent VTE
           ►   VTE 2nd most common cause of death in ambulatory
               cancer patients (tied with infection)


Heit et.al. Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et.al. Blood 2002;100:3484-3488;
White et.al. Thromb Haemost 2003;90:446-455; Sorensen et.al. New Engl J Med 2000;343:1846-1850); Levitan et.al.
Medicine 1999;78:285-291; Khorana et.al. J Thromb Haemost 2007;5:632-4
    Mechanisms of Cancer-Induced Thrombosis:
                  The Interface



1. Pathogenesis?

2. Biological significance?


3. Potential importance for cancer therapy?
    Trousseau’s Observations (continued)


“There appears in the cachexiae…a
particular condition of the blood that
predisposes it to spontaneous
coagulation.”

Lectures in Clinical Medicine, 1865
                         Interface of Biology and Cancer
                                                         Tumor cells

     Angiogenesis,                  Fibrinolytic                            Procoagulant Activities
     Basement matrix                activities:
     degradation.                   t-PA, u-PA, u-PAR,
                                    PAI-1, PAI-2


                                                          IL-1,                      Activation of
                                                          TNF-a,                     coagulation
                                                          VEGF



          PMN leukocyte                                                         FIBRIN




                                                                                                     Platelets

                                Monocyte                    Endothelial cells




Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, 2007
            Pathogenesis of Thrombosis in Cancer
                    A Modification of Virchow’s Triad

1. Stasis
  ●   Prolonged bed rest
  ●   Extrinsic compression of blood vessels by tumor
2. Vascular Injury
  ●   Direct invasion by tumor
  ●   Prolonged use of central venous catheters
  ●   Endothelial damage by chemotherapy drugs
  ●   Effect of tumor cytokines on vascular endothelium
3. Hypercoagulability
  ●   Tumor-associated procoagulants and cytokines (tissue factor, CP,
      TNFa, IL-1, VEGF, etc.)
  ●   Impaired endothelial cell defense mechanisms (APC resistance;
      deficiencies of AT, Protein C and S)
  ●   Enhanced selectin/integrin-mediated, adhesive interactions
      between tumor cells,vascular endothelial cells, platelets and host
      macrophages
     Mechanisms of Cancer-Induced Thrombosis:
             Clot and Cancer Interface


1. Pathogenesis?


2. Biological significance?


3. Potential importance for cancer therapy?
         Activation of Blood Coagulation in Cancer
                         Biological Significance?



►   Epiphenomenon?
    Is this a generic secondary event where
    thrombosis is an incidental finding


    or, is clotting activation . . .


►   A Primary Event?
    Linked to malignant transformation
                          Interface of Clotting Activation
                                and Tumor Biology

                             FVII/FVIIa
     Tumor                                              Blood Coagulation
                        TF                                  Activation
      Cell

              VEGF
                                                          THROMBIN



                                                            FIBRIN
                                                                      Angiogenesis
                                                                       IL-8
      PAR-2                   TF


                                    Endothelial cells
 Angiogenesis

Falanga and Rickles, New Oncology:Thrombosis, 2005
                    Coagulation Cascade and Tumor Biology

                            Clotting-                                        Clotting-
                           dependent                                        dependent
           TF                                     Thrombin                                       Fibrin

                      VIIa               Xa           Clotting-
                                                    independent
        Clotting-                                                                                 Clotting-
      independent                                                                                dependent


                                                     PARs


                                         Angiogenesis, Tumor
                                         Growth and Metastasis




Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
                                   VEGF and Angiogenesis

      Regulation of Vascular Endothelial Growth Factor Production
       and Angiogenesis by the Cytoplasmic Tail of Tissue Factor


          1.      TF regulates VEGF expression in human cancer
                  cell lines

          2.      Human cancer cells with increased TF are more
                  angiogenic (and, therefore, more “metastatic’) in
                  vivo due to high VEGF production




Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668; Ruf et.al. Nature Med 2004;10:502-509
                                    VEGF and Angiogenesis

    Regulation of Vascular Endothelial Growth Factor Production
     and Angiogenesis by the Cytoplasmic Tail of Tissue Factor


        3.       The cytoplasmic tail of TF, which contains three
                 serine residues, appears to play a role in regulating
                 VEGF expression in human cancer cells, perhaps
                 by mediating signal transduction

        4.      Data consistent with new mechanism(s) by which
                TF signals VEGF synthesis in human cancer cells
                may provide insight into the relationship between
                clotting and cancer

Abe et.al. Proc Nat Acad Sci 1999;96:8663-8668; Ruf et.al. Nature Med. 2004;10:502-509
            Tissue Factor Expression, Angiogenesis, and
                 Thrombosis in Pancreatic Cancer
                      Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan,
               Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter,
                               Jennifer Harvey and Mark B.Taubman
                                (U Rochester, U Pitt, Johns Hopkins,
                                      Translational Genomics)
                                  Clin Cancer Res 2007;13:2870


►   Retrospective IH and microarray study of TF, VEGF and MVD in:
    ●   Normal pancreas (10)
    ●   Intraductal papillary mucinous neoplasms (IPMN; 70)
    ●   Pancreatic intrepithelial neoplasia (PanIN; 40)
    ●   Resected or metastatic pancreatic adenoca(130)


►   Survival


►   VTE Rate
                    Correlation of Tissue Factor Expression with the
                Expression of Other Angiogenesis Cariables in Resected
                                   Pancreatic Cancer


                                           High TF      Low TF
                                                                      P
                                          expression   expression

         VEGF expression
          Negative                            13           41       <0.0001
          Positive                            53           15

       Microvessel density
        V6 per tissue core                    27           33        0.047
        >6 per tissue core                    39           23
        Median                                8            6         0.01




Khorana et.al. Clin CA Res 2007:13:2870
                           Symptomatic VTE in Pancreatic Cancer

                      30
                                               5/19; 26.3%
                      25
    Rate of VTE (%)




                      20

                      15

                      10
                                1/22; 4.5%
                      5

                      0
                                  Low TF        High TF


Khorana et.al. Clin CA Res 2007:13:2870
              Activation of Blood Coagulation
           in Cancer: Malignant Transformation
►    Epiphenomenon?
►    Linked to malignant transformation?
    1.   MET oncogene induction produces DIC in
         human liver carcinoma
         (Boccaccio et. al. Nature 2005;434:396-400)

    2.   Pten loss produces TF activation and
         pseudopalisading necrosis in human
         glioblastoma
         (Rong et.al. Ca Res 2005;65:1406-1413)

    3.   K-ras oncogene, p53 inactivation and TF
         induction in human colorectal carcinoma
         (Yu et.al. Blood 2005;105:1734-1741)
                        Activation of Blood Coagulation
                     in Cancer: Malignant Transformation

           “1. MET Oncogene Drives a Genetic Programme
                    Linking Cancer to Haemostasis”

        ►    MET encodes a tyrosine kinase receptor for hepatocyte
             growth factor/scatter factor (HGF/SF) 
               ●    Drives physiological cellular program of “invasive
                    growth” (tissue morphogenesis, angiogenesis
                    and repair)
               ●    Aberrant execution (e.g. hypoxia-induced
                    transcription) is associated with neoplastic
                    transformation, invasion, and metastasis


Boccaccio et al Nature 2005;434:396-400
         “MET Oncogene Drives a Genetic Programme
               Linking Cancer to Haemostasis”

►   Mouse model of Trousseau’s Syndrome

    ●   Targeted activated human MET to the mouse liver with
        lentiviral vector and liver-specific promoter  slowly,
        progressive hepatocarcinogenesis

