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The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

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Page 1: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith
Page 2: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer

 

The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer

 

Edith Nutescu, PharmD, FCCPClinical Associate Professor

Pharmacy PracticeAffiliate Faculty, Center for

Pharmacoeconomic ResearchDirector, Antithrombosis Center

The University of Illinois at Chicago College of Pharmacy & Medical Center

Chicago, IL

Edith Nutescu, PharmD, FCCPClinical Associate Professor

Pharmacy PracticeAffiliate Faculty, Center for

Pharmacoeconomic ResearchDirector, Antithrombosis Center

The University of Illinois at Chicago College of Pharmacy & Medical Center

Chicago, IL

A Year 2009 Update for A Year 2009 Update for The Health System PharmacistThe Health System Pharmacist

Samuel Z. Goldhaber, MDProfessor of Medicine

Harvard Medical SchoolCardiovascular Division

Director, Venous Thromboembolism Research Group

Brigham and Women’s HospitalBoston, MA

Samuel Z. Goldhaber, MDProfessor of Medicine

Harvard Medical SchoolCardiovascular Division

Director, Venous Thromboembolism Research Group

Brigham and Women’s HospitalBoston, MA

Program Co-ChairsProgram Co-Chairs

Page 3: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

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

Jointly sponsored by the University of Massachusetts Medical Center, Jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLCoffice of CME and CMEducation Resources, LLC

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

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

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

COI: COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

Welcome and Program OverviewWelcome and Program Overview

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The University of Florida College of Pharmacy is The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy Education as a provider of continuing pharmacy education. education.   The University of Florida College of Pharmacy will mail The University of Florida College of Pharmacy will mail the Statements of Continuing Pharmacy Education the Statements of Continuing Pharmacy Education Credit within 4 weeks after the course.Credit within 4 weeks after the course.  To receive credit you must attend the sessions for To receive credit you must attend the sessions for which you want credit and complete an evaluation form. which you want credit and complete an evaluation form.

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

CEU Credit Designation StatementCEU Credit Designation Statement

Page 5: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Program Educational ObjectivesProgram Educational Objectives

As a result of this session, attendees will be able to:As a result of this session, attendees will be able to: ► List the recent trials, research, and expert analysis of issues focused on List the recent trials, research, and expert analysis of issues focused on

thrombosis and cancer.thrombosis and cancer.

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

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

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

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

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Program FacultyProgram Faculty

Program Co-ChairsEdith Nutescu, PharmD, FCCPClinical Associate Professor, Pharmacy PracticeAffiliate Faculty, Center for Pharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at Chicago College of Pharmacy & Medical CenterChicago, IL

 

Samuel Z. Goldhaber, MDProfessor of Medicine Harvard Medical SchoolCardiovascular Division Director, Venous Thromboembolism Research GroupBrigham and Women’s HospitalBoston, MA 

Program Co-ChairsEdith Nutescu, PharmD, FCCPClinical Associate Professor, Pharmacy PracticeAffiliate Faculty, Center for Pharmacoeconomic ResearchDirector, Antithrombosis CenterThe University of Illinois at Chicago College of Pharmacy & Medical CenterChicago, IL

 

Samuel Z. Goldhaber, MDProfessor of Medicine Harvard Medical SchoolCardiovascular Division Director, Venous Thromboembolism Research GroupBrigham and Women’s HospitalBoston, MA 

 

Distinguished Experts and PresentersJohn Fanikos, RPh, MBAAssistant Director of PharmacyBrigham and Women’s HospitalAssistant Clinical Professor of PharmacyNortheastern UniversityMassachusetts College of PharmacyBoston, MA

 

Karen Fiumara, PharmDMedication Safety OfficerBrigham and Women’s HospitalAdjunct Assistant Professor of Pharmacy PracticeMassachusetts College of Pharmacy and Allied Health SciencesAdjunct Assistant Professor of Pharmacy PracticeBouve’ College of Health Sciences Northeastern UniversityBoston, MA

 

Distinguished Experts and PresentersJohn Fanikos, RPh, MBAAssistant Director of PharmacyBrigham and Women’s HospitalAssistant Clinical Professor of PharmacyNortheastern UniversityMassachusetts College of PharmacyBoston, MA

 

Karen Fiumara, PharmDMedication Safety OfficerBrigham and Women’s HospitalAdjunct Assistant Professor of Pharmacy PracticeMassachusetts College of Pharmacy and Allied Health SciencesAdjunct Assistant Professor of Pharmacy PracticeBouve’ College of Health Sciences Northeastern UniversityBoston, MA

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Faculty COI Financial DisclosuresFaculty COI Financial Disclosures

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

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

Karen Fiumara, PharmDNothing to disclose

John Fanikos, RPh, MBAJohn Fanikos, RPh, MBASpeakers Bureau and ConsultingSpeakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai : Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines CompanyCompany

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

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

Karen Fiumara, PharmDNothing to disclose

John Fanikos, RPh, MBAJohn Fanikos, RPh, MBASpeakers Bureau and ConsultingSpeakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai : Abbott Laboratories, Astra-Zeneca, Eisai Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines CompanyCompany

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Cancer and Prevention of VTE

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

Cancer and Prevention of VTE

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

A Year 2009 Update for A Year 2009 Update for The Health System PharmacistThe Health System Pharmacist

Program Co-ChairSamuel Z. Goldhaber, MD

Professor of Medicine Harvard Medical SchoolCardiovascular Division

Director, Venous Thromboembolism Research GroupBrigham and Women’s Hospital

Boston, MA

Program Co-ChairSamuel Z. Goldhaber, MD

Professor of Medicine Harvard Medical SchoolCardiovascular Division

Director, Venous Thromboembolism Research GroupBrigham and Women’s Hospital

Boston, MA

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VTE and Cancer—A Looming VTE and Cancer—A Looming National Healthcare CrisisNational Healthcare Crisis

MISSION AND CHALLENGESMISSION AND CHALLENGES

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

MISSION AND CHALLENGESMISSION AND CHALLENGES

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

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COMORBIDITYCOMORBIDITYCONNECTIONCONNECTION

CAPCAPUTIUTICancerCancerHeart Failure Heart Failure ABE/COPDABE/COPDRespiratory FailureRespiratory Failure Myeloproliferative DisorderMyeloproliferative DisorderThrombophiliaThrombophiliaSurgerySurgeryHistory of DVTHistory of DVTOtherOther

COMORBIDITYCOMORBIDITYCONNECTIONCONNECTION

CAPCAPUTIUTICancerCancerHeart Failure Heart Failure ABE/COPDABE/COPDRespiratory FailureRespiratory Failure Myeloproliferative DisorderMyeloproliferative DisorderThrombophiliaThrombophiliaSurgerySurgeryHistory of DVTHistory of DVTOtherOther

SUBSPECIALISTSUBSPECIALISTSTAKEHOLDERSSTAKEHOLDERS

Infectious diseasesInfectious diseasesOncologyOncologyPHARMACISTSPHARMACISTSCardiology Cardiology Pulmonary medicinePulmonary medicineHematologyHematologyOncology/hematologyOncology/hematologyInterventional RadiologyInterventional RadiologyHospitalistHospitalistSurgeonsSurgeonsEMEMPCPPCP

SUBSPECIALISTSUBSPECIALISTSTAKEHOLDERSSTAKEHOLDERS

Infectious diseasesInfectious diseasesOncologyOncologyPHARMACISTSPHARMACISTSCardiology Cardiology Pulmonary medicinePulmonary medicineHematologyHematologyOncology/hematologyOncology/hematologyInterventional RadiologyInterventional RadiologyHospitalistHospitalistSurgeonsSurgeonsEMEMPCPPCP

Comorbidity ConnectionComorbidity Connection

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Epidemiology of First-Time VTEEpidemiology of First-Time VTE

White R. White R. CirculationCirculation. 2003;107:I-4 –I-8.). 2003;107:I-4 –I-8.)

VariableVariable FindingFinding

Seasonal VariationSeasonal Variation Possibly more common in winter and less Possibly more common in winter and less common in summercommon in summer

Risk FactorsRisk Factors25% to 50% “idiopathic”25% to 50% “idiopathic”

15%-25% associated with cancer15%-25% associated with cancer20% following surgery (3 months)20% following surgery (3 months)

Recurrent VTERecurrent VTE

6-month incidence, 7%;6-month incidence, 7%;Higher rate in patients with cancerHigher rate in patients with cancer

Recurrent PE more likely after PE than Recurrent PE more likely after PE than after DVTafter DVT

Death After Treated VTEDeath After Treated VTE

30-day incidence 6% after incident DVT30-day incidence 6% after incident DVT30-day incidence 12% after PE30-day incidence 12% after PE

Death strongly associated with Death strongly associated with cancercancer, , age, and cardiovascular diseaseage, and cardiovascular disease

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Epidemiology of VTEEpidemiology of VTE

White R. White R. CirculationCirculation. 2003;107:I-4 –I-8.). 2003;107:I-4 –I-8.)

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

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

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

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Comorbidity ConnectionComorbidity Connection

ComorbidityComorbidityConnectionConnection

Overview Overview

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Acute Medical Illness and VTEAcute Medical Illness and VTE

Multivariate Logistic Regression ModelMultivariate Logistic Regression Modelfor Definite Venous Thromboembolism (VTE)for Definite Venous Thromboembolism (VTE)

Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968

Risk FactorRisk Factor Odds RatioOdds Ratio(95% CI)(95% CI)

XX22

Age > 75 yearsAge > 75 yearsCancerCancer

Previous VTEPrevious VTE

1.03 (1.00-1.06)1.03 (1.00-1.06)1.62 (0.93-2.75)1.62 (0.93-2.75)2.06 (1.10-3.69)2.06 (1.10-3.69)

0.00010.00010.080.080.020.02

Acute infectious Acute infectious diseasedisease

1.74 (1.12-2.75)1.74 (1.12-2.75) 0.020.02

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Comorbid Condition and DVT Risk Comorbid Condition and DVT Risk

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

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

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

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

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

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

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

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VTE RecurrenceVTE Recurrence

Predictors of First Overall VTE RecurrencePredictors of First Overall VTE Recurrence

Heit J, Mohr D, et al. Heit J, Mohr D, et al. Arch Intern MedArch Intern Med. 2000;160:761-768. 2000;160:761-768

Baseline CharacteristicBaseline Characteristic Hazard RatioHazard Ratio(95% CI)(95% CI)

AgeAge 1.17 (1.11-1.24)1.17 (1.11-1.24)

Body Mass IndexBody Mass Index 1.24 (1.04-1.7)1.24 (1.04-1.7)

Neurologic disease with extremity Neurologic disease with extremity paresisparesis

1.87 (1.28-2.73)1.87 (1.28-2.73)

Malignant neoplasmMalignant neoplasmWith chemotherapyWith chemotherapy

Without chemotherapyWithout chemotherapy4.24 (2.58-6.95)4.24 (2.58-6.95)2.21 (1.60-3.06)2.21 (1.60-3.06)

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ICOPER Cumulative MortalityICOPER Cumulative MortalityM

orta

lity

(%)

Mor

talit

y (%

)

Days From DiagnosisDays From Diagnosis

17.5%17.5%

00

55

1010

1515

2020

2525

Lancet 1999;353:1386-1389Lancet 1999;353:1386-1389

77 1414 3030 6060 9090

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Stages of Chronic Venous InsufficiencyStages of Chronic Venous Insufficiency

1.1. Varicose veinsVaricose veins

2.2. Ankle/ leg edemaAnkle/ leg edema

3.3. Stasis dermatitisStasis dermatitis

4.4. LipodermatosclerosisLipodermatosclerosis

5.5. Venous stasis ulcerVenous stasis ulcer

1.1. Varicose veinsVaricose veins

2.2. Ankle/ leg edemaAnkle/ leg edema

3.3. Stasis dermatitisStasis dermatitis

4.4. LipodermatosclerosisLipodermatosclerosis

5.5. Venous stasis ulcerVenous stasis ulcer

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Progression of Chronic Venous InsufficiencyProgression of Chronic Venous Insufficiency

From UpToDate 2006From UpToDate 2006

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Rising VTE Incidence in Rising VTE Incidence in Hospitalized PatientsHospitalized Patients

Stein PD et al. Am J Cardiol 2005; 95: 1525-1526Stein PD et al. Am J Cardiol 2005; 95: 1525-1526

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DVT Registry (N=5,451):DVT Registry (N=5,451):Top 5 Medical ComorbiditiesTop 5 Medical Comorbidities

1.1. HypertensionHypertension

2.2. ImmobilityImmobility

3.3. CancerCancer

4.4. Obesity (BMI > 30)Obesity (BMI > 30)

5.5. Cigarette SmokingCigarette Smoking

1.1. HypertensionHypertension

2.2. ImmobilityImmobility

3.3. CancerCancer

4.4. Obesity (BMI > 30)Obesity (BMI > 30)

5.5. Cigarette SmokingCigarette Smoking

Am J Cardiol 2004; 93: 259-262Am J Cardiol 2004; 93: 259-262

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Implementation of VTE prophylaxis Implementation of VTE prophylaxis continues to be problematic, despite continues to be problematic, despite

detailed North American and European detailed North American and European Consensus guidelines.Consensus guidelines.

Implementation of VTE prophylaxis Implementation of VTE prophylaxis continues to be problematic, despite continues to be problematic, despite

detailed North American and European detailed North American and European Consensus guidelines.Consensus guidelines.

ImplementationImplementation

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SURGEON SURGEON GENERAL:GENERAL:CALL TO CALL TO

ACTION TO ACTION TO PREVENT DVT PREVENT DVT

AND PEAND PE

September 15, 2008September 15, 2008

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Surgeon General’s Call to Action Surgeon General’s Call to Action 42-Page Document42-Page Document

► Issued September 15, 2008 Issued September 15, 2008

► Endorsed by Secretary, HHS Endorsed by Secretary, HHS

► Endorsed by Director, NHLBI Endorsed by Director, NHLBI

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

► Issued September 15, 2008 Issued September 15, 2008

► Endorsed by Secretary, HHS Endorsed by Secretary, HHS

► Endorsed by Director, NHLBI Endorsed by Director, NHLBI

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

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Call to Action for VTECall to Action for VTE

► Dr. Galson’s 1Dr. Galson’s 1stst Call To Action Call To Action

► >> 350,000-600,000 Americans suffer VTE 350,000-600,000 Americans suffer VTE annuallyannually

► > 100,000 U.S. deaths per year > 100,000 U.S. deaths per year

► Negative impact on QOL of survivorsNegative impact on QOL of survivors

► ““Must disseminate info widely” to “address gap” Must disseminate info widely” to “address gap” because we’re not applying knowledge because we’re not applying knowledge systematicallysystematically

► Dr. Galson’s 1Dr. Galson’s 1stst Call To Action Call To Action

► >> 350,000-600,000 Americans suffer VTE 350,000-600,000 Americans suffer VTE annuallyannually

► > 100,000 U.S. deaths per year > 100,000 U.S. deaths per year

► Negative impact on QOL of survivorsNegative impact on QOL of survivors

► ““Must disseminate info widely” to “address gap” Must disseminate info widely” to “address gap” because we’re not applying knowledge because we’re not applying knowledge systematicallysystematically

ForewordForeword

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I. I. Major Public Health ProblemMajor Public Health Problem

II. II. Reducing VTE RiskReducing VTE Risk

III. Gaps in Application, Awareness of III. Gaps in Application, Awareness of EvidenceEvidence

IV. Public Health ResponseIV. Public Health Response

V. V. Catalyst for Action Catalyst for Action

Call to Action for VTECall to Action for VTE

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Symposium ThemesSymposium Themes

1.1. Cancer rates are increasing as heart Cancer rates are increasing as heart disease Rx improves and as cancer Rx disease Rx improves and as cancer Rx improves.improves.

2.2. Cancer increases VTE risk.Cancer increases VTE risk.

3.3. VTE is preventable (immunize!)VTE is preventable (immunize!)

4.4. VTE prophylaxis may slow cancerVTE prophylaxis may slow cancer

5.5. Increased emphasis on prophylaxis: OSG, Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATFNCCN, ASCO, ACCP, NATF

6.6. Facilitate Facilitate prophylaxis with alertsprophylaxis with alerts..

1.1. Cancer rates are increasing as heart Cancer rates are increasing as heart disease Rx improves and as cancer Rx disease Rx improves and as cancer Rx improves.improves.

2.2. Cancer increases VTE risk.Cancer increases VTE risk.

3.3. VTE is preventable (immunize!)VTE is preventable (immunize!)

4.4. VTE prophylaxis may slow cancerVTE prophylaxis may slow cancer

5.5. Increased emphasis on prophylaxis: OSG, Increased emphasis on prophylaxis: OSG, NCCN, ASCO, ACCP, NATFNCCN, ASCO, ACCP, NATF

6.6. Facilitate Facilitate prophylaxis with alertsprophylaxis with alerts..

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Edith Nutescu, PharmD, FCCPClinical Associate Professor

Pharmacy PracticeAffiliate Faculty, Center for

Pharmacoeconomic ResearchDirector, Antithrombosis Center

The University of Illinois at Chicago College of Pharmacy & Medical Center

Chicago, IL

Edith Nutescu, PharmD, FCCPClinical Associate Professor

Pharmacy PracticeAffiliate Faculty, Center for

Pharmacoeconomic ResearchDirector, Antithrombosis Center

The University of Illinois at Chicago College of Pharmacy & Medical Center

Chicago, IL

Cancer and Prevention of VTE

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

Cancer and Prevention of VTE

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

A Year 2009 Update for A Year 2009 Update for The Health System PharmacistThe Health System Pharmacist

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Peculiar Relationship Peculiar Relationship Between Cancer and ThrombosisBetween Cancer and Thrombosis

may indicatemay indicate

may causemay cause

Hypercoagulation/Hypercoagulation/thrombosisthrombosis

Hypercoagulation/Hypercoagulation/thrombosisthrombosis

Occult CancerOccult Cancer

CancerCancer

Page 30: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Thromboembolism in MalignancyThromboembolism in Malignancy

► 15% of cancer patients develop venous or arterial 15% of cancer patients develop venous or arterial thrombosisthrombosis1 1

► Annual incidence of VTE in all patients: 117 in 100,000Annual incidence of VTE in all patients: 117 in 100,0002 2

► Cancer increases risk of thrombosis 4.1-foldCancer increases risk of thrombosis 4.1-fold33

► Chemotherapy increases risk of thrombosis 6.5-foldChemotherapy increases risk of thrombosis 6.5-fold33

► Annual incidence of VTE in patients with cancer: 1 in 200Annual incidence of VTE in patients with cancer: 1 in 2004 4

► 15% of cancer patients develop venous or arterial 15% of cancer patients develop venous or arterial thrombosisthrombosis1 1

► Annual incidence of VTE in all patients: 117 in 100,000Annual incidence of VTE in all patients: 117 in 100,0002 2

► Cancer increases risk of thrombosis 4.1-foldCancer increases risk of thrombosis 4.1-fold33

► Chemotherapy increases risk of thrombosis 6.5-foldChemotherapy increases risk of thrombosis 6.5-fold33

► Annual incidence of VTE in patients with cancer: 1 in 200Annual incidence of VTE in patients with cancer: 1 in 2004 4

1. Green KB, Silverstein RL. 1. Green KB, Silverstein RL. Hematol Oncol Clin North AmHematol Oncol Clin North Am. 1996;10:499-530.. 1996;10:499-530.2. Silverstein MD et al. 2. Silverstein MD et al. Arch Intern Med.Arch Intern Med. 1998;158:585-593 1998;158:585-5933. Heit JA et al. 3. Heit JA et al. Arch Intern Med.Arch Intern Med. 2000;160:809-815 2000;160:809-815 4. Lee AYY, Levine MN. 4. Lee AYY, Levine MN. Circulation.Circulation. 2003;107(23 Suppl 1):I17-21. 2003;107(23 Suppl 1):I17-21.

Page 31: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Factors That May Affect Risk for Factors That May Affect Risk for Cancer-Associated VTECancer-Associated VTE

Patient-related factorsPatient-related factors► Older age Older age

► ComorbiditiesComorbidities

Patient-related factorsPatient-related factors► Older age Older age

► ComorbiditiesComorbidities

Treatment-related factorsTreatment-related factors► Recent surgery Recent surgery

► Hospitalization Hospitalization

► Chemotherapy Chemotherapy

► Hormonal therapy Hormonal therapy

► Antiangiogenic agentsAntiangiogenic agents

► Erythropoiesis-stimulating agentsErythropoiesis-stimulating agents

Treatment-related factorsTreatment-related factors► Recent surgery Recent surgery

► Hospitalization Hospitalization

► Chemotherapy Chemotherapy

► Hormonal therapy Hormonal therapy

► Antiangiogenic agentsAntiangiogenic agents

► Erythropoiesis-stimulating agentsErythropoiesis-stimulating agents

Biological factors (biomarkers)Biological factors (biomarkers)► Elevated pre-chemotherapy platelet Elevated pre-chemotherapy platelet

countcount► D-dimerD-dimer► Tissue factor expression by tumor Tissue factor expression by tumor

cellscells

Cancer-related factorsCancer-related factors► Site of cancer Site of cancer ► Advanced stageAdvanced stage► Initial period after diagnosisInitial period after diagnosis

Rao MV, et al., In Khorana AA, Francis CW, eds.Rao MV, et al., In Khorana AA, Francis CW, eds. 20072007

Page 32: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Risk of Inpatient VTE by Risk of Inpatient VTE by Type of CancerType of Cancer

Khorana AA et al. Khorana AA et al. J Clin OncolJ Clin Oncol. 2006;24:484-490.. 2006;24:484-490.

Rat

e of

VT

E,

%

00

22

4

6

8

10

12

14

AllAllBra

inBra

inLu

ngLu

ng

Stom

ach

Stom

ach

Colon

Colon

Pancr

eatic

Pancr

eatic

Other

Other

Abdom

inal

Abdom

inal

Ovaria

n

Ovaria

n

Endom

etria

l/

Endom

etria

l/

Cervic

al

Cervic

al

n=3550 n=68 n=326 n=43 n=51 n=53 n=55 n=127 n=95n=3550 n=68 n=326 n=43 n=51 n=53 n=55 n=127 n=95

In hospitalized neutropenic cancer patientsIn hospitalized neutropenic cancer patients

5.37

9.50

7.00 7.416.75

12.10

7.646.50

8.96

Page 33: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Risk of Inpatient VTE by Risk of Inpatient VTE by Type of Cancer Type of Cancer

Khorana AA et al. Khorana AA et al. J Clin OncolJ Clin Oncol. 2006;24:484-490.. 2006;24:484-490.

Rat

e of

VT

E,

%R

ate

of V

TE

, %

0

1

2

3

4

5

6

7

All Leukemia NHL MyelomaHodgkin’s Breast

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

5.37

4.395.01

3.87

5.79

3.93

In hospitalized neutropenic cancer patientsIn hospitalized neutropenic cancer patients

Page 34: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Patients With Cancer Represent Patients With Cancer Represent About 20% of All DVT and PEAbout 20% of All DVT and PE

Heit JA. et al. Heit JA. et al. Arch Intern Med Arch Intern Med 2002;162:1245-1248.2002;162:1245-1248.

Patients with cancer: Patients with cancer: approximately 19.8%approximately 19.8%

All DVT and PE

Page 35: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

00 20 20 40 40 60 60 80 80 100 100 120 120 140 160 180 140 160 1800.000.00

0.200.20

0.400.40

1.001.00

0.800.80

0.600.60

DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease

Malignant DiseaseMalignant Disease

DVT/PE OnlyDVT/PE Only

Nonmalignant DiseaseNonmalignant Disease

Number of DaysNumber of Days

Pro

babi

lity

of

Pro

babi

lity

of

Dea

thD

eath

Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285

VTE, Cancer, and SurvivalVTE, Cancer, and Survival

N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancerN = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer

Page 36: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

VTE and Inpatient MortalityVTE and Inpatient Mortality

Khorana AA et al. Khorana AA et al. J Clin Oncol. J Clin Oncol. 2006;24:484-490.2006;24:484-490.

All All (n=66,016)(n=66,016)

NonmetastaticNonmetastaticCancer Cancer

(n=20,591)(n=20,591)

MetastaticMetastaticCancer Cancer

(n=17,360)(n=17,360)

Mor

talit

y, %

Mor

talit

y, %

No Venous ThromboembolismNo Venous Thromboembolism

Venous ThromboembolismVenous Thromboembolism

7.987.98

10.5910.598.678.67

14.8514.8516.1316.13 16.4116.41

0022446688

101012121414161618182020

Page 37: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Amin A et al. Amin A et al. J Thromb Haemost. J Thromb Haemost. 2007; 5:1610-6.2007; 5:1610-6.

Prophylaxis Rates in Hospitalized PatientsProphylaxis Rates in Hospitalized Patients

Page 38: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Thromboprophylaxis Is UnderutilizedThromboprophylaxis Is Underutilizedin Non-surgical Patients With Cancer in Non-surgical Patients With Cancer P

atie

nts

Rec

eiv

ing

P

atie

nts

Rec

eiv

ing

A

ppr

op

riate

DV

T P

roph

yla

xis,

A

ppr

op

riate

DV

T P

roph

yla

xis,

%%

Premiere Perspective™ database: 72,391 Premiere Perspective™ database: 72,391 discharges from 225 hospitals between discharges from 225 hospitals between

January 2002 and September 2005 January 2002 and September 2005

Amin AN et al. Amin AN et al. J Clin OncolJ Clin Oncol. 2007;25 (suppl):Abstract 9047.. 2007;25 (suppl):Abstract 9047.

Page 39: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Clots and Cancer—A Looming Clots and Cancer—A Looming National Healthcare CrisisNational Healthcare Crisis

MISSION AND CHALLENGESMISSION AND CHALLENGES

Recognizing cancer patients at risk for DVT and Recognizing cancer patients at risk for DVT and identifying patients who are appropriate identifying patients who are appropriate

candidates for long-term prophylaxis and/or candidates for long-term prophylaxis and/or treatment with approved and indicated therapies treatment with approved and indicated therapies

are among the most important and difficult are among the most important and difficult challenges encountered in contemporary challenges encountered in contemporary

pharmacy and clinical practice.pharmacy and clinical practice.

MISSION AND CHALLENGESMISSION AND CHALLENGES

Recognizing cancer patients at risk for DVT and Recognizing cancer patients at risk for DVT and identifying patients who are appropriate identifying patients who are appropriate

candidates for long-term prophylaxis and/or candidates for long-term prophylaxis and/or treatment with approved and indicated therapies treatment with approved and indicated therapies

are among the most important and difficult are among the most important and difficult challenges encountered in contemporary challenges encountered in contemporary

pharmacy and clinical practice.pharmacy and clinical practice.

Page 40: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

A Systematic Analysis of VTE Prophylaxis A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer in the Setting of Cancer

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

A Systematic Analysis of VTE Prophylaxis A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer in the Setting of Cancer

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

Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies

Program Co-ChairmanSamuel Z. Goldhaber, MD

Professor of Medicine Harvard Medical SchoolCardiovascular Division

Director, Venous Thromboembolism Research GroupBrigham and Women’s Hospital

Boston, MA

Program Co-ChairmanSamuel Z. Goldhaber, MD

Professor of Medicine Harvard Medical SchoolCardiovascular Division

Director, Venous Thromboembolism Research GroupBrigham and Women’s Hospital

Boston, MA

Page 41: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology

► Of all cases of VTE:Of all cases of VTE:● About 20% occur in cancer patientsAbout 20% occur in cancer patients● Annual incidence of VTE in cancer Annual incidence of VTE in cancer

patients ≈ 1/250patients ≈ 1/250

► Of all cancer patients:Of all cancer patients:● 15% will have symptomatic VTE15% will have symptomatic VTE● As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy

► Compared to patients without cancer:Compared to patients without cancer:● Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE● Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants● Higher risk of dyingHigher risk of dying

► Of all cases of VTE:Of all cases of VTE:● About 20% occur in cancer patientsAbout 20% occur in cancer patients● Annual incidence of VTE in cancer Annual incidence of VTE in cancer

patients ≈ 1/250patients ≈ 1/250

► Of all cancer patients:Of all cancer patients:● 15% will have symptomatic VTE15% will have symptomatic VTE● As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy

► Compared to patients without cancer:Compared to patients without cancer:● Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE● Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants● Higher risk of dyingHigher risk of dying

Lee AY, Levine MN. Lee AY, Levine MN. CirculationCirculation. 2003;107:23 Suppl 1:I17-I21. 2003;107:23 Suppl 1:I17-I21

Page 42: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

1.1. Ambrus JL et al. Ambrus JL et al. J MedJ Med. 1975;6:61-64. 1975;6:61-642.2. Donati MB. Donati MB. HaemostasisHaemostasis. 1994;24:128-131. 1994;24:128-1313.3. Johnson MJ et al. Johnson MJ et al. Clin Lab HaemClin Lab Haem. 1999;21:51-54. 1999;21:51-544.4. Prandoni P et al. Prandoni P et al. Ann Intern MedAnn Intern Med. 1996;125:1-7. 1996;125:1-7

DVT and PE in CancerDVT and PE in Cancer Facts, Findings, and Natural HistoryFacts, Findings, and Natural History

► VTE is the second leading cause of death VTE is the second leading cause of death in hospitalized in hospitalized cancer patientscancer patients1,21,2

► The risk of VTE in cancer patients undergoing surgery is The risk of VTE in cancer patients undergoing surgery is 3- 3- to 5-fold higher to 5-fold higher than those without cancerthan those without cancer22

► Up to Up to 50% of cancer patients 50% of cancer patients may have evidence of may have evidence of asymptomatic DVT/PEasymptomatic DVT/PE33

► Cancer patients with symptomatic DVT exhibit a Cancer patients with symptomatic DVT exhibit a high risk high risk for recurrent DVT/PE that persists for many yearsfor recurrent DVT/PE that persists for many years44

► VTE is the second leading cause of death VTE is the second leading cause of death in hospitalized in hospitalized cancer patientscancer patients1,21,2

► The risk of VTE in cancer patients undergoing surgery is The risk of VTE in cancer patients undergoing surgery is 3- 3- to 5-fold higher to 5-fold higher than those without cancerthan those without cancer22

► Up to Up to 50% of cancer patients 50% of cancer patients may have evidence of may have evidence of asymptomatic DVT/PEasymptomatic DVT/PE33

► Cancer patients with symptomatic DVT exhibit a Cancer patients with symptomatic DVT exhibit a high risk high risk for recurrent DVT/PE that persists for many yearsfor recurrent DVT/PE that persists for many years44

Page 43: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Clinical Features of VTE in CancerClinical Features of VTE in Cancer

► VTE has significant negative impact on quality VTE has significant negative impact on quality of lifeof life

► VTE may be the presenting sign of occult VTE may be the presenting sign of occult malignancymalignancy• 10% with idiopathic VTE develop cancer within 10% with idiopathic VTE develop cancer within

2 years2 years• 20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE• 25% have bilateral DVT25% have bilateral DVT

► VTE has significant negative impact on quality VTE has significant negative impact on quality of lifeof life

► VTE may be the presenting sign of occult VTE may be the presenting sign of occult malignancymalignancy• 10% with idiopathic VTE develop cancer within 10% with idiopathic VTE develop cancer within

2 years2 years• 20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE• 25% have bilateral DVT25% have bilateral DVT

Bura Bura et. al.,et. al., J Thromb HaemostJ Thromb Haemost 2004;2:445-51 2004;2:445-51

Page 44: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Thrombosis and SurvivalThrombosis and SurvivalLikelihood of Death After HospitalizationLikelihood of Death After Hospitalization

00 20 20 40 40 60 60 80 80 100 100 120 120140 160 180140 160 1800.000.00

0.200.20

0.400.40

1.001.00

0.800.80

0.600.60

DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease

Malignant DiseaseMalignant Disease

DVT/PE OnlyDVT/PE Only

Nonmalignant DiseaseNonmalignant Disease

Number of DaysNumber of Days

Pro

babi

lity

of

Pro

babi

lity

of

Dea

thD

eath

Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285

Page 45: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Hospital Mortality With or Without VTEHospital Mortality With or Without VTE

Khorana, JCO, 2006Khorana, JCO, 2006

Mor

talit

y (%

)M

orta

lity

(%)

Mor

talit

y (%

)M

orta

lity

(%)

N=66,016N=66,016 N=20,591N=20,591 N=17,360N=17,360

Page 46: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Trends in VTE in Hospitalized Cancer PatientsTrends in VTE in Hospitalized Cancer Patients

VTE- patients on chemotherapyVTE- patients on chemotherapy VTE-all patientsVTE-all patients DVT-all patientsDVT-all patients

PE-all patientsPE-all patients

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.0

19951995 19961996 19971997 19981998 19991999 20002000 20012001 20022002 20032003

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

P<0.0001P<0.0001

Khorana AA et al. Khorana AA et al. Cancer. Cancer. 2007.2007.

Page 47: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Thrombosis Risk In Cancer Thrombosis Risk In Cancer

Primary ProphylaxisPrimary Prophylaxis

► Medical InpatientsMedical Inpatients

► SurgerySurgery

► RadiotherapyRadiotherapy

► Central Venous CathetersCentral Venous Catheters

Page 48: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Risk Factors for Cancer-Associated VTERisk Factors for Cancer-Associated VTE

► CancerCancer● Type Type

• Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung• Women: breast, ovary, lungWomen: breast, ovary, lung

● StageStage► TreatmentsTreatments

● SurgerySurgery• 10-20% proximal DVT10-20% proximal DVT• 4-10% clinically evident PE4-10% clinically evident PE• 0.2-5% fatal PE0.2-5% fatal PE

● ChemotherapyChemotherapy● Central venous cathetersCentral venous catheters (~4% generate clinically (~4% generate clinically

relevant VTE)relevant VTE)

► PatientPatient● Prior VTEPrior VTE● ComorbiditiesComorbidities● Genetic backgroundGenetic background

► CancerCancer● Type Type

• Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung• Women: breast, ovary, lungWomen: breast, ovary, lung

● StageStage► TreatmentsTreatments

● SurgerySurgery• 10-20% proximal DVT10-20% proximal DVT• 4-10% clinically evident PE4-10% clinically evident PE• 0.2-5% fatal PE0.2-5% fatal PE

● ChemotherapyChemotherapy● Central venous cathetersCentral venous catheters (~4% generate clinically (~4% generate clinically

relevant VTE)relevant VTE)

► PatientPatient● Prior VTEPrior VTE● ComorbiditiesComorbidities● Genetic backgroundGenetic background

Page 49: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

VTE Risk And Cancer TypeVTE Risk And Cancer Type“Solid And Liquid Malignancies”“Solid And Liquid Malignancies”

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

Rel

ativ

e R

isk

of V

TE

inR

elat

ive

Ris

k of

VT

E in

Can

cer

Pat

ient

sC

ance

r P

atie

nts

Pan

crea

sP

ancr

eas

Bra

inB

rain

Mye

lopr

olM

yelo

prol

Sto

mac

hS

tom

ach

Lym

phom

aLy

mph

oma

Ute

rus

Ute

rus

Lung

Lung

Eso

phag

usE

soph

agus

Pro

stat

eP

rost

ate

Rec

tal

Rec

tal

Kid

ney

Kid

ney

Col

onC

olon

Ova

ryO

vary

Live

rLi

ver

Leuk

emia

Leuk

emia

Bre

ast

Bre

ast

Cer

vix

Cer

vix

Bla

dder

Bla

dder

4.54.5

44

3.53.5

33

2.52.5

22

1.51.5

11

0.50.5

Relative Risk of VTE Ranged From 1.02 to 4.34Relative Risk of VTE Ranged From 1.02 to 4.34

Page 50: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Medical InpatientsMedical Inpatients

Cancer and ThrombosisCancer and Thrombosis

Page 51: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Thromboembolism in Hospitalized Thromboembolism in Hospitalized Neutropenic Cancer PatientsNeutropenic Cancer Patients

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

► 66,106 adult neutropenic cancer 66,106 adult neutropenic cancer patients between 1995 and 2002 at patients between 1995 and 2002 at 115 centers115 centers

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

► 66,106 adult neutropenic cancer 66,106 adult neutropenic cancer patients between 1995 and 2002 at patients between 1995 and 2002 at 115 centers115 centers

Khorana, JCO, 2006Khorana, JCO, 2006

Page 52: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Neutropenic Patients: ResultsNeutropenic Patients: Results

► 8% had thrombosis8% had thrombosis

► 5.4% venous and 1.5% arterial in 15.4% venous and 1.5% arterial in 1stst hospitalization hospitalization

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

disease, obesity)disease, obesity)

► 8% had thrombosis8% had thrombosis

► 5.4% venous and 1.5% arterial in 15.4% venous and 1.5% arterial in 1stst hospitalization hospitalization

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

disease, obesity)disease, obesity)

Khorana, JCO, 2006Khorana, JCO, 2006

Page 53: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Predictors of VTE in Predictors of VTE in Hospitalized Cancer PatientsHospitalized Cancer Patients

CharacteristicCharacteristic OROR PP ValueValue

Site of CancerSite of Cancer

LungLung

StomachStomach

PancreasPancreas

Endometrium/cervixEndometrium/cervix

BrainBrain

1.31.3

1.61.6

2.82.8

22

2.22.2

<0.001<0.001

0.00350.0035

<0.001<0.001

<0.001<0.001

<0.001<0.001

Age Age 65 y65 y 1.11.1 0.0050.005

Arterial thromboembolismArterial thromboembolism 1.41.4 0.0080.008

Comorbidities (lung/renal disease, Comorbidities (lung/renal disease, infection, obesity)infection, obesity) 1.3-1.61.3-1.6 <0.001<0.001

Khorana AA et al. Khorana AA et al. J Clin Oncol. J Clin Oncol. 2006;24:484-490.2006;24:484-490.

Page 54: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

PharmacologicPharmacologic(Prophylaxis & Treatment)(Prophylaxis & Treatment)

NonpharmacologicNonpharmacologic(Prophylaxis)(Prophylaxis)

Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices

IntermittentPneumatic

Compression

Elastic Stockings

InferiorVena Cava

FilterOral

Anticoagulants

UnfractionatedHeparin (UH)

Low Molecular Weight Heparin (LMWH)

New Agents: e.g. Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?

Page 55: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Prophylaxis Studies in Medical PatientsProphylaxis Studies in Medical Patients

Francis, NEJM, 2007Francis, NEJM, 2007

Placebo EnoxaparinPlacebo Enoxaparin

MEDENOX TrialMEDENOX Trial

Placebo DalteparinPlacebo Dalteparin

PREVENTPREVENT

Placebo FondaparinuxPlacebo Fondaparinux

ARTEMISARTEMIS

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Relative Relative risk risk

reduction reduction 63%63%

Relative Relative risk risk

reduction reduction 44%44%

Relative Relative risk risk

reduction reduction 47%47%

Page 56: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

ASCO GuidelinesASCO Guidelines

1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITHCANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FORVTE PROPHYLAXISVTE PROPHYLAXIS??

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

1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITHCANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FORVTE PROPHYLAXISVTE PROPHYLAXIS??

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

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

Page 57: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Surgical PatientsSurgical Patients

Cancer and ThrombosisCancer and Thrombosis

Page 58: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

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

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

Kakkar AK, et al. Kakkar AK, et al. Thromb HaemostThromb Haemost 2001; 86 (suppl 1): OC1732 2001; 86 (suppl 1): OC1732

Incidence of VTE in Surgical PatientsIncidence of VTE in Surgical Patients

No CancerNo CancerN=16,954N=16,954

CancerCancerN=6124N=6124

P-valueP-value

Post-op VTEPost-op VTE 0.61%0.61% 1.26%1.26% <0.0001<0.0001

Non-fatal PENon-fatal PE 0.27%0.27% 0.54%0.54% <0.0003<0.0003

Autopsy PEAutopsy PE 0.11%0.11% 0.41%0.41% <0.0001<0.0001

DeathDeath 0.71%0.71% 3.14%3.14% <0.0001<0.0001

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Natural History of VTE in Cancer Surgery: Natural History of VTE in Cancer Surgery: The @RISTOS RegistryThe @RISTOS Registry

► Web-Based Registry of Cancer SurgeryWeb-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patientsTracked 30-day incidence of VTE in 2373 patients

Type of surgeryType of surgery • • 52% General 52% General • • 29% Urological29% Urological • • 19% Gynecologic19% Gynecologic

82% received in-hospital thromboprophylaxis82% received in-hospital thromboprophylaxis

31% received post-discharge thromboprophylaxis31% received post-discharge thromboprophylaxis

FindingsFindings

► 2.1% incidence of clinically overt VTE (0.8% fatal)2.1% incidence of clinically overt VTE (0.8% fatal)

► Most events occur after hospital discharge Most events occur after hospital discharge

► Most common cause of 30-day post-op deathMost common cause of 30-day post-op death

► Web-Based Registry of Cancer SurgeryWeb-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patientsTracked 30-day incidence of VTE in 2373 patients

Type of surgeryType of surgery • • 52% General 52% General • • 29% Urological29% Urological • • 19% Gynecologic19% Gynecologic

82% received in-hospital thromboprophylaxis82% received in-hospital thromboprophylaxis

31% received post-discharge thromboprophylaxis31% received post-discharge thromboprophylaxis

FindingsFindings

► 2.1% incidence of clinically overt VTE (0.8% fatal)2.1% incidence of clinically overt VTE (0.8% fatal)

► Most events occur after hospital discharge Most events occur after hospital discharge

► Most common cause of 30-day post-op deathMost common cause of 30-day post-op death

Agnelli, Ann Surg 2006; 243: 89-95Agnelli, Ann Surg 2006; 243: 89-95

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LMWH vs. UFHLMWH vs. UFH► Abdominal or pelvic surgery for cancer (mostly colorectal)Abdominal or pelvic surgery for cancer (mostly colorectal)

► LMWH once daily vs. UFH tid for 7–10 days post-opLMWH once daily vs. UFH tid for 7–10 days post-op

► DVT on venography at day 7–10 and symptomatic VTEDVT on venography at day 7–10 and symptomatic VTE

LMWH vs. UFHLMWH vs. UFH► Abdominal or pelvic surgery for cancer (mostly colorectal)Abdominal or pelvic surgery for cancer (mostly colorectal)

► LMWH once daily vs. UFH tid for 7–10 days post-opLMWH once daily vs. UFH tid for 7–10 days post-op

► DVT on venography at day 7–10 and symptomatic VTEDVT on venography at day 7–10 and symptomatic VTE

1. ENOXACAN Study Group. 1. ENOXACAN Study Group. Br J SurgBr J Surg 1997;84:1099–103 1997;84:1099–1032. McLeod R, et al. 2. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-444 2001;233:438-444

Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients

StudyStudy NN DesignDesign RegimensRegimens

ENOXACAN ENOXACAN 11 631631 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH

Canadian Colorectal Canadian Colorectal DVT Prophylaxis DVT Prophylaxis 22 475475 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH

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Canadian Canadian Colorectal DVT Colorectal DVT Prophylaxis TrialProphylaxis Trial

13.9%13.9%

1.5% 2.7%1.5% 2.7%

16.9%16.9%

N=234N=234

N=241N=241

McLeod R, et al. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-444 2001;233:438-444

P=0.052P=0.052

In

cide

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of O

utco

me

Eve

ntIn

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nt

VTEVTE Major BleedingMajor Bleeding(Cancer) (All)(Cancer) (All)

Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients

Page 62: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

VTE Prox Any MajorVTE Prox Any Major DVT Bleeding BleedingDVT Bleeding Bleeding

P=0.02

5.1%

1.8%

Bergqvist D, et al. (for the ENOXACAN II investigators) Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-980 2002;346:975-980

ENOXACAN IIENOXACAN II

In

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ntIn

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of O

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nt

N=167

N=165

0% 0.4%

12.0%

4.8%

NNT = 140.6%

3.6%

Extended Prophylaxis inExtended Prophylaxis inSurgical PatientsSurgical Patients

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► A multicenter, prospective, assessor-blinded, open-label, A multicenter, prospective, assessor-blinded, open-label, randomized trial: randomized trial: Dalteparin administered for 28 days Dalteparin administered for 28 days after major abdominal surgeryafter major abdominal surgery compared to 7 days of compared to 7 days of treatmenttreatment

► RESULTS:RESULTS: Cumulative Cumulative incidence of VTE was reduced incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3%patients) to 7.3% after prolonged thromboprophylaxis after prolonged thromboprophylaxis (12/165) ((12/165) (relative risk reduction 55%;relative risk reduction 55%; 95% confidence 95% confidence interval 15-76; P=0.012).interval 15-76; P=0.012).

► CONCLUSIONS:CONCLUSIONS: 4-week administration of dalteparin, 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTEsignificantly reduces the rate of VTE, without increasing , without increasing the risk of bleeding, compared with 1 week of the risk of bleeding, compared with 1 week of thromboprophylaxis.thromboprophylaxis.

► A multicenter, prospective, assessor-blinded, open-label, A multicenter, prospective, assessor-blinded, open-label, randomized trial: randomized trial: Dalteparin administered for 28 days Dalteparin administered for 28 days after major abdominal surgeryafter major abdominal surgery compared to 7 days of compared to 7 days of treatmenttreatment

► RESULTS:RESULTS: Cumulative Cumulative incidence of VTE was reduced incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3%patients) to 7.3% after prolonged thromboprophylaxis after prolonged thromboprophylaxis (12/165) ((12/165) (relative risk reduction 55%;relative risk reduction 55%; 95% confidence 95% confidence interval 15-76; P=0.012).interval 15-76; P=0.012).

► CONCLUSIONS:CONCLUSIONS: 4-week administration of dalteparin, 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTEsignificantly reduces the rate of VTE, without increasing , without increasing the risk of bleeding, compared with 1 week of the risk of bleeding, compared with 1 week of thromboprophylaxis.thromboprophylaxis.

Major Abdominal Surgery: FAME InvestigatorsMajor Abdominal Surgery: FAME Investigators—Dalteparin Extended —Dalteparin Extended

Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

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ASCO Guidelines: VTE ProphylaxisASCO Guidelines: VTE Prophylaxis

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

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

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

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

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

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

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

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Thrombosis is a potential complication of central Thrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events:

–Fibrin sheath formationFibrin sheath formation

–Superficial phlebitisSuperficial phlebitis

–Ball-valve clotBall-valve clot

–Deep vein thrombosis (DVT)Deep vein thrombosis (DVT)

Thrombosis is a potential complication of central Thrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events:

–Fibrin sheath formationFibrin sheath formation

–Superficial phlebitisSuperficial phlebitis

–Ball-valve clotBall-valve clot

–Deep vein thrombosis (DVT)Deep vein thrombosis (DVT)

Central Venous CathetersCentral Venous Catheters

Geerts W, et al. Geerts W, et al. ChestChest Jun 2008: 381S–453S Jun 2008: 381S–453S

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Placebo-Controlled TrialsPlacebo-Controlled TrialsPlacebo-Controlled TrialsPlacebo-Controlled Trials

StudyStudy RegimenRegimen NN CRT (%)CRT (%)

Reichardt* Reichardt* 20022002

Dalteparin 5000 U dailyDalteparin 5000 U dailyplaceboplacebo

285285140140

11 (3.7)11 (3.7) 5 (3.4)5 (3.4)

Couban*Couban*20022002

Warfarin 1mg dailyWarfarin 1mg dailyplaceboplacebo

130130125125

6 (4.6)6 (4.6) 5 (4.0)5 (4.0)

ETHICSETHICS††

20042004Enoxaparin 40 mg dailyEnoxaparin 40 mg daily

placeboplacebo155155155155

22 (14.2)22 (14.2)28 (18.1)28 (18.1)

**symptomatic outcomessymptomatic outcomes;; ††routine venography at 6 weeksroutine venography at 6 weeks

Prophylaxis for Venous CathetersProphylaxis for Venous Catheters

Reichardt P, et al. Reichardt P, et al. Proc ASCOProc ASCO 2002;21:369a; Couban S, et al, 2002;21:369a; Couban S, et al, BloodBlood 2002;100:703a; Agnelli G, et 2002;100:703a; Agnelli G, et al. al. Proc ASCOProc ASCO 2004;23:730 2004;23:730

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Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin

► 95 cancer patients receiving FU-based infusion 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailychemotherapy and 1 mg warfarin daily

► INR measured at baseline and four time pointsINR measured at baseline and four time points

► 10% of all recorded INRs >1.510% of all recorded INRs >1.5

► Patients with elevated INRPatients with elevated INR2.0–2.92.0–2.9 6% 6%

3.0–4.93.0–4.9 19%19%

>5.0>5.0 7% 7%

Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin

► 95 cancer patients receiving FU-based infusion 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailychemotherapy and 1 mg warfarin daily

► INR measured at baseline and four time pointsINR measured at baseline and four time points

► 10% of all recorded INRs >1.510% of all recorded INRs >1.5

► Patients with elevated INRPatients with elevated INR2.0–2.92.0–2.9 6% 6%

3.0–4.93.0–4.9 19%19%

>5.0>5.0 7% 7%

Central Venous Catheters: WarfarinCentral Venous Catheters: Warfarin

Masci et al. J Clin Oncol. 2003;21:736-739

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SummarySummary► Recent studies demonstrate a low Recent studies demonstrate a low

incidence of symptomatic catheter-related incidence of symptomatic catheter-related thrombosis (~4%)thrombosis (~4%)

► Routine prophylaxis is Routine prophylaxis is not warrantