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					                         A Year 2009 Update for
                      The Health System Pharmacist


  The Pharmacologic Foundations of DVT
    Prophylaxis in the Setting of Cancer


                       Program Co-Chairs
Edith Nutescu, PharmD, FCCP         Samuel Z. Goldhaber, MD
      Clinical Associate Professor               Professor of Medicine
           Pharmacy Practice                    Harvard Medical School
      Affiliate Faculty, Center for             Cardiovascular Division
     Pharmacoeconomic Research            Director, Venous Thromboembolism
    Director, Antithrombosis Center                  Research Group
  The University of Illinois at Chicago     Brigham and Women’s Hospital
 College of Pharmacy & Medical Center                 Boston, MA
               Chicago, IL
             Welcome and Program Overview

Jointly sponsored by the University of Florida College of Pharmacy and
CMEducation Resources, LLC.

Jointly sponsored by the 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
               CEU Credit Designation Statement

The University of Florida College of Pharmacy is
accredited by the Accreditation Council for Pharmacy
Education as a provider of continuing pharmacy
education.

The University of Florida College of Pharmacy will mail
the Statements of Continuing Pharmacy Education
Credit within 4 weeks after the course.

To receive credit you must attend the sessions for
which you want credit and complete an evaluation form.

The College of Pharmacy will award 2 (two) continuing
pharmacy education credits (2.0 CEU’s) upon
completion of this program.
                  Program Educational Objectives

As a result of this session, attendees will be able to:

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

► Outline specific strategies for risk-directed prophylaxis against DVT in
  at-risk patients with cancer.

► Describe dose anticoagulation therapy for patients requiring prophylaxis
  in special patient populations.

► Outline steps for avoiding medication errors using anticoagulation in
  cancer patients at risk for DVT.

► List the guidelines for DVT prophylaxis in cancer issued by the National
  Comprehensive Cancer Network (NCCN), the American College of
  Chest Physicians (ACCP), and the Surgeon General’s Report.
                                  Program Faculty

Program Co-Chairs                                 Distinguished Experts and Presenters
Edith Nutescu, PharmD, FCCP                       John Fanikos, RPh, MBA
Clinical Associate Professor, Pharmacy Practice   Assistant Director of Pharmacy
Affiliate Faculty, Center for Pharmacoeconomic    Brigham and Women’s Hospital
 Research                                         Assistant Clinical Professor of Pharmacy
Director, Antithrombosis Center                   Northeastern University
The University of Illinois at Chicago             Massachusetts College of Pharmacy
 College of Pharmacy & Medical Center             Boston, MA
Chicago, IL

                                                  Karen Fiumara, PharmD
Samuel Z. Goldhaber, MD                           Medication Safety Officer
Professor of Medicine                             Brigham and Women’s Hospital
Harvard Medical School                            Adjunct Assistant Professor of Pharmacy Practice
Cardiovascular Division                           Massachusetts College of Pharmacy and Allied
Director, Venous Thromboembolism Research          Health Sciences
 Group                                            Adjunct Assistant Professor of Pharmacy Practice
Brigham and Women’s Hospital                      Bouve’ College of Health Sciences Northeastern
Boston, MA                                         University
                                                  Boston, MA
                Faculty COI Financial Disclosures

Samuel Z. Goldhaber, MD
Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK;
sanofi-aventis;
Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; sanofi-aventis

Edith Nutescu, PharmD
Speakers Bureau: Eisai Inc., GlaxoSmithKline, sanofi-aventis U.S.
Advisory Committees or Review Panels, Board Membership, etc.: Boehringer
Ingelheim Pharmaceuticals, Inc., Scios Inc.

Karen Fiumara, PharmD
Nothing to disclose

John Fanikos, RPh, MBA
Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai
Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines
Company
               A Year 2009 Update for
            The Health System Pharmacist

   Cancer and Prevention of VTE

Landmark Advances and New Paradigms of Care
      for the Health System Pharmacist



                Program Co-Chair
             Samuel Z. Goldhaber, MD
                    Professor of Medicine
                   Harvard Medical School
                   Cardiovascular Division
    Director, Venous Thromboembolism Research Group
               Brigham and Women’s Hospital
                         Boston, MA
               VTE and Cancer—A Looming
                National Healthcare Crisis


           MISSION AND CHALLENGES

Recognizing cancer patients at risk for DVT and identifying
appropriate candidates for long-term prophylaxis and/or
treatment with approved and indicated therapies are
among the most important challenges encountered in
contemporary pharmacy and clinical practice.
            Comorbidity Connection


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




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
                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
                                   ICOPER Cumulative Mortality

                          25


                          20                  17.5%
          Mortality (%)




                          15


                          10


                          5



                          0
                               7   14    30               60     90
                                         Days From Diagnosis


Lancet 1999;353:1386-1389
     Stages of Chronic Venous Insufficiency



1.   Varicose veins
2.   Ankle/ leg edema
3.   Stasis dermatitis
4.   Lipodermatosclerosis
5.   Venous stasis ulcer
                Progression of Chronic Venous Insufficiency




From UpToDate 2006
                                        Rising VTE Incidence in
                                         Hospitalized Patients




Stein PD et al. Am J Cardiol 2005; 95: 1525-1526
                                  DVT Registry (N=5,451):
                                 Top 5 Medical Comorbidities

               1. Hypertension


               2. Immobility


               3. Cancer


               4. Obesity (BMI > 30)


               5. Cigarette Smoking

Am J Cardiol 2004; 93: 259-262
              Implementation



  Implementation of VTE prophylaxis
 continues to be problematic, despite
detailed North American and European
        Consensus guidelines.
  SURGEON
  GENERAL:
   CALL TO
 ACTION TO
PREVENT DVT
   AND PE

September 15, 2008
           Surgeon General’s Call to Action
                  42-Page Document


►   Issued September 15, 2008


►   Endorsed by Secretary, HHS


►   Endorsed by Director, NHLBI


►   Foreword by Acting Surgeon General, Steven K.
    Galson, MD, MPH (RADM, U.S. Public Health
    Service)
               Call to Action for VTE

                   Foreword

►   Dr. Galson’s 1st Call To Action
►   > 350,000-600,000 Americans suffer VTE
    annually
►   > 100,000 U.S. deaths per year
►   Negative impact on QOL of survivors
►   ―Must disseminate info widely‖ to ―address gap‖
    because we’re not applying knowledge
    systematically
                    Call to Action for VTE


I.     Major Public Health Problem

II.    Reducing VTE Risk

III.   Gaps in Application, Awareness of
       Evidence

IV.    Public Health Response

V.     Catalyst for Action
              Symposium Themes

1.   Cancer rates are increasing as heart
     disease Rx improves and as cancer Rx
     improves.
2.   Cancer increases VTE risk.
3.   VTE is preventable (immunize!)
4.   VTE prophylaxis may slow cancer
5.   Increased emphasis on prophylaxis: OSG,
     NCCN, ASCO, ACCP, NATF
6.   Facilitate prophylaxis with alerts.
             A Year 2009 Update for
          The Health System Pharmacist

   Cancer and Prevention of VTE

Landmark Advances and New Paradigms of Care
      for the Health System Pharmacist


        Edith Nutescu, PharmD, FCCP
              Clinical Associate Professor
                   Pharmacy Practice
              Affiliate Faculty, Center for
             Pharmacoeconomic Research
            Director, Antithrombosis Center
          The University of Illinois at Chicago
         College of Pharmacy & Medical Center
                       Chicago, IL
                  Peculiar Relationship
             Between Cancer and Thrombosis



Hypercoagulation/   may indicate
                                    Occult Cancer
   thrombosis




                    may cause
    Cancer                         Hypercoagulation/
                                      thrombosis
                             Thromboembolism in Malignancy

      ►   15% of cancer patients develop venous or arterial
          thrombosis1
      ►   Annual incidence of VTE in all patients: 117 in 100,0002
      ►   Cancer increases risk of thrombosis 4.1-fold3
      ►   Chemotherapy increases risk of thrombosis 6.5-fold3
      ►   Annual incidence of VTE in patients with cancer: 1 in 2004



1.   Green KB, Silverstein RL. Hematol Oncol Clin North Am. 1996;10:499-530.
2.   Silverstein MD et al. Arch Intern Med. 1998;158:585-593
3.   Heit JA et al. Arch Intern Med. 2000;160:809-815
4.   Lee AYY, Levine MN. Circulation. 2003;107(23 Suppl 1):I17-21.
                             Factors That May Affect Risk for
                                Cancer-Associated VTE

Patient-related factors                          Treatment-related factors
►   Older age                                    ►     Recent surgery
►   Comorbidities                                ►     Hospitalization
                                                 ►     Chemotherapy
                                                 ►     Hormonal therapy
Cancer-related factors                           ►     Antiangiogenic agents
► Site of cancer                                 ►     Erythropoiesis-stimulating agents
► Advanced stage
                                                 Biological factors (biomarkers)
► Initial period after diagnosis
                                                 ► Elevated pre-chemotherapy platelet
                                                   count
                                                 ► D-dimer
                                                 ► Tissue factor expression by tumor
                                                   cells
Rao MV, et al., In Khorana AA, Francis CW, eds. 2007
                                         Risk of Inpatient VTE by
                                             Type of Cancer

                         n=3550 n=68 n=326 n=43         n=51    n=53    n=55 n=127 n=95
                    14
                                                               12.10
                    12
   Rate of VTE, %




                    10          9.50
                                                                                        8.96
                     8                         7.41                    7.64
                                       7.00            6.75                      6.50
                     6   5.37

                     4
                     2
                     0




                                   In hospitalized neutropenic cancer patients

Khorana AA et al. J Clin Oncol. 2006;24:484-490.
                                        Risk of Inpatient VTE by
                                            Type of Cancer

                      7   N=3550    n=641          n=650     n=79        n=262    n=204

                      6                                                   5.79
                           5.37
     Rate of VTE, %




                                                   5.01
                      5
                                     4.39
                      4                                      3.87                  3.93

                      3
                      2
                      1
                      0
                           All     Leukemia        NHL     Hodgkin’s   Myeloma    Breast

                                    In hospitalized neutropenic cancer patients



Khorana AA et al. J Clin Oncol. 2006;24:484-490.
                                Patients With Cancer Represent
                                 About 20% of All DVT and PE


      Patients with cancer:
      approximately 19.8%




                                                      All DVT and PE




Heit JA. et al. Arch Intern Med 2002;162:1245-1248.
                                    VTE, Cancer, and Survival
   N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer

                        1.00
                                          DVT/PE and Malignant Disease
                        0.80
       Probability of
          Death




                        0.60
                                                        Malignant Disease
                        0.40
                                                                    DVT/PE Only
                        0.20
                                                      Nonmalignant Disease
                        0.00
                               0   20    40   60     80 100 120       140 160     180
                                                   Number of Days

Levitan N, et al. Medicine 1999;78:285
                                  VTE and Inpatient Mortality

                                    No Venous Thromboembolism
                                    Venous Thromboembolism
                      20
                      18
                      16                               16.13           16.41
                      14
       Mortality, %




                                  14.85
                      12
                      10                       10.59
                       8                                        8.67
                           7.98
                       6
                       4
                       2
                       0      All              Nonmetastatic     Metastatic
                           (n=66,016)             Cancer          Cancer
                                                (n=20,591)      (n=17,360)



Khorana AA et al. J Clin Oncol. 2006;24:484-490.
                       Prophylaxis Rates in Hospitalized Patients




Amin A et al. J Thromb Haemost. 2007; 5:1610-6.
                                 Thromboprophylaxis Is Underutilized
  Appropriate DVT Prophylaxis,
                                 in Non-surgical Patients With Cancer



                                    Premiere Perspective™ database: 72,391
       Patients Receiving




                                     discharges from 225 hospitals between
                                       January 2002 and September 2005
               %




Amin AN et al. J Clin Oncol. 2007;25 (suppl):Abstract 9047.
              Clots and Cancer—A Looming
                National Healthcare Crisis


        MISSION AND CHALLENGES


Recognizing cancer patients at risk for DVT and
       identifying patients who are appropriate
    candidates for long-term prophylaxis and/or
 treatment with approved and indicated therapies
     are among the most important and difficult
      challenges encountered in contemporary
           pharmacy and clinical practice.
          Clotting, Cancer, and Controversies


A Systematic Analysis of VTE Prophylaxis
        in the Setting of Cancer

Linking Science and Evidence to Clinical Practice—What Do
        Trials Teach the Health System Pharmacist?


                   Program Co-Chairman
                  Samuel Z. Goldhaber, MD
                           Professor of Medicine
                          Harvard Medical School
                          Cardiovascular Division
           Director, Venous Thromboembolism Research Group
                      Brigham and Women’s Hospital
                                Boston, MA
                          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
     Mortality (%)   Hospital Mortality With or Without VTE




                       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
   Rate of VTE (%)




                     5.0
                     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
                                                            PE-all patients
Khorana AA et al. Cancer. 2007.
        Thrombosis Risk In Cancer



              Primary Prophylaxis
►   Medical Inpatients

►   Surgery

►   Radiotherapy

►   Central Venous Catheters
    Risk Factors for Cancer-Associated VTE

►   Cancer
    ●   Type
        • Men: prostate, colon, brain, lung
        • Women: breast, ovary, lung
    ●   Stage
►   Treatments
    ●   Surgery
        • 10-20% proximal DVT
        • 4-10% clinically evident PE
        • 0.2-5% fatal PE
    ●   Chemotherapy
    ●   Central venous catheters (~4% generate clinically
        relevant VTE)
►   Patient
    ●   Prior VTE
    ●   Comorbidities
    ●   Genetic background
                                           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
                                                                                                                                                                     Liver




                                                                                                                                                                                                          Bladder
                                                   Brain




                                                                                                     Lung




                                                                                                                                                                             Leukemia
                                                                                 Lymphoma




                                                                                                                                                                                        Breast
                                                                                                                                                     Colon
                                                                       Stomach


                                                                                            Uterus



                                                                                                                        Prostate
                                                           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
Compression                                                  Heparin
                                                             (LMWH)

            Inferior
           Vena Cava                          Oral
             Filter                      Anticoagulants

                                        New Agents: e.g.
                                        Fondaparinux,
                                        Direct anti-Xa inhibitors,
                                        Direct anti-IIa, etc.?
    Rate of VTE (%)   Prophylaxis Studies in Medical Patients




                                 Relative                                 Relative
                                   risk                                     risk
                                reduction                                reduction
                                                    Relative               47%
                                  63%                 risk
                                                   reduction
                                                     44%




                      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 GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
  Cancer and Thrombosis




Surgical Patients
                        Incidence of VTE in Surgical Patients

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


                                       No Cancer          Cancer
                                                                       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, Ann Surg 2006; 243: 89-95
                       Prophylaxis in Surgical Patients

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


              Study                N         Design         Regimens

          ENOXACAN 1              631     double-blind   enoxaparin vs. UFH

      Canadian Colorectal
                                  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



                                                                        Canadian
                                         16.9%
                                                      P=0.052           Colorectal DVT
          Incidence of Outcome Event




                                              13.9%
                                                                        Prophylaxis Trial

                                                                        N=234


                                                                        N=241

                                                         1.5% 2.7%



                                         VTE           Major Bleeding
                                        (Cancer)             (All)
McLeod R, et al. Ann Surg 2001;233:438-444
                                                  Extended Prophylaxis in
                                                     Surgical Patients
             Incidence of Outcome Event




                                          12.0%
                                                                                    ENOXACAN II

                                                    P=0.02
                                                                                    N=167

                                             4.8%                  5.1%
                                                            3.6%                    N=165

                                                  1.8%
                                                         0.6%             0% 0.4%      NNT = 14


                                          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 GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
                               Central Venous Catheters



       Thrombosis is a potential complication of central
           venous catheters, including these events:
                     –Fibrin sheath formation
                     –Superficial phlebitis
                     –Ball-valve clot
                     –Deep vein thrombosis (DVT)



Geerts W, et al. Chest Jun 2008: 381S–453S
                          Prophylaxis for Venous Catheters

                                             Placebo-Controlled Trials

            Study                           Regimen                   N             CRT (%)

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

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

           ETHICS†                Enoxaparin 40 mg daily             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
                      8th ACCP Consensus Guidelines




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




Chest Jun 2008: 454S–545S
      Primary Prophylaxis in Cancer Radiotherapy
                  The Ambulatory Patient

►   No recommendations from ACCP
►   No data from randomized trials (RCTs)
►   Weak data from observational studies in
    high risk tumors (e.g. brain tumors; mucin-
    secreting adenocarcinomas: Colorectal,
    pancreatic, lung, renal cell, ovarian)
►   Recommendations extrapolated from
    other groups of patients if additional risk
    factors present (e.g., hemiparesis in brain
    tumors, etc.)
  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
                                          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
                           10
    VTE (%) / 2.4 months




                            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 mos.             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
                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                                 Days Post Randomization
Engl 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                336   9     0.002   6    NS     39 NS
                                     6
(Lee 2003)         OAC                       336   17            4           41


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


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


ONCENOX            Enox (Low)                32    3.4
                   Enox (High)                            NS          NS        NR
(Deitcher ISTH                       6       36    3.1
                   OAC
2003)                                        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)
Chest Jun 2008: 454S–545S
                                                       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 AY et al. J Clin Oncol. 2005; 23:2123-9.
                                                      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 AY et al. J Clin Oncol. 2005; 23:2123-9.
                           LMWH for Small Cell Lung Cancer
                                                  Turkish Study

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

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

                                                Chemotherapy
                                                                  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, %




                                            3891 Clinician
                                            Respondents


                                            Cancer:
                                            Surgical                           Major                         Confirmed DVT
                                                                          Abdominothoracic                    (Inpatients)5
                                                                          Surgery (Elderly)3     Medical
                                                                                               Inpatients4


                                                          Cancer:
                                                          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
                Conclusions and Summary

► Risk factors for VTE in the setting of cancer have
  been well characterized: solid tumors, chemotherapy,
  surgery, thrombocytopenia
► Long-term secondary prevention with LMWH has
  been shown to produce better outcomes than warfarin
► Guidelines and landmark trials support administration
  of LMWH in at risk patients
► Cancer patients are under-prophylaxed for VTE
► Health system pharmacists can play a pivotal role in
  improving clinical outcomes in this patient population
        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
                  Prophylaxis Rates in Hospitalized Patients




Amin A et al. J Thromb Haemost. 2007; 5:1610-6.
                                    VTE, Cancer, and Survival
   N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer

                        1.00
                                          DVT/PE and Malignant Disease
                        0.80
       Probability of
          Death




                        0.60
                                                        Malignant Disease
                        0.40
                                                                    DVT/PE Only
                        0.20
                                                      Nonmalignant Disease
                        0.00
                               0   20    40   60     80 100 120       140 160     180
                                                   Number of Days

Levitan N, et al. Medicine 1999;78:285
                                Time Distribution of VTE Events
                                   Following Cancer Surgery

                         @RISTOS Registry: prospective cohort N=2373

                               12

                               10


       VTE Events               8

                                6

                                4

                                2

                                0
                                      1-5 d   6-10 d   11-15 d   16-20 d   21-25 d   26-30 d   > 30 d


Agnelli G et al. Ann Surg 2006; 243:89-95.
• 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.
               Incidence and Relative Risk of High-Grade VTE
                             with Bevacizumab
Tumor Type No.              Bevacizumab               Control          Incidence   RR
           Studies
Overall        13                 235/3795            134/3167             6.3     1.38

Colo-rectal        4              96/1315              50/1128             7.3     1.56

NSCLC              4              78/1228               41/862             6.6     1.24

Breast             2               20/594               13/561             3.9     1.47
Cancer
Renal Cell         1                7/337                2/304             2.0     2.86

Mesothelioma       1                 9/53                 5/55             17.0    1.89

Pancreatic         1               24/268               23/257             9.0     1.00
Cancer
                       SR Nalluri et al. JAMA 2008;300(19):2277-2285
         ►   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
                       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
► Meta-analysis                      LMWH vs UFH
► 36 randomized                      DVT                                                 Risk
  controlled trials                  Study                                       Reduction (95% CI)      Weight %
                                     Harenberg et al, 1990                            0.70 (0.16-3.03)        3.4
► 23,000 hospitalized
  medical patients                   Turpie et al, 1992                               0.29 (0.10-0.81)       11.4
                                     Dumas et al, 1994                                0.74 (0.38-1.43)      14.4
► UFH 5,000 units TID is             Bergmann & Neuhart                              0.94 (0.39-2.26)        8.1
  more effective in                  et al, 1996
  preventing DVT than                Harenberg et al, 1996                           2.89 (0.30-27.71)      0.8
  UFH BID                            Lechler et al, 1996                             0.25 (0.03-2.23)        3.3

► Low  molecular weight              Hillbom et al, 2002                             0.55 (0.31-0.98)       20.5

  heparin is 33% more                Kleber, et al 2003                              0.77 (0.43-1.38)       19.4
  effective than                     Diener et al, 2006                              0.76 (0.42-1.38)       18.9
  unfractionated heparin             Overall (95% CI)                                0.68 (0.52-0.88)
  in preventing DVT
    ●   RR for DVT 0.68                                      0.1      1.0       10
        (p=0.004)                                                  Risk Ratio

                                                   LMWH Better           LMWH Worse

Wein L et al. Arch Intern Med. 2007;167:1476-86.
                     BWH/DFCI Partners
                    Cancer Care Experience




• 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




Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777
                                 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
                                   Dalteparin* 150 units/kg q24h
                                           (GRADE 1A)

                 * Dalteparin Approved 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
                                  Warfarin vs. Dalteparin for
                                 VTE Treatment in Malignancy

 Recurrent Thrombosis
                                                                                                           25                                                 P=0.002

 Dalteparin: 9.0% of 336




                                                   Probability of Recurrent Venous
                                                                                                           20
 Warfarin:   17% of 336




                                                                                     Thromboembolism (%)
                                                                                                                                                    Oral anticoagulant

                                                                                                           15
 Dalteparin: 200 units/kg/day
 x 1 mo, then 150 units/kg/day                                                                             10

                                                                                                                                                    Dalteparin
 Warfarin dosed to INR 2-3                                                                                  5


                                                                                                            0
 Duration: 6 months
                                                                                                                0   30         60     90    120   150   180    210
                                                                                                                               Days after Randomization
                                                                                                                                 No. at Risk
                                                 Dalteparin                                                              336        301    264    235   227      210    164
                                                 Oral anticoagulant                                                      336        280    242    221   200      194    154




Lee AY et al. New Engl J Med 2003; 349:146-53.
                                          Subgroup Analysis

                            12-month Cumulative Mortality Rate


                                Dalteparin       Warfarin        P Value

         Metastatic
          Disease                    72%           69%           P = 0.46
          (n=452)

      Non-metastatic
         Disease                     20%           36%           P=0.03
         (n=150)




Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
                                Dalteparin Cost Effectiveness
                                      in Recurrent VTE

        Cost            Dalteparin      Warfarin
      Parameter          (n=338)        (n=338)
   Drug                    2852           269
   Laboratory               303           437
   Diagnostic
                            253           267
   Tests
   Unscheduled
                            286           300
   Visits
   Transfusions             143           208
   Major bleeding          97.5           92.3
   VTE
                            228           429
   Recurrence
   Mean Cost Per
                           4162           2003
   Patient



Dranitsaris G. Pharmacoeconomics 2006; 24(6):5093-607
                        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
        ►Survey  of 38 U.S.
          Hospitals
        ►n=939       DVT or PE
        ►50%   patients
          reached INR >2 for
          2 consecutive days


         Therapy         n (%)
         LMWH        527 (56.1%)
         UFH         562 (59.8%)
         UFH SC        78 (8.3%)
         DTI           6 (0.6%)




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
                                         737                                      inability to give
                                                                                  written consent
                                      Randomized

      369 assigned to LMWH                                   369 assigned to usual care
                                                              with heparin and 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
                      Barriers to Long-term Use of LMWH for
                       Treatment of Cancer-associated VTE


       Initial treatment
                 LMWH for 3-6 months                    19%
                 UFH/LMWH for 5-7 days                  81%
                   followed by warfarin

       Reasons LMWH not used long-term
                 Not covered by medical insurance       49.4%
                 Physician preference                   32.0%
                 Patient refused long-term injections   13.6%
                 History of HIT                          2.5%
                 Severe renal insufficiency              2.5%


Wittkowsky AK. J Thromb Haemost. 2006; 4:2090-1.
                   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
            A Year 2009 Update for
         The Health System Pharmacist


Pharmacologic Prophylaxis of DVT in
       Special Populations



      Edith Nutescu, PharmD, FCCP
            Clinical Associate Professor
                 Pharmacy Practice
            Affiliate Faculty, Center for
           Pharmacoeconomic Research
          Director, Antithrombosis Center
        The University of Illinois at Chicago
       College of Pharmacy & Medical Center
                     Chicago, IL
                         Objectives


1. Differentiate data with various LMWHs in special
   populations


2. Review appropriate dosing and monitoring of
   LMWHs in patients with obesity and renal failure


3. Discuss cautions of using emerging agents in
   special populations
                                Risk of Inadequate Therapy
                                   in High Risk Patients

                ►   524 VTE Patients
                     ●   Active Cancer in 26%
                          • Only 1/3rd on LMWH monotherapy

                     ●   Weight > 100Kg in 15%
                         • Under-dosing of LMWH by > 10%
                                  – 36% of > pts 100Kg
                                  – 8% of pts < 100Kg (p < 0.001)


                     ●   CrCL < 30mL/min in 5%
                         • LMWH tx in 67%

Cook LM, et.al. J Thromb Hemost 2007;5;937-41.
                         8th ACCP Conference on Antithrombotic
                                       Therapy

                                         Obese Patients

           ―In obese patients given LMWH prophylaxis or
             treatment, we suggest weight-based dosing
                            (Grade 2C).‖

   ►    What is this weight-based dosing and how does it differ
        from typical dosing?

   ►    At what weight do we move away from standard dosing
        and move to weight-based dosing?



Hirsh J et al. Chest. 2008;133(suppl):141S-159S.
              Pharmacokinetic Characteristics of
               Low Molecular Weight Heparins


Lipid solubility                LOW
Plasma protein binding          HIGH
Tissue binding                  LOW
Volume of Distribution          5-7 L



                   Logical conclusion:
 IBW may be a better predictor of LMWH dosing than TBW
                     LMWH: Maximum Weights Studied



                                           Kinetic
                                                           Clinical Trials
                                           Studies
             Dalteparin                      190 kg              128 kg*

             Enoxaparin                      144 kg              194 kg

             Tinzaparin                      165 kg              88 kg

             Fondaparinux                             175.5 kg


* max dose 18,000 - 20,000 IU/day

Duplaga BA et al. Pharmacotherapy 2001; 21:218-34.
Synergy Trial: Data on File
Davidson, et al. J Thromb Haem 2007;5:1191-4
                    LMWH Pharmacokinetics in Obesity




   Actual body weight correlates best with anticoagulant response to
             LMWHs as measured by anti-factor Xa levels

Clin Pharmacol Ther 2002;72:308-18. Thromb Haemost 2002;87:817-23.
                                           Dalteparin
                                    Pharmacokinetics in Obesity


           Dose: 200 U/kg qd
            Duration: routine
                                            Obese (BMI > 30)      Normal (BMI < 30)
                N                                       10                10

                TBW (mean +/- SD)                106.4 +/- 22.1       69.7 +/- 9.3

                LBW (mean +/- SD)                 64.1 +/- 12.3       66.1 +/- 8.7

                Mean Vd (l)                           12.39              8.36

                Mean CI (l/hr)                         1.30              1.11




Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56:293-7.
                                        Dalteparin
                                 Pharmacokinetics In Obesity

Correlation Coefficient Between Vd and:
        LBW              0.05
        ABW              0.52
        TBW              0.55

Correlation Coefficient Between Cl and:
        LBW              0.01
        ABW              0.32
        TBW              0.39

                                         Conclusion:
      TBW may be a better predictor of LMWH dose than IBW


Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7.
                                           Dalteparin
                                    Pharmacokinetics In Obesity

     Dose: 200 U/kg qd
       Duration: 5 Days
      Max TBW: 190kg                    <20% of       20-40% of        > 40% of
                                          IBW            IBW             IBW
                  N                           13         14                10
          Mean Dose (U)                      14,030     17,646           23,565
      Ant-Xa Activity (u/ml)
            Day 3 Peak                        1.01       0.97           1.12 NS
           Day 3 Trough                       0.12       0.11            0.11 NS


     Conclusion: Body mass does not appear to have an important effect on the
    response to LMWH up to a weight of 190kg in patients with normal renal function.


Wilson SJ et al. Hemostasis 2001; 31:42-8.
                     LMWH Safety and Effectiveness Using TBW
                                 Enoxaparin In ACS (ESSENCE/TIMI IIb)


                      P=0.39
                             16.1%
                    14.3%




                                                 P=0.13
                                                      1.6%
                                               0.4%


                                                             Obese: BMI > 30mg/m2
                                                             Enox max weight 158 kg

Spinler SA et al. Am Heart J 2003; 146:33-41
                           Safety Of TBW-based Dosing of Dalteparin
                         for Treatment of Acute VTE in Obese Patients

      N = 193 patients                 3 month outcomes: major bleeding = 1.0% (n=2)
         > 90 kg                                         recurrent VTE = 1.6% (n=3)

          WEIGHT                         Mean        Full dose    QD       BID
                              N
           (kg)                          Dose         +/- 5%     Dosing   Dosing
             90-99            40         19,300         39         24       16

            100-109           52         20,850         49         25       17

            110-119           41         21,470         21         26       15

            120-129           25         24,300         22         16       9

            130-139           16         25,250          8         10       6

            140-149           9          26,920          6         5        4

             > 150            10         28,280          6         6        4


Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.
                                  Fondaparinux In Obesity
                               Results From the Matisse Trials


     Fondaparinux:                                        No weight-dependent
   < 50kg: 5mg qd                                             difference in
  50-100kg: 7.5mg qd                                       efficacy or safety
  > 100kg: 10mg qd

      Enoxaparin:
     (Matisse DVT)
      1mg/kg q12h

       Heparin:
     (Matisse PE)
  Adjusted per aPTT




Davidson BL et al. J Thrombosis Haemost 2007; 5:1191-4.
                                                         Body Weight and Anti-Xa Activity
                                                         for Prophylactic Doses of LMWH
     N = 17 patients and 2 volunteers
     Enoxaparin 40mg SQ x1 dose
     AntiXa levels hourly x10 hours

                                                                                Regression line
              Area under the curve for 10 h




                                              200                               95% CI for line
                                                                                95% CI for data points

                                              150


                                              100


                                               50


                                                0
                                                    40    60   80       100     120      140     160

                                                                    Body Weight (kg)


Frederiksen SG et al. Br J Surgery 2003; 90:547-8
                                         Dalteparin:
                              Fixed Dosing For VTE Prevention
       Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)

           BMI (kg/m2)            Patients %          Favors Dalteparin       Favor Placebo
          < 25                     37.5
          25-29.9                  33.1
          30-34.9                  18.9
          35-39.9                    7.1
          > 40                       3.3


            Overall Prevent Trial
                                               0.01         0.1     0.55 1.0            10.0
                                                                  Relative Risk

 Dalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except pts
             with BMI>40) with no observed difference in mortality or major bleeding


Kucher N et al. Arch Int Med 2005;165:341-5.
                            Enoxaparin VTE Prophylaxis in
                                 TKA/THA/Trauma

                                            31.8%


                                                         p<0.001

                                                       16.7%




              N: 807       Dose: 40 mg qd           Obese : BMI>32kg/m2


Samama MM et al. Thromb Haemost 1995; 73:977.
                                   Enoxaparin:
                         VTE Prophylaxis in Bariatric Surgery


                                      5.4%




                                             p<0.01




                                             0.6%




            30mg bid: n=92                   40mg bid: n=389
                      BMI 51.7kg/m2                    BMI 50.3kg/m2

Scholten Obes Surg 2002; 12:19-24.
                   Dalteparin in Morbid Obesity: Bariatric Surgery

                                                            200                          P=0.031




                                         Body Weight (kg)
                                                            180
                                                                               P=0.052
   N=135                                                                                           P=0.444
                                                            160
   Bariatric Surgery
                                                            140
   Mean Weight: 148.8Kg
                                                            120
   Mean BMI: 53.7
                                                            0
   Dalteparin: 7,500 IU daily                                       Under target value Target value Over target value
                                                                       <0.2 IU/mL     <0.2-0.5 IU/mL  <>0.5 IU/mL
                                                                         n-=41            n-=81           n=13


              Anti-factor Xa level                                Number of patient (%) Body weight (kg)
       Below target value (<0.2 UI/ml)                                   41 (30.4%)                   159.4 ± 35.8
       Target value (0.2–0.5 UI/ml)                                      81 (60.0%)                   145.7 ± 28.4
       Above target value (>0.5 UI/ml)                                    13 (9.6%)                   134.6 ± 24.2
       p value                                                                                           0.0152
Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]
                            LMWH in Obesity: Summary
 ►   Treatment: in controlled trials, LMWH dosing has been based on TBW
     (max 160-190 kg)
       ●   Dalteparin
             • Dose based on TBW
             • PI recommends dose capping
             • Recent clinical data supports TBW dosing
                    – QD or BID dosing
       ●   Enoxaparin
             • Dose based on TBW
             • Dose capping NOT recommended
             • BID dosing preferred
       ●   Tinzaparin
             • Dose based on TBW, NO dose adjustment or capping
       ●   Anti-Xa monitoring not necessary for TBW < 190kg
 ►   Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients)

Nutescu E, et.al. Ann Pharmacother; 2009; in press.
                     8th ACCP Conference on Antithrombotic Therapy
                                              Renal Impairment

   ►   For each of the antithrombotic agents, we recommend that
       clinicians follow manufacturer-suggested dosing guidelines
       (Grade 1C)

   ►   We recommend that renal function be considered when
       making decisions about the use of and/or dose of LMWH or
       fondaparinux (Grade 1A)

   ►   Options for patients with renal impairment (Grade 1B)
         ●   Avoid agents that renal accumulate
         ●   Use a lower dose
         ●   Monitor the drug level or anticoagulant effect



Geerts WH. Chest 2008;133(suppl):381S-453S.
                  LMWH in Renal Dysfunction
                 Manufacturer Recommendations

Dalteparin
●   ―should be used with caution in patients with severe kidney
    insufficiency.‖
     • Monitor anti-Factor Xa for dose guiding with therapeutic doses


Enoxaparin
●   ―adjustment of dose is recommended for patients with severe
    renal impairment (CrCL < 30 mL/min).‖


Tinzaparin
●   ―patients with severe renal impairment should be dosed with
    caution.‖


Fondaparinux
- Contraindicated in CrCL < 30mL/min
                              Recent Meta-Analysis of LMWHs and Bleeding
                               In Patients With Severe Renal Dysfunction
                                Patients w/    Patients w/ no
                                                                      Peto OR               Weight               Peto OR
Study; year                    renal insuff.    renal insuff.
                                                                      (95%, CI)              (%)                 (95%, CI)
                                   (n/n)            (n/n)
Collet, et al; 2001                0/28            1/83                                        2.01   0.26 (0.00 – 23.94)
Paulas, et al; 2002                0/51            3/149                                       6.02   0.26 (0.02 – 3.50)
Siguret, et al; 2000               0/17            0/13                                               Not estimable
Chow, et al; 2003                  0/5             0/13                                               Not estimable
Khazan, et al. (adj.); 2003        0/10            3/42                                      4.78     0.28 (0.01 – 5.16)
   (Prophylactic) 2003             3/36            3/47                                     14.77     1.33 (0.25 – 7.05)
   (Therapeutic) 2003              2/17            3/61                                      8.62     3.09 (0.35 – 27.31)
Spinler, et al; 2003               5/69          74/3,432                                   15.93     10.05 (2.02 – 49.98)
Green, et al; 2005                 1/18            0/20                                        2.66   8.26 (0.16 – 418.42)
Kruse & Lee; 2004                  0/50            1/120                                       2.22   0.24 (0.00 – 17.90)
Macie, et al; 2004                 2/7             6/201                                       2.68   977.78 (19.61 – 48,752.07)
Peng, et al; 2004                  0/7             0/43                                               Not estimable
Thorevska, et al; 2004             7/65           11/171                                    35.56     1.85 (0.63 – 5.40)
Bazinet, et al; 2005               1/36            2/160                                       4.75   2.74 (0.15 – 51.73)
Total (95%, CI)                   21/416         107/4,555                                 100.00     2.25 (1.19 – 4.27)
                                                                0.01 0.1   1      10     100                  Dosage adjustments
                                                                 Favors ↓’ed           Favors ↑’ed
                                                                                                              for renal dysfunction
                                                                                         bleeding
Lim W, et al. Ann Intern Med. 2006;144:673-684.
               Enoxaparin PK and PD in Renal Impairment

   Result:
     Tmax: 3-4 hours
     Amax: 10-35% higher in RI groups
     CI/F‖linearly correlated with CrCl


                                    CL/F      Half-life   AUC (0-24)
               Day 4
                                    (L/h)       (h)       (h●IU/mL)
         Normals                     0.98       6.87

         Mild RI                     0.87       9.94        20% ↑

         Moderate RI                 0.76       11.3        21% ↑

         Severe RI                   0.58       15.9        65% ↑



Sanderink GJCM. Thromb Res 2002;105:225-31.
                    LMWH Renal Dosing in NSTE ACS Patients

                                                                •   Dose may be  to 0.6mg/kg/
   ►   56 UA pts with CrCl <60                                      q12h if CrCL <30mL/min; or 0.8
       ml/min                                                       mg/kg/q12h if CrCl 30-60 ml/min
   ►   Enoxaparin dose empirically                              •   Anti-Xa monitoring
        and anti-Xa level measured                             •   Doses ―appeared safe‖
       after 3rd dose                                           •   Further prospective evaluation
                                                                    needed

                    CrCl                              <30                 >30 and <60
                   (ml/min)                         (n = 28)                (n =28)
                       Age                           76+/-3                    73+/-3

         Enoxaparin (mg/kg/12h)                          0.64                   0.84


                Anti-Xa (IU/ml)                          0.95                   0.95

Collet JP et al. International J Cardiol 2001;80:81-2.
                                                       Clinical Use Of Recommended
                                                   Enoxaparin Dosage in Renal Impairment

                               N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h
                             1.0.                                                                  6
                                        PEAK ANTI-Xa LEVELS                                                  TROUGH ANTI-Xa LEVELS
                             0.9
Antifactor X1 Level (U/mL)




                                                                                                   5
                             0.8




                                                                              Number of Patients
                             0.7                                                                   4

                             0.6
                                                                                                   3
                             0.5

                             0.4                                                                   2

                             0.3
                                                                                                   1
                             0.2

                             0.1                                                                   0
                                    First dose          Subsequent doses                               0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55
                                                        (second and third)

                               Median            25-75% interquartile range                                     Trough Antifactor Xa Level (U/mL)


                         Lachish T et al. Pharmacotherapy 2007; 27:1347-52.
                               Influence of Renal Function
                            Fondaparinux vs Enoxaparin in ACS



   OASIS-5:
   Fondaparinux 2.5mg qd
   vs enoxaparin 1mg/kg q12h
   for 2-8 days




Fox KAA et al. Ann Intern Med 2007; 147:304-10.
                A Year 2009 Update for
             The Health System Pharmacist



               Electronic Alerts:
               Future Horizons


             Karen Fiumara, PharmD
                  Medication Safety Officer
               Brigham and Women’s Hospital
      Adjunct Assistant Professor of Pharmacy Practice
Massachusetts College of Pharmacy and Allied Health Sciences
      Adjunct Assistant Professor of Pharmacy Practice
  Bouve’ College of Health Sciences Northeastern University
                         Boston, MA
                                        Background

   ►   Past 10 years the prevention of medication errors
       has become a primary focus in healthcare


   ►   In 1995 Bates et al. published landmark study
       indicating 28% of hospital admissions are
       attributed to preventable medication errors


   ►   The IOM report ―To Err is Human‖ have led to
       increased research and development of both
       medical informatics and computerized alerting
       systems
Bates DW et al. JAMA 1995;274:1311-16
                                      CPOE : Friend or Foe?

    ►   Recently, institutions are beginning to critically
        assess electronic systems, such as CPOE
    ►   VA Medical Center in Salt Lake City:
          ●   74% of medication errors occur during prescribing
          ●   11% during administration
          ●   0% during transcription
    ►   Bates et al. study:
          ●   56% of medication errors - prescribing
          ●   24% of medication errors – administration
          ●   6% of medication errors – transcription


Nebeker JR et al. Arch of Intern Med 2005;165:1111-16.
                                      CPOE : Friend or Foe?

     ►   VA Medical Center attributed low error rates
         during the transcription and administration to
         information system upgrades such as:
          ●    Bar code technology during administration, EMAR and
               computerized drug-drug interaction and allergy
               screening


     ►   Concluded that their systems are working as
         designed but lack decision support within CPOE
         leading to high error rates during prescribing


Nebeker JR et al. Arch of Intern Med 2005;165:1111-16.
                                                 CPOE Alerts

        ►   Institutions that utilize decision support and
            computerized alerts during prescribing have
            reported high rates of physician override

        ►   A study conducted at BIDMC reported that
            94.2% of computerized alerts were overridden

        ►   Reviewers concluded of the 189 rules studied,
            36.5% of the rules were invalid and agreed
            with the physician’s decision 97.9% of the
            time

Weingart SN et al. Arch of Intern Med 2003;163:2625-31.
              Saving CPOE from Extinction

► CPOE must evolve to keep up with the growing
  demand for effective medical informatics and
  technology solutions

► Next generation of CPOE will utilize algorithms
  that take into account patient specific factors and
  generate prescribing recommendations to
  providers

► One area in which CPOE has proven beneficial is
  VTE prophylaxis
                                   Medical Error Rates

     ►   Two errors per day = 99% proficiency level

     ►    If 99% was good enough:
                        –Airline industry = 2 unsafe landings per day
                –Mail industry = 16,000 pieces of mail lost every hour
          –Banking industry = 32,000 checks deducted from the wrong
                               account per hour

     ►   How do we transform health care into a high
         reliability industry?



Leape LL. JAMA. 1994;272:1851-7.
                     Background



►   At Brigham and Women’s Hospital,
    we have initiated a series of trials
    aimed at increasing prophylaxis by:
    ●   Changing MD behavior and
    ●   Improving the implementation of
        prophylaxis strategies
                Types of Interventions



►   Electronic computer generated alerting
    systems


►   Efficacy of these alerting systems have
    been studied in:
    ●   RCT trial of a 1-screen alert
    ●   Cohort study of a 3-screen alert
              First Generation Electronic Alerts


►   BWH utilizes BICS (Brigham Integrated
    Computing System) for all order entry functions

    ●   Admitting records, demographic information,
        lab results, medication orders, etc.

►   VTE group utilized computer system to screen
    all patients admitted to the hospital for High Risk
    VTE status
          First Generation Alert: Development

►   Aim: to increase rate of prophylaxis in patients
    at risk for DVT and PE


►   Developed computer program to detect and
    identify which patients were at risk


►   Alert the responsible physician of high risk
    patient (via e alert) and offer opportunity to
    order appropriate prophylaxis
   Study Schema

 All Adult Patients


DVT Risk Score > 4

               YES

    Presence of
    Prophylaxis


              NO
  Generate Alert
                  Definition of ―High Risk‖

VTE risk score ≥ 4 points:
►   Cancer                   3   (ICD codes)
►   Prior VTE                3   (ICD codes)
►   Hypercoagulability       3   (Leiden, ACLA)
►   Major surgery            2   (> 60 minutes)
►   Bed rest                 1   (―bed rest‖ order)
►   Advanced age             1   (> 70 years)
►   Obesity                  1   (BMI > 29 kg/m2)
►   HRT/OC                   1   (order entry)
                                           Randomization

                                   VTE Risk Score > 4
                                         No Prophylaxis
                                           N = 2506




             Intervention                                  Control
             Single Alert                                  No Alert
               n = 1255                                    n = 1251

Kucher N, et al. NEJM 2005;352:969-977
Physician Notification of Alerts
                                First Generation
                      Computerized Alerts for VTE Prevention

     ►   Utilization of computer
         generated alerts to house
         staff reduced the
         incidence of VTE by 41%
     ►   VTE prophylaxis was
         prescribed in 33.5% of
         patients in the
         intervention group
     ►   Following study
         conclusion a follow up
         cohort study was
         conducted

Kucher N, et al. NEJM. 2005;352:969-977.
        Alerts




Second Generation:
Electronic Computer
 Generated Alerts
              BWH VTE Alerts: The Future


►   Goals:
    ● Engage the house officer with an
      interactive alert to increase acceptance
      and gain feedback

    ●   Update the DVT prophylaxis template to
        meet current practice guidelines

    ●   Provide real-time knowledge links
                  Interactive Techniques

►   Provide objective data to the house officer
    that this alert positively impacts patient
    outcome
►   Create opportunity to capture rationale for
    declining alert
    ●   Hypothesized that many physicians fear a risk
        of bleeding with anticoagulation
►   Provide a final opportunity to order
    mechanical prophylaxis
►   Alert attending physician if alert is not
    acknowledged after 24 hours
DVT Alert Screen
Rule Logic – Alert Details
Option A
Option C or ―Done‖
            Escalation and Timing of Alerts


►   Alerts should be set up to generate each day
    at 8:30 AM


►   If an alert was not acknowledged after 24
    hours the attending physician on record
    should be text paged.
                  Quality Assurance

►   Weekly reports are reviewed


►   Allows core team to review all aspects of the
    alerts including:
     ● Type of action taken

     ● Rate of overrides

     ● Rational for declining the alerts



►   Results coming soon
        Alerts




Pharmacy/Physician
   Collaboration

 Human Alerts
                 VTE Prophylaxis: hALERT


►   Multicentered RCT of human alerts (hALERT).


►   Objective: to recruit hospitals that differ from BWH
    re: IT, community vs. academic, urban vs.
    suburban/rural, location within USA.


►   Can a human alert be more effective than an
    electronic alert?
                         Methodology

►   Patients admitted to the hospital are screen by
    human for increased VTE risk
►   High risk patients are randomized to alert or no
    alert
►   Physicians of patients in alert group receive
    page alerting them of high risk status
►   Records are checked for prophylaxis order 48
    hours after alert
►   90 day follow up for clinically significant VTE
    and clinically importing bleeding
                    hALERT: Capturing New
                      Prophylaxis Orders


►   Enrolled patients must be reexamined in 24-48
    hours to determine whether prophylaxis orders
    were written.


►   Capturing prophylaxis orders after enrollment
    applies to both the Intervention Group and to the
    Control Group.
              Human Alert Trial


1. Human (often RN or pharmacist) issues the
   Alert, not a computer

2. The attending physician, not the intern,
   receives the Alert

3. Diversity of centers: community, suburban,
   throughout the USA

4. Will attendings pay more attention than house
   staff?
                         Conclusions

►   Changing behavior is challenging


►   Multi-disciplinary team involvement is critical to
    successful implementation


►   Need to engage providers and obtain feedback


►   Designing ―smart alerts‖ that include decision
    support functionality or ―human alerts‖ that require
    face to face contact may be effective
           Alerts




  Electronic Alerts to
Prevent Infusion Errors
             Patient Case—Infusion Pump Error


Error Description
► 57 YOM endstage CMP            ►   8:45 PM aPTT = 75.1
►   EF = 10%                     ►   1:13 AM Protamine 25mg
►   Heart transplant candidate   ►   1:28 AM aPTT = >150
    with BIVAD                   ►   3:13 AM aPTT = >150
►   Receiving UFH 900 units
                                 ►   3:32 AM Protamine 26mg
    per hour (9 mls/hr)
                                 ►   2 Units PRBC
►   New order to reduce
    Heparin 800 units per hour   ►   4:08 AM aPTT = >150
    @ 10:22 PM                   ►   8:21 AM aPTT = 44.4
►   Infusion pump set for 800
    mls per hour
                                        Background
             National Data                        •Heparin has been identified both
                                                  nationally and internally at BWH as a
  Rank       Medications Causing Harm             medication frequently associated with
  1.       Insulin                                ADE
  2.       Morphine                                   •Removed access to different formulations
  3.       Heparin                                    •Standardized UFH Concentration
  4.       Warfarin                                   •Calculate infusion rates in OE
  5.       Potassium
  6.       Furosemide
  7.       Vancomycin
  8.       Hydromorphone
  9.       Meperidine
  10.      Diltiazem


MEDMARXSM 2001. The United States Pharmacopoeia
(USP)Convention Inc.
                                      UFH Error Analysis: BWH


     ►    1 event per 1,000 patients
           ●    52% - Administration related
           ●    31% - Equipment failure, rate or dosing error
           ●    23% - Infusion Pump
     ►    6% - Prolonged LOS or significant harm

 ***Patient Safety Initiative: Hospital invested 3
 million dollars in state of the art infusion pumps***


Fanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol
2004;94:532-535
                     Objectives


►   Evaluate impact of ―smart‖ infusion
    technology on anticoagulation
    administration


►   To determine if infusion technology
    equipped with drug libraries may
    reduce medication errors
              Features of the ―Smart‖ Pumps


►   ―Smart‖ pumps share safety features of older
    pumps including dose calculation functions, free-
    flow protection and occlusion alerts


►   ―Smart‖ pumps also equipped with a drug library
    ●   Provide dose and rate limits on commonly used
        medications
    ●   Provide users with overdose and underdose
        alerts based on predetermined limits defined by
        the drug library
                                        Methods

►   We programmed the drug
                                                    Underdose         Overdose
    library to alert for overdoses   Medication
    or underdoses                                     Alert             Alert

                                                                        >2,800
                                     UFH           <300 units/hour
►   Alerts where subsequently                                          units/hour
    recorded in the device’s
    electronic memory, along
    with the user’s next action      Argatroban    <0.5 mcg/kg/min >10 mcg/kg/min


►   We retrospectively reviewed      Lepirudin       <5 mg/hour      >16.5 mg/hour
    all anticoagulant alerts and
    the user’s next action for all
    devices from 10/2003                                                >1.8
    through 1/2005                   Bivalirudin   <0.2 mg/kg/hour
                                                                      mg/kg/hour
Dosing Errors and their Magnitude
Data Entry Errors Frequently
    Repeated with UFH




        27.2 % entry errors User
           repeated the error
Alerts by Time of Day
                      Conclusions



►   The drug library and its alerting system
    intercept programming errors

►   Despite alerts, data entry errors are
    frequently repeated by the user

►   The highest alert incidence occurs on
    weekdays between 2 PM and 4 PM,
    corresponding to Nursing Shift change

				
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