    ●   Preceded and accompanied by a thrombohemorrhagic
        syndrome

    ●   Venous thrombosis in tail vein occurred early and was
        followed by fatal internal hemorrhage

    ●   Syndrome characterized by  d-dimer and PT and 
        platelet count (DIC)
                       Blood Coagulation Parameters in Mice
                        Transduced with the MET Oncogene


                                           Time after Transduction (days)
 Transgene                  Parameter       0          30         90
 GFP                  Platelets (x103)    968         656        800
                      D-dimer (µg/ml)     <0.05      <0.05      <0.05
                      PT (s)              12.4        11.6      11.4
 _________            ________________    _______________________________
 MET                  Platelets (x103)    974         350        150
                      D-dimer (µg/ml)     <0.05       0.11      0.22
                      PT (s)              12.9        11.8      25.1




Boccaccio et al Nature 2005;434:396-400
        “MET Oncogene Drives a Genetic Programme
              Linking Cancer to Haemostasis”


►   Mouse model of Trousseau’s Syndrome

    ●   Genome-wide expression profiling of hepatocytes
        expressing MET upregulation of PAI-1 and COX-2
        genes with 2-3x  circulating protein levels

    ●   Using either XR5118 (PAI-1 inhibitor) or Rofecoxib
        (Vioxx; COX-2 inhibitor) resulted in inhibition of
        clinical and laboratory evidence for DIC in mice
                                Activation of Blood Coagulation
                             in Cancer: Malignant Transformation

               2. “Pten and Hypoxia Regulate Tissue Factor
                   Expression and Plasma Coagulation By
                               Glioblastoma”
        ►    Pten = Tumor suppressor with lipid and protein
             phosphatase activity
        ►    Loss or inactivation of Pten (70-80% of
             glioblastomas) leads to Akt activation and
             upregulation of Ras/MEK/ERK signaling cascade




Rong, Brat et.al. Ca Res 2005;65:1406-1413
     “Pten and Hypoxia Regulate Tissue Factor Expression
           and Plasma Coagulation By Glioblastoma”


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


Results:
1. Hypoxia and PTEN loss  TF (mRNA, Ag and
   procoagulant activity); partially reversed with
   induction of PTEN

2. Both Akt and Ras pathways modulated TF in
   sequentially transformed astrocytes.

3. Ex vivo data:  TF (by immunohistochemical
   staining) in pseudopalisades of # 7 human
   glioblastoma specimens
                        Both Akt and Ras Pathways Modulate TF
                         Expression By Transformed Astrocytes



N=Normoxia
H=hypoxia




Rong, Brat et.al. Ca Res 2005;65:1406-1413
                    “Pten and Hypoxia Regulate Tissue Factor Expression
                          and Plasma Coagulation By Glioblastoma”
                                                       pseudopalisading
                                                       necrosis




                                                                           H&E




                                             Vascular
                                             Endothelium



                                                                          TF Immuno-
                                                                          histochemistry
Rong, Brat et.al. Ca Res 2005;65:1406-1413
                               Activation of Blood Coagulation
                              in Cancer: Malignant Transformation

             3. “Oncogenic Events Regulate Tissue Factor
             Expression In Colorectal Cancer Cells: Implications for
             Tumor Progression And Angiogenesis”

         ►   Activation of K-ras oncogene and inactivation of p53 tumor
             suppressor  TF expression in human colorectal cancer cells
         ►   Transforming events dependent on MEK/MAPK and PI3K
         ►   Cell-associated and MP-associated TF activity linked to
             genetic status of cancer cells
         ►   TF siRNA reduced cell surface TF expression, tumor growth
             and angiogenesis
         ►   TF may be required for K-ras-driven phenotype



Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
                                                      Activation of Blood Coagulation
                                                    in Cancer: Malignant Transformation
                                     “Oncogenic Events Regulate Tissue Factor Expression In
                                    Colorectal Cancer Cells: Implications For Tumor Progression
                                                       And Angiogenesis”
                                   TF expression in cancer cells parallels genetic tumor progression
                                                        with an impact of K-ras and p53 status
    Mean Channel TF Flourescence




                                   450                                                                   160




                                                                             TF Activity (U/106 cells)
                                   400                                                                   140
                                   350                                                                   120
                                   300
                                                                                                         100
                                   250
                                                                                                         80
                                   200
                                                                                                         60
                                   150
                                   100                                                                   40
                                    50                                                                   20
                                     0                                                                    0
                                          HKh-2      HCT116      379.2                                         HKh-2   HCT116   379.2

                                          del/+      mut/+      mut/+
                                          +/+         +/+       del/del


Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
                                  Activation of Blood Coagulation
                               in Cancer: Malignant Transformation

                       “Oncogenic Events Regulate Tissue Factor
                         Expression In Colorectal Cancer Cells:
                        Implications For Tumor Progression And
                                     Angiogenesis”
                  Effect of TF si mRNA on tumor growth in vitro and in vivo




Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
                                      “Oncogenic Events Regulate Tissue Factor
                                        Expression In Colorectal Cancer Cells”

                         Effect of TF si mRNA on new vessel formation in colon cancer


                                 14
            %VWF-Positive Area




                                 12
                                 10
                                 8
                                 6
                                 4
                                 2
                                 0
                                      HCT116     SI-2      SI-3      MG only



Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
                               Activation of Blood Coagulation
                             in Cancer: Malignant Transformation


        “Oncogenic Events Regulate Tissue Factor Expression In
            Colorectal Cancer Cells: Implications For Tumor
                    Progression And Angiogenesis”
              Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology




Yu, Mackman, Rak et.al. Blood 2005;105:1734-41
Mechanisms of Cancer-Induced Thrombosis:
              Implications


1. Pathogenesis?


2. Biological significance?


3. Potential importance for cancer
   therapy?
              Cancer and Thrombosis
       Year 2008 State-of-the-Science Update

             Key Questions
1. Does activation of blood coagulation affect
the biology of cancer positively or negatively?

2. Can we treat tumors more effectively using
coagulation protein targets?

3. Can anticoagulation alter the biology of cancer?
                Cancer and Thrombosis
         Year 2008 State-of-the-Science Update


              Tentative Answers
1.   Epidemiologic evidence is suggestive that VTE is a
     bad prognostic sign in cancer

2.    Experimental evidence is supportive of the use of
     antithrombotic strategies for both prevention of
     thrombosis and inhibition of tumor growth

3.    Results of recent, randomized clinical trials of LMWH
     in cancer patients indicate superiority in preventing
     recurrent VTE and suggest increased survival (not
     due to just preventing VTE)— “Titillating”
          Coagulation Cascade and Tumor Biology
                    Clotting-                                        Clotting-
                   dependent                                        dependent
   TF                                     Thrombin                                         Fibrin

              VIIa              Xa
                                               Clotting-
                                             independent
  Clotting-                                                                                  Clotting-
independent                                                                                 dependent
                    ?
                                             PARs


                                  Angiogenesis, Tumor
                                 Growth and Metastasis


LMWH (e.g. dalteparin)
 Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584
        Clotting, Cancer, and Controversies


A Systematic Overview of VTE Prophylaxis
        in the Setting of Cancer

       Linking Science to Clinical Practice
                  Program Chairman
                Charles W. Francis, MD
           Professor of Medicine and Pathology and
                     Laboratory Medicine
                   Department of Medicine
                   University of Rochester
               School of Medicine and Dentistry
                     Rochester, New York
                             VTE and Cancer: Epidemiology

           ►   Of all cases of VTE:
                 ●    About 20% occur in cancer patients
                 ●    Annual incidence of VTE in cancer
                      patients ≈ 1/250
           ►   Of all cancer patients:
                 ●    15% will have symptomatic VTE
                 ●    As many as 50% have VTE at autopsy
           ►   Compared to patients without cancer:
                 ●    Higher risk of first and recurrent VTE
                 ●    Higher risk of bleeding on anticoagulants
                 ●    Higher risk of dying



Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
                                           DVT and PE in Cancer
                                      Facts, Findings, and Natural History


             ►   VTE is the second leading cause of death in
                 hospitalized cancer patients1,2
             ►   The risk of VTE in cancer patients undergoing
                 surgery is 3- to 5-fold higher than those without
                 cancer2
             ►   Up to 50% of cancer patients may have evidence of
                 asymptomatic DVT/PE3
             ►   Cancer patients with symptomatic DVT exhibit a
                 high risk for recurrent DVT/PE that persists for
                 many years4

1.   Ambrus JL et al. J Med. 1975;6:61-64
2.   Donati MB. Haemostasis. 1994;24:128-131
3.   Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4.   Prandoni P et al. Ann Intern Med. 1996;125:1-7
                          Clinical Features of VTE in Cancer


   ► VTE     has significant negative impact on
        quality of life
   ► VTE     may be the presenting sign of occult
        malignancy
        • 10% with idiopathic VTE develop cancer
          within 2 years
        • 20% have recurrent idiopathic VTE

        • 25% have bilateral DVT


Bura et. al., J Thromb Haemost 2004;2:445-51
                                         Thrombosis and Survival
                                Likelihood of Death After Hospitalization


                         1.00
                                             DVT/PE and Malignant Disease
                         0.80
        Probability of
           Death




                         0.60
                                                         Malignant Disease
                         0.40
                                                                   DVT/PE Only
                         0.20
                                                      Nonmalignant Disease
                         0.00
                                 0   20 40   60      80 100 120140 160 180
                                                  Number of Days


Levitan N, et al. Medicine 1999;78:285
                          Hospital Mortality With or Without VTE

                                           No VTE      VTE
                     18                          16.13              16.41
                     16           14.85
                     14
     Mortality (%)




                     12                     10.59
                     10    7.98
                                                             8.67
                      8
                      6
                      4
                      2
                      0
                              All         Non-metastatic     Metastatic
                            N=66,016        N=20,591         N=17,360

Khorana, JCO, 2006
                            Trends in VTE in Hospitalized Cancer Patients

                     7.0
                     6.5
                     6.0
                     5.5
                     5.0
   Rate of VTE (%)




                     4.5
                     4.0
                     3.5
                     3.0
                     2.5
                     2.0
                     1.5
                     1.0
                     0.5                                                              P<0.0001
                     0.0
                           1995    1996    1997      1998      1999    2000    2001   2002     2003

                     VTE- patients on chemotherapy                VTE-all patients           DVT-all patients

Khorana AA et al. Cancer. 2007.
                                                            PE-all patients
      Thrombosis Risk In Cancer

              Primary Prophylaxis
►   Medical Inpatients

►   Surgery

►   Radiotherapy

►   Central Venous Catheters
    Risk Factors for Cancer-Associated VTE

►   Cancer
    ●   Type
        • Men: prostate, colon, brain, lung
        • Women: breast, ovary, lung
    ●   Stage
►   Treatments
    ●   Surgery
        • 10-20% proximal DVT
        • 4-10% clinically evident PE
        • 0.2-5% fatal PE
    ●   Systemic therapy
    ●   Central venous catheters (~4% generate clinically
        relevant VTE)
►   Patient
    ●   Prior VTE
    ●   Co-morbities
    ●   Genetic backgroud
                                             VTE Risk And Cancer Type
                                             “Solid And Liquid Malignancies”
                               Relative Risk of VTE Ranged From 1.02 to 4.34
                                             4.5
                                             4
                   Relative Risk of VTE in


                                             3.5
                      Cancer Patients


                                             3
                                             2.5
                                             2
                                             1.5
                                             1
                                             0.5




                                                                                                                                                                        Ovary
                                                                                                                                                       Kidney




                                                                                                                                                                                                            Cervix
                                                                                                                Lung




                                                                                                                                                                                Liver
                                                                                                                                                                Colon
                                                              Brain




                                                                                                                                                                                                   Breast


                                                                                                                                                                                                                     Bladder
                                                                                            Lymphoma
                                                                                                       Uterus



                                                                                                                                   Prostate




                                                                                                                                                                                        Leukemia
                                                                                  Stomach
                                                                      Myeloprol




                                                                                                                                              Rectal
                                                                                                                       Esophagus
                                                   Pancreas




Stein PD, et al. Am J Med 2006; 119: 60-68
Cancer and Thrombosis




Medical Inpatients
                     Thromboembolism in Hospitalized
                       Neutropenic Cancer Patients



     ►Retrospective cohort study of discharges using
      the University Health System Consortium


     ►66,106 adult neutropenic cancer patients
      between 1995 and 2002 at 115 centers




Khorana, JCO, 2006
                     Neutropenic Patients: Results

   ►8% had thrombosis


   ►5.4% venous and 1.5% arterial in 1st hospitalization


   ►Predictors of thrombosis
         ●   Age over 55
         ●   Site (lung, GI, gynecologic, brain)
         ●   Comorbidities (infection, pulmonary and renal
             disease, obesity)


Khorana, JCO, 2006
                                       Predictors of VTE in
                                    Hospitalized Cancer Patients

                      Characteristic                   OR          P Value
                      Site of Cancer
                           Lung                        1.3          <0.001
                         Stomach                       1.6          0.0035
                         Pancreas                      2.8          <0.001
                    Endometrium/cervix                  2           <0.001
                           Brain                       2.2          <0.001

                            Age 65 y                  1.1          0.005
               Arterial thromboembolism                1.4          0.008
         Comorbidities (lung/renal disease,
                                                      1.3-1.6       <0.001
               infection, obesity)


Khorana AA et al. J Clin Oncol. 2006;24:484-490.
           Antithrombotic Therapy: Choices

      Nonpharmacologic               Pharmacologic
           (Prophylaxis)        (Prophylaxis & Treatment)



 Intermittent      Elastic    Unfractionated             Low Molecular
 Pneumatic        Stockings   Heparin (UH)               Weight Heparin
Compression                                                (LMWH)


            Inferior
           Vena Cava                         Oral
             Filter                     Anticoagulants
                                      New Agents: e.g.
                                      Fondaparinux,
                                      Direct anti-Xa inhibitors,
                                      Direct anti-IIa, etc.?
                           Prophylaxis Studies in Medical Patients

                      20

                            14.9
                      15
    Rate of VTE (%)




                                      Relative                                      Relative
                                        risk
                                                                     10.5             risk
                                                                                   reduction
                      10             reduction            Relative                   47%
                                       63%                  risk
                                                         reduction
                                   5.5           5         44%               5.6
                      5
                                                       2.8


                      0
                           Placebo Enoxaparin Placebo Dalteparin     Placebo Fondaparinux
                            MEDENOX Trial            PREVENT                ARTEMIS


Francis, NEJM, 2007
                          ASCO Guidelines


     1. SHOULD HOSPITALIZED PATIENTS WITH
     CANCER RECEIVE ANTICOAGULATION FOR
     VTE PROPHYLAXIS?


          Recommendation. Hospitalized patients with cancer
          should be considered candidates for VTE prophylaxis
          with anticoagulants in the absence of bleeding or other
          contraindications to anticoagulation.




Lyman, JCO, 2007
Cancer and Thrombosis




Surgical Patients
                            Incidence of VTE in Surgical Patients

      ►   Cancer patients have 2-fold risk of post-operative DVT/PE
          and >3-fold risk of fatal PE despite prophylaxis:


                                              No Cancer       Cancer
                                                                       P-value
                                                 N=16,954     N=6124

                 Post-op VTE                      0.61%       1.26%    <0.0001

                 Non-fatal PE                     0.27%       0.54%    <0.0003

                  Autopsy PE                      0.11%       0.41%    <0.0001

                      Death                       0.71%       3.14%    <0.0001




Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
                       Natural History of VTE in Cancer Surgery:
                                     The @RISTOS Registry

      ►    Web-Based Registry of Cancer Surgery
                     Tracked 30-day incidence of VTE in 2373 patients
                     Type of surgery
                          • 52% General
                          • 29% Urological
                          • 19% Gynecologic
                     82% received in-hospital thromboprophylaxis
                     31% received post-discharge thromboprophylaxis
                                      Findings
      ►    2.1% incidence of clinically overt VTE (0.8% fatal)
      ►    Most events occur after hospital discharge
      ►    Most common cause of 30-day post-op death

Agnelli, abstract OC191, ISTH 2003
                           Prophylaxis in Surgical Patients

               LMWH vs. UFH
               ►   Abdominal or pelvic surgery for cancer (mostly colorectal)
               ►   LMWH once daily vs. UFH tid for 7–10 days post-op
               ►   DVT on venography at day 7–10 and symptomatic VTE


                Study                   N             Design        Regimens
            ENOXACAN 1                 631        double-blind   enoxaparin vs. UFH

       Canadian Colorectal
                                       475        double-blind   enoxaparin vs. UFH
       DVT Prophylaxis 2




1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103
2. McLeod R, et al. Ann Surg 2001;233:438-444
                                            Prophylaxis in Surgical Patients

                                          20%
                                                18.2%
                                                                P>0.05
             Incidence of Outcome Event




                                                       14.7%                     ENOXACAN
                                          15%

                                                                                 UFH 5000 U tid
                                          10%                                     N=319
                                                                                 enoxaparin 40 mg
                                                                   2.9%   4.1%    N=312
                                          5%


                                          0%
                                                 VTE           Major Bleeding


ENOXACAN Study Group. Br J Surg 1997;84:1099–103
                                          Prophylaxis in Surgical Patients


                                    20%
                                            16.9%
                                                                           Canadian
       Incidence of Outcome Event




                                                         P=0.052           Colorectal DVT
                                                 13.9%
                                    15%                                    Prophylaxis Trial
                                                                            UFH 5000 U tid
                                                                            N=234
                                    10%
                                                                            enoxaparin 40 mg
                                                                            N=241
                                    5%
                                                            1.5% 2.7%


                                    0%
                                            VTE           Major Bleeding
                                           (Cancer)             (All)
McLeod R, et al. Ann Surg 2001;233:438-444
                               Prophylaxis in Surgical Patients

       Extended prophylaxis
       ►    Abdominal or pelvic surgery for cancer
       ►    LMWH for ~ 7 days vs. 28 days post-op
       ►    Routine bilateral venography at ~day 28

             Study                   N             Design                           Regimens

       ENOXACAN II                  332        Double-blind                Enoxaparin vs. placebo

          FAME
                                    198          Open-label            Dalteparin vs. no prophylaxis
          (subgroup)




1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
2. Rasmussen M, et al (FAME) Blood 2003;102:56a
                                                      Extended Prophylaxis in
                                                         Surgical Patients

                                          15%
             Incidence of Outcome Event




                                                12.0%
                                                                                          ENOXACAN II
                                          10%
                                                          P=0.02                          placebo
                                                                                          N=167

                                                   4.8%                  5.1%             enoxaparin 40 mg
                                          5%                      3.6%                    N=165

                                                        1.8%
                                                               0.6%             0% 0.4%      NNT = 14

                                          0%
                                                VTE     Prox      Any      Major
                                                        DVT       Bleeding Bleeding


Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
               Major Abdominal Surgery: FAME Investigators—
                           Dalteparin Extended
      ►    A multicenter, prospective, assessor-blinded, open-label,
           randomized trial: Dalteparin administered for 28 days
           after major abdominal surgery compared to 7 days of
           treatment
      ►    RESULTS: Cumulative incidence of VTE was reduced
           from 16.3% with short-term thromboprophylaxis (29/178
           patients) to 7.3% after prolonged thromboprophylaxis
           (12/165) (relative risk reduction 55%; 95% confidence
           interval 15-76; P=0.012).
      ►    CONCLUSIONS: 4-week administration of dalteparin,
           5000 IU once daily, after major abdominal surgery
           significantly reduces the rate of VTE, without increasing
           the risk of bleeding, compared with 1 week of
           thromboprophylaxis.
Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
                   ASCO Guidelines: VTE Prophylaxis

         ►   All patients undergoing major surgical intervention
             for malignant disease should be considered for
             prophylaxis.


         ►   Patients undergoing laparotomy, laparoscopy, or
             thoracotomy lasting > 30 min should receive
             pharmacologic prophylaxis.


         ►   Prophylaxis should be continued at least 7 – 10
             days post-op. Prolonged prophylaxis for up to 4
             weeks may be considered in patients undergoing
             major surgery for cancer with high-risk features.

Lyman, JCO, 2007
                            Central Venous Catheters

        Thrombosis is a potential complication of central
            venous catheters, including these events:
                        –Fibrin sheath formation
                        –Superficial phlebitis
                        –Ball-valve clot
                        –Deep vein thrombosis (DVT)
        • Incidence up to 60% from historical data

        • ACCP guidelines recommended routine prophylaxis
          with low dose warfarin or LMWH

Geerts W, et al. Chest 2001;119:132S-175S
                       Prophylaxis for Venous Catheters

                                               Placebo-Controlled Trials

              Study                           Regimen                            N               CRT (%)

           Reichardt*                 Dalteparin 5000 U od                      285               11 (3.7)
           2002                             placebo                             140                5 (3.4)

             Couban*                      Warfarin 1mg od                       130                 6 (4.6)
             2002                            placebo                            125                 5 (4.0)

             ETHICS†                  Enoxaparin 40 mg od                       155              22 (14.2)
             2004                          placebo                              155              28 (18.1)
           *symptomatic outcomes; †routine venography at 6 weeks



Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et al. Proc ASCO
2004;23:730
                    Central Venous Catheters: Warfarin

                                Tolerability of Low-Dose Warfarin
       ►    95 cancer patients receiving FU-based infusion
            chemotherapy and 1 mg warfarin daily
       ►    INR measured at baseline and four time points
       ►    10% of all recorded INRs >1.5
       ►    Patients with elevated INR
                                  2.0–2.9    6%
                                  3.0–4.9    19%
                                  >5.0       7%


Masci et al. J Clin Oncol. 2003;21:736-739
          Prophylaxis for Central Venous
                 Access Devices
Summary
►   Recent studies demonstrate a low
    incidence of symptomatic catheter-related
    thrombosis (~4%)
►   Routine prophylaxis is not warranted to
    prevent catheter-related thrombosis, but
    catheter patency rates/infections have not
    been studied
►   Low-dose LMWH and fixed-dose warfarin
    have not been shown to be effective for
    preventing symptomatic and asymptomatic
    thrombosis
                             7th ACCP Consensus Guidelines



              No routine prophylaxis to prevent
          thrombosis secondary to central venous
         catheters, including LMWH (2B) and fixed-
                      dose warfarin (1B)




Geerts W, et al. Chest 2004; 126: 338S-400S
      Primary Prophylaxis in Cancer Radiotherapy
                   The Ambulatory Patient


►   No recommendations from ACCP
►   No data from randomized trials (RCTs)
►   Weak data from observational studies in
    high risk tumors (e.g. brain tumors; mucin-
    secreting adenocarcinomas: Colorectal,
    pancreatic, lung, renal cell, ovarian)
►   Recommendations extrapolated from
    other groups of patients if additional risk
    factors present (e.g. hemiparesis in brain
    tumors, etc.)
      Cancer and Thrombosis




Ambulatory Chemotherapy Patients
               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 with institutionalization             21.72
       Trauma                                               12.69
       Institutionalization without recent surgery          7.98
       Malignancy with chemotherapy                         6.53
       Prior CVAD or pacemaker                              5.55
       Prior superficial vein thrombosis                    4.32
       Malignancy without chemotherapy                      4.05

       Neurologic disease w/ extremity paresis              3.04
       Serious liver disease                                0.10

Heit JA et al. Thromb Haemost. 2001;86:452-463
                       VTE Incidence In Various Tumors

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

►Recommended for hospitalized
 cancer patients


►Not recommended or generally used
 for outpatients
  ●   Very little data
  ●   Heterogeneous


      Need for risk stratification
                   Ambulatory Cancer plus Chemotherapy

                               Study Methods

                  ► Prospective observational study of
                    ambulatory cancer patients initiating a new
                    chemotherapy regimen, and followed for a
                    maximum of 4 cycles

                  ► 115 U.S. centers participated

                  ► Patients enrolled between March, 2002 and
                    August, 2004 who had completed at least
                    one cycle of chemotherapy were included in
                    this analysis

Khorana, Cancer, 2005
                  Ambulatory Cancer plus Chemotherapy

                                    Study Methods
       ► VTE events were recorded during mid-cycle or new-cycle
         visits

       ► Symptomatic VTE was a clinical diagnosis made by the
         treating clinician

       ► Statistical analysis
             ●    Odds ratios to estimate relative risk
             ●    Multivariate logistic regression to adjust for other risk factors




Khorana, Cancer, 2005
                                Patient Characteristics

                  Characteristic                No. (%)
                        All patients              3,196

                         Age > 65               1,243 (39)

                         Female                 2,136 (67)

                         Stage IV               1,150 (37)

               Performance status 0-1           2,912 (91)

       Pre-chemotherapy platelet count >
                                                691 (22)
                350,000/mm3




Khorana, Cancer, 2005
                                Patient Characteristics (2)

                         Site of Cancer              No. (%)
                           All patients               3,196

                             Breast                 1,137 (36)

                              Lung                   612 (19)
                             Colon                   353 (11)
                             Ovary                   225 (7)

                            Upper GI                  91 (3)

                Non-Hodgkin’s lymphoma               287 (9)

                        Hodgkin’s disease             53 (2)

                             Others                  438 (14)

Khorana, Cancer, 2005
                                           Incidence of VTE

                      3.0%
                      2.5%
    Rate of VTE (%)




                      2.0%
                      1.5%
                      1.0%
                      0.5%
                      0.0%
                               Baseline       Cycle 1     Cycle 2    Cycle 3

                                                                     Cumulative rate
            VTE / 2.4 months              VTE/month     VTE /cycle
                                                                       (95% CI)
                       1.93%                0.8%          0.7%       2.2% (1.7-2.8)

Khorana, Cancer, 2005
                            Risk Factors: Site of Cancer


                       12
VTE (%) / 2.4 months




                       10
                        8
                        6
                        4
                        2
                        0




                                  Site of Cancer   Khorana, Cancer, 2005
                                  Incidence of Venous Thromboembolism By
                                 Quartiles of Pre-chemotherapy Platelet Count


                               5.0%
                                                            p for trend=0.005
                               4.5%
   Incidence Of VTE Over 2.4




                               4.0%
                               3.5%
          Months(%)




                               3.0%
                               2.5%
                               2.0%
                               1.5%
                               1.0%
                               0.5%
                               0.0%
                                      <217        217-270        270-337         >337
                                       Pre-chemotherapy Platelet Count/mm   3 (x1000)
Khorana, Cancer, 2005
                        Risk Factors: Multivariate Analysis

                        Characteristic          OR     P value
                        Site of Cancer                   0.03
                          Upper GI              3.88    0.0076
                            Lung                1.86     0.05
                  Lymphoma                      1.5      0.32
      Pre-chemotherapy platelet count >
                                                2.81    0.0002
                 350,000/mm3
     Hgb < 10g/dL or use of red cell growth
                                                1.83     0.03
                      factor
     Use of white cell growth factor in high-
                                                2.09    0.008
                   risk sites




Khorana, Cancer, 2005
                                           Predictive Model

                                  Patient Characteristic        Score

                   Site of Cancer
                   Very high risk (stomach, pancreas)
                                                                  2
                   High risk (lung, lymphoma, gynecologic, GU
                                                                  1
                   excluding prostate)

                           Platelet count > 350,000/mm3          1

                             Hgb < 10g/dL or use of ESA          1

                          Leukocyte count > 11,000/mm3           1

                                          BMI > 35               1


Khorana AA et al. JTH Suppl Abs O-T-002
                                                       Predictive Model
                                                       Actual Incidence
                                                       Estimated Incidence
Incidence of VTE Over 2.4 Months




                                   18%                 95 % Confidence Limits

                                   16%
                                   14%
                                   12%
                                   10%
                                   8%
                                   6%
                                   4%
                                   2%
                                   0%
                                                 0         1              2          3          4

                                         Risk Score               0             1   2     3          4
                                             N                  1,352         974   476   160       33
                                    VTE(%) /2.4 mo.s             0.8          1.8   2.7   6.3       13.2
                                                 Predictive Model Validation
                                      8%
       Rate of VTE over 2.5 mos (%)

                                                                                    7.1%
                                      7%        Development cohort                         6.7%

                                      6%        Validation cohort

                                      5%

                                      4%

                                      3%

                                      2%                             1.8% 2.0%

                                      1%      0.8%
                                                     0.3%
                                      0%
                                             n=734 n=374            n=1627 n=842   n=340 n=149

                                      Risk   Low (0)         Intermediate(1-2)     High(>3)

Khorana AA et al. JTH Suppl Abs O-T-002
Cancer and Thrombosis




VTE Treatment
           Standard Treatment of VTE
              Can We Do Better Than This?



Initial treatment      5 to 7 days

 LMWH or UFH



Long-term therapy                       > 3 months

 Vitamin K antagonist (INR 2.0 - 3.0)
                                 Recurrent VTE in Cancer

                   Subset Analysis of the Home Treatment 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 Treatment Studies

                             Major Bleeding
                     Events per 100 patient years
                                                      P-value
                                           Non-
                      Malignant
                                          malignant

                            13.3             2.1      0.002




Hutten et.al. J Clin Oncol 2000;18:3078
               Oral Anticoagulant Therapy
            in Cancer Patients: Problematic

► Warfarin       therapy is complicated by:

    ●   Difficulty maintaining tight therapeutic control, due
        to anorexia, vomiting, drug interactions, etc.
    ●   Frequent interruptions for thrombocytopenia and
        procedures
    ●   Difficulty in venous access for monitoring
    ●    Increased risk of both recurrence and bleeding

►   Is it reasonable to substitute long-term LMWH
    for warfarin ? When? How? Why?
                          CLOT: Landmark Cancer/VTE Trial


                                                                 Dalteparin    Dalteparin

 CANCER PATIENTS WITH
                      Randomization
    ACUTE DVT or PE


                [N = 677]                                        Dalteparin   Oral Anticoagulant


       ►     Primary Endpoints: Recurrent VTE and Bleeding

       ►     Secondary Endpoint: Survival


Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
                                                             Landmark CLOT Cancer Trial
                                                                  Reduction in Recurrent VTE

                      Probability of Recurrent VTE, %   25                          Risk reduction = 52%
                                                                  Recurrent VTE
                                                                                    p-value = 0.0017
                                                        20


                                                        15                                  OAC


                                                        10
                                                                                            Dalteparin
                                                         5


                                                        0

                                                              0     30   60   90    120   150      180   210
Lee, Levine, Kakkar, Rickles et.al. N Engl                               Days Post Randomization
J Med, 2003;349:146
                                       Bleeding Events in CLOT



                                             Dalteparin           OAC         P-value*
                                                    N=338         N=335


             Major bleed                         19 ( 5.6%)      12 ( 3.6%)    0.27


               Any bleed                         46 (13.6%)      62 (18.5%)    0.093



              * Fisher’s exact test



Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
                   Treatment of Cancer-Associated VTE

                                 Length of         Recurrent    Major
                                                                           Death
     Study            Design     Therapy      N      VTE       Bleeding
                                                                            (%)
                                 (Months)            (%)         (%)
CLOT Trial         Dalteparin
(Lee 2003)         OAC                       336   9 0.002     6    NS     39 NS
                                    6
                                             336   17          4           41

CANTHENOX          Enoxaparin
(Meyer 2002)       OAC                       67    11 0.09     7    0.09   11
                                    3                                         0.03
                                             71    21          16          23

LITE               Tinzaparin
(Hull ISTH 2003)   OAC                       80    6    0.03   6    NS     23 NS
                                    3
                                             87    11          8           22

ONCENOX            Enox (Low)                32    3.4
(Deitcher ISTH     Enox (High)                         NS           NS        NR
                                    6        36    3.1
2003)              OAC
                                             34    6.7
                         Treatment and 2° Prevention of VTE
                              in Cancer – Bottom Line
                                        New Development

►   New standard of care is LMWH at therapeutic doses
    for a minimum of 3-6 months (Grade 1A
    recommendation—ACCP)
►   NOTE: Dalteparin is only LMWH approved (May,
    2007) for both the treatment and secondary
    prevention of VTE in cancer
►   Oral anticoagulant therapy to follow for as long as
    cancer is active (Grade 1C recommendation—ACCP)


Buller et.al. Chest Suppl 2004;126:401S-428S
                                                      CLOT 12-month Mortality
                                                           All Patients

                                            100
                                            90
               Probability of Survival, %




                                            80
                                            70
                                                                           Dalteparin
                                            60
                                            50                OAC
                                            40
                                            30
                                            20
                                            10                             HR 0.94 P-value = 0.40
                                             0

                                                  0   30 60 90 120   180      240    300     360
                                                             Days Post Randomization
Lee A, et al. ASCO. 2003
                                                      Anti-Tumor Effects of LMWH
                                                         CLOT 12-month Mortality
                                                        Patients Without Metastases (N=150)

                                            100
                                            90                                 Dalteparin
               Probability of Survival, %




                                            80
                                            70
                                            60                                     OAC
                                            50
                                            40
                                            30
                                            20
                                            10
                                                                        HR = 0.50 P-value = 0.03
                                             0

                                                  0   30 60 90 120 150 180   240    300     360

                                                             Days Post Randomization
Lee A, et al. ASCO. 2003
                                LMWH for Small Cell Lung Cancer
                                                  Turkish Study

        ►   84 patients randomized: CEV +/- LMWH (18 weeks)

        ►   Patients balanced for age, gender, stage, smoking history,
            ECOG performance status

                                                Chemotherapy
                                                                  Chemo alone   P-value
                                                plus Dalteparin

     1-y overall survival, %                         51.3            29.5        0.01

     2-y overall survival, %                         17.2             0.0        0.01

     Median survival, m                              13.0             8.0        0.01

              CEV = cyclophosphamide, epirubicin, vincristine;
              LMWH = Dalteparin, 5000 units daily

Altinbas et al. J Thromb Haemost 2004;2:1266.
                                                              VTE Prophylaxis Is Underused
                                                                in Patients With Cancer

                                                   Cancer:                  Major
                                                   FRONTLINE Survey1—      Surgery2
        Rate of Appropriate Prophylaxis, %



                                             100
                                                   3891 Clinician            89
                                              90   Respondents
                                              80
                                                   Cancer:
                                              70   Surgical                                Major                            Confirmed DVT
                                              60       52
                                                                                      Abdominothoracic                       (Inpatients)5
                                                                                      Surgery (Elderly)3      Medical
                                              50                                                            Inpatients4
                                                                                                                                   42
                                                                                              38
                                              40                                                                33
                                                                 Cancer:
                                              30                 Medical
                                              20
                                              10                    5
                                               0
                                                   FRONTLINE FRONTLINE:    Stratton        Bratzler           Rahim           DVT FREE
                                                    Surgical   Medical

1. Kakkar AK et al. Oncologist. 2003;8:381-388
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340                           4. Rahim SA et al. Thromb Res. 2003;111:215-219
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912                         5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
     Clotting, Cancer, and Clinical Strategies


  Venous Thromboembolism (VTE)
        Prophylaxis in the
    Cancer Patient and Beyond

Guidelines and Implications for Clinical Practice

             John Fanikos, RPh, MBA
                Assistant Director of Pharmacy
                Brigham and Women’s Hospital
            Assistant Clinical Professor of Pharmacy
                    Northeastern University
             Massachusetts College of Pharmacy
                           Boston, MA
         Outline of Presentation


►   Guidelines for VTE prevention
►   Performance to date
►   Opportunities for improvement
►   Guidelines for VTE Treatment
►   Performance to date
• www.nccn.org
• NCCN Clinical Practice Guidelines in
Oncology™
• “…The panel of experts includes medical
and surgical oncologists, hematologists,
cardiologists, internists, radiologists. And a
pharmacist.”
• www.asco.org
•Recommendations for VTE Prophylaxis &
Treatment in Patients with Cancer
                              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
        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

                                1A is the highest possible grade
                        Indicates that benefits outweigh risks, burdens, and costs,
                                   with consistent RCT level of evidence

Geerts WH et al. Chest. 2004;126(suppl):338S-400S
                       NCCN Practice Guidelines in VTE Disease
     At Risk Population                                       Initial Prophylaxis
   ►    Adult patient
                                                                      Continue
                                                                Prophylactic anticoagulation
                                                                therapy (category 1) + sequential
   ►    Diagnosis or
        clinical
        suspicion of
                                 Relative contra-
                                 indication to
                                                                  Prophylaxis
                                                                compression device (SCD)

                                                                Mechanical prophylaxis (options)

   ►
        cancer
        Inpatient
                                 anticoagulation
                                 treatment
                                                                - SCD
                                                                           After
                                                                - Graduated compression stockings


   ►    Age
               RISK FACTOR ASSESSMENT                             Discharge ?
                                                                Modifiable risk factors: Lifestyle,
                                                                smoking, tobacco, obesity,
   ►    Prior VTE                                               activity level/exercise
   ►    Familial thrombophilia
   ►    Active cancer                                                 AGENTS ASSOCIATED
   ►    Trauma                                                        WITH INCREASED RISK
   ►    Major surgical procedures                                 ►   Chemotherapy
   ►    Acute or chronic medical illness requiring                ►   Exogenous estrogen
        hospitalization or prolonged bed rest                         compounds
   ►    Central venous catheter/IV catheter                           - HRT
   ►    Congestive heart failure                                      - Oral contraceptives
   ►    Pregnancy                                                     - Tamoxifen/Raloxifene
   ►    Regional bulky lymphadenopathy with                           - Diethystilbestrol
        extrinsic vascular compression                            ►   Thalidomide/lenalidomide
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
                                 NCCN Practice Guidelines
                                    in VTE Disease

            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 subcutaneous daily

   ► Pentasaccharide
        - Fondaparinux 2.5 mg subcutaneous daily

   ► Unfractionated heparin 5,000 units subcutaneous 3 times daily



http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
                                      NCCN Practice Guidelines
                                         in VTE Disease
                           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

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
           ►   Should hospitalized patients with cancer
               receive anticoagulation for VTE
               prophylaxis ?
           ●   “Hospitalized patients with cancer should be
               considered candidates for VTE prophylaxis in
               the absence of bleeding or other
               contraindications to anticoagulation”




Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
          ►    Should ambulatory patients with cancer
               receive anticoagulation for VTE
               prophylaxis during systemic
               chemotherapy?
          ●    “Routine prophylaxis is not recommended.”
          ●    “Patients receiving thalidomide or lenalidomide
               with chemotherapy or dexamethasone are at high
               risk for thrombosis and warrant prophylaxis.”




Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
        ►   Should hospitalized patients with cancer
            undergoing surgery receive perioperative VTE
            prophylaxis ?
        ●   All patients should be considered for
            thromboprophylaxis.
        ●   Procedures greater than 30 minutes should receive
            pharmacologic prophylaxis.
        ●   Mechanical methods should not be used as
            monotherapy.
        ●   Prophylaxis should continue for at least 7-10 days
            post-op. Prolonged prophylaxis may be considered
            for cancer with high risk features.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
                                                  Compliance With ACCP VTE
                                                 Prophylaxis Guidelines Is Poor
 Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group

                              70,000                   62,012
                                                                                At risk for DVT/PE
                                                                      35,124
                                                                                Received compliant care

                              10,000
                                                                                                  9175
         Number of patients




                              5,000


                                         2324

                                                                                 1388

                                                        15.3%         12.7%                9.9%          6.7%
                                         52.4%
                                 0
                                       Orthopedic   At-risk Medical   General   Urologic      Gynecologic
                                        Surgery       Conditions      Surgery   Surgery         Surgery

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
                                 Reasons for Inadequate Duration
                                      of VTE Prophylaxis


                                                             Started late &
                                             Started Late                     Ended Early
                                                             Ended Early
         At-Risk Medical                      1,347 (22.5)    2,961 (49.4)    1,686 (28.1)
               (n=5,994)
       Abdominal Surgery                        824 (25.4)    1,764 (54.4)     652 (20.1)
               (n=3,240)
         Urologic surgery                        18 (11.4)      73 (46.2)      67 (42.4)
                (n=158)
      Gynecologic surgery                        13 (8.0)       43 (26.4)      107 (65.6)
                (n=163)
           Neurosurgery                          66 (26.4)     125 (50.0)      59 (23.6)
                (n=250)




HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76
                                      Predictors of the Use of
                                       Thromboprophylaxis
             Effect                Odds Ratio (95% CI)
               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
Kahn SR et Al. Thromb Res 2007; 119:145-155                     Odds Ratio
                                  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
MD Computer Alert
                                      Electronic Alerts to Prevent VTE


                            100
                            98
            DVT or PE (%)
            Freedom from




                            96                                                         Intervention group
                            94
                            92                                                             Control group
                            90                P<0.001

                            88
                                  0                     30                  60               90
                                                                   Time (days)
  Number at risk
  Intervention group                  1,255                  977                 900              853
  Control group                       1,251                  876                 893              839


Kucher N, et al. N Engl J Med. 2005;352:969-77
                   Mechanical Thromboprophylaxis In Critically Ill Patients:
                                Review And Meta-analysis
           RESULTS: 21 relevant studies (5 randomized controlled trials, 13
           observational studies, and 3 surveys) were found. A total of 811 patients
           were randomized in the 5 randomized controlled trials; 3421 patients
           participated in the observational studies.
           Trauma patients only were enrolled in 4 randomized controlled trials and 4
           observational studies. Meta-analysis of 2 randomized controlled trials with
           similar populations and outcomes revealed that use of compression and
           pneumatic devices did not reduce the incidence of venous
           thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).
           A range of methodological issues, including bias and confounding variables,
           make meaningful interpretation of the observational studies difficult.

           CONCLUSIONS: The role of mechanical approaches to
           thromboprophylaxis for intensive care patients remains
           uncertain


Limbus A et al. Am J Crit Care, 2006;15:402-10
                          Fatal Pulmonary Embolism During
                              Anticoagulant Prophylaxis
Study,
Year                          Prophylaxis          Placebo              RR Fixed                     RR Fixed
(Reference)                           n/n                  n/n          (95% CI)                     (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

                                                           0.001 0.01 0.1 1.0 10 100 1000
                                                 Favors Treatment          Favors Placebo

     Dentali, F. et. al. Ann Intern Med 2007;146:278-288
                         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
                                       Heparin, Low Molecular
                                      Weight Heparin Prophylaxis
                                           LMWH vs UFH
►Meta-analysis
                                           DVT                                             Risk
►36  randomized                            Study                                      Reduction (95% CI)       Weight %
 controlled trials                         Harenberg et al, 1990                           0.70 (0.16-3.03)        3.4

►23,000 hospitalized                       Turpie et al, 1992                              0.29 (0.10-0.81)       11.4

 medical patients                          Dumas et al, 1994                               0.74 (0.38-1.43)        14.4
                                           Bergmann & Neuhart                              0.94 (0.39-2.26)        8.1
►UFH 5,000 units TID                       et al, 1996
 is more effective in                      Harenberg et al, 1996                           2.89 (0.30-27.71)       0.8
 preventing DVT than                       Lechler et al, 1996                             0.25 (0.03-2.23)        3.3
 UFH BID                                   Hillbom et al, 2002                             0.55 (0.31-0.98)        20.5
                                           Kleber, et al 2003                              0.77 (0.43-1.38)        19.4
►Low molecular weight
                                           Diener et al, 2006                              0.76 (0.42-1.38)       18.9
 heparin is 33% more
 effective than                            Overall (95% CI)                                0.68 (0.52-0.88)

 unfractionated heparin
 in preventing DVT                                                 0.1      1.0       10
                                                                         Risk Ratio
  ● RR for DVT 0.68
      (p=0.004)                                          LMWH Better           LMWH Worse


Wein L et al. Arch Intern Med. 2007;167:1476-86.
                                      BWH/DFCI Partners
                                     Cancer Care Experience
                Compliance with UFH TID                             Reasons for Non-Compliance

          100       95                                  80
           90                82                                                              68
                                                        70
           80
           70                                           60
Percent




           60
           50                                           50




                                              Percent
           40                         29                40
           30                                                                  28
           20                                           30
           10                                           20
            0
                   <3       <3      4 doses             10      4
                  doses    Doses                        0
                  Day 1    Day 2+                            Off Floor       Refused       Unknown


                 • Consecutive    patients, < 60 days
                 • 2 Nursing units
                 • LOS ranged from 3 days to 31 days
                 • Number of days where doses were omitted ranged from
                 1 to 6 days
                                    VTE Incidence: More Common
                                      in the Outpatient Setting
   ►    Medical records of residents (n=477,800)
   ►    587 VTE events (104 per 100,000 population)
   ►    30 Day recurrence 4.8 %
                                                                 Patients receiving prophylaxis
                                                                    during high risk periods
            VTE Event Location                             52%
                                                           51%
                                      25%                  51%
                                                           50%
                                                           50%
         75%                                               49%
                                                           49%
                                                           48%
           Inpatient         Outpatient                          Prophylaxis          None


Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777
                           DVT, PE Diagnosis and Treatment




http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
                                       Thrombosis in Malignancy
                             7TH ACCP Consensus Conference Recommendations



                  Initial Phase                                  Chronic Phase
                 5-7 days                                       Continue anticoagulation
                                                             (warfarin or LMWH) long-term or
          Dalteparin 200/kg q24h
                                                                until malignancy resolves
               (GRADE 1A)                                              (GRADE 1C)




       5 - 7 days                                3 - 6 mos             6 mos - indefinite


                                          Subacute Phase
                                     3 - 6 months
                                          PRESS RELEASE: May 2, 2007
                          Dalteparin 150 units/kg q24h
                                     (GRADE 1A)
       FDA Approves Dalteparin as First Low-Molecular Weight Heparin for Extended
         Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer

Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s
                       NCCN Practice Guidelines—Venous
                          Thromboembolic Disease
                            Therapeutic Anticoagulation Treatment for
                          DVT, PE, and Catheter-Associated Thrombosis

   Immediate
   ► LMWH
       - Dalteparin (200 units/kg subcutaneous daily)
       - Enoxaparin (1 mg/kg subcutaneous every 12 hrs)
       -Tinzaparin (175 units/kg subcutaneous daily)


   ►      Pentasaccharide
           - Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50-100 lg]; 10 mg [>100 kg]
              subcutaneous daily

   ►      Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour,
          target aPTT to 2.0-2.9 x control)


http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
                       NCCN Practice Guidelines—Venous
                          Thromboembolic Disease
                           Therapeutic Anticoagulation Treatment for
                         DVT, PE, and Catheter-Associated Thrombosis

  Long Term
  ►      LMWH is preferred as monotherapy without warfarin in patients with
         proximal DVT or PE and prevention of recurrent VTE in patients with
         advanced or metastatic cancer
  ►      Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR
         value; target INR 2.0-3.0)

  Duration of Long Term Therapy
  ►      Minimum time of 3-6 mo for DVT and 6-12 mo for PE
  ►      Consider indefinite anticoaugulation if active cancer or persistent risk
         factors
  ►      For catheter associated thrombosis, anticoagulate as long as catheter
         is in place and for 1-3 mo after catheter removal
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
       ►    What is the best treatment for patients with
            cancer with established VTE to prevent recurrent
            VTE ?
       ●    LMWH is the preferred approach for the initial 5-10
            days.
       ●    LMWH, given for at least 6 months, is the preferred
            for long-term anticoagulant therapy.
       ●    After 6 months, anticoagulation therapy should be
            considered for select patients.
       ●    For CNS malignancies, elderly patients
            anticoagulation is recommended with careful
            monitoring and dose adjustment.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
      ►    Should patients with cancer receive
           anticoagulants in the absence of
           established VTE to improve survival?

      ●    “Anticoagulants are not recommended to improve
           survival in patients with cancer without VTE.”




Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
                            Antithrombotic Therapy Practices
                                    in U.S. Hospitals
                                                     70%
         ►Survey   of 38 U.S.                        60%                                          50.7%




                                       Percent (%)
            Hospitals                                50%
                                                     40%
                                                                                26.6%
                                                     30%
         ►n=939         DVT or PE                    20%                                                            14.8%
                                                              7.9%
                                                     10%
         ►50%    patients                            0%
            reached INR >2 for                             Acute (n=72)   Bridge (n=241)      Long Term
                                                                                                (n=460)
                                                                                                              Other (n=134)

            2 consecutive days                                                          Therapy

                                                     14                                                    12.7
                                                     12
          Therapy            n (%)
                                       LOS, Days

                                                     10
          LMWH           527 (56.1%)                                                        8.1
                                                      8
          UFH            562 (59.8%)                          6.1
                                                      6
          UFH SC           78 (8.3%)                                        4
                                                      4
          DTI              6 (0.6%)
                                                      2
                                                      0
                                                            Acute         Bridge         Long term         Other
                                                            (n=72)        (n=241)         (n=460)         (n=134)
Tapson V et al. Arch Intern Med 2005
                Self-Managed Long Term LMWH Therapy
                          2212 patients with proximal vein thrombosis assessed
                                               for eligibility                      1475 excluded for
                                                                                  anticoagulant violations
                                                                                     or inability to give
                                                                                      written consent
                                             737
                                          Randomized

    369 assigned to LMWH                                       369 assigned to usual care with
                                                               heparin & warfarin




                3 lost to follow=up                                      3 lost to follow-up

               1 withdrew consent                                        5 withdrew consent




    369 included in Analysis                                   369 included in Analysis


Hull R. Am Jour Med 2007; 120:72-82
                     Self-Managed Long Term LMWH Therapy

                                 Tinzaparin       Usual Care      Absolute Difference
       Outcomes                                                                          p-value
                                      (n=369)       (n=368)             (95% CI)

    New VTE at 3 Mos                  18 (4.9)      21 (5.7)         -0.8 (-4.2-2.4)       NS


   New VTE at 12 Mos                  33 (8.9)      36 (9.8)         -0.8 (-5.5-3.5)       NS

        All Bleeding                  48 (13.0)     73 (19.8)        -6.8 (-12.4--1.5)   p=.011
      Major Bleeding                  12 (3.3)      17 (4.6)         -1.4 (-4.3-1.4)       NS
      Minor Bleeding                  36 (9.8)      56 (15.2)        -5.5 (-10.4--0.6)   p=.022

   Stratified Bleeding-
                                31/144 (21.5)     39/146 (26.7)     -5.2 (-15%-4.6%)       NS
        High Risk

 Stratified Bleeding-Low
                                 17/225 (7.6)     34/222 (15.3)     -7.8 (-13.6--1.9%)    p=.01
            Risk

    Thrombocytopenia
                                      21 (5.7)       9 (2.4)          1.6 (-3.6-0.3)       NS
         (<150)
      Bone Fracture                    4 (1.1)       7 (1.9)         -0.8 (-0.9-2.6)       NS
Hull R. Am Jour Med 2007; 120:72-82
                                 LMWHs and Bleeding in Patients
                                    with Renal Dysfunction




                                                      Dosage adjustments
                                                      for renal dysfunction




Lim W et al. Ann Intern Med 2006; 144:673-84
                  Conclusions

Examine your current practices of VTE
      prophylaxis and treatment

► Review available guidelines as a benchmark
► Consider the use of a pharmacologic or
  mechanical intervention
► Evaluate use of Reminder or Risk Scoring
  Systems
► Utilize the regimen providing the best efficacy in
  reducing events and offering best compliance
► Follow-up with patients to monitor and avoid
  adverse events and to ensure optimal outcomes

				
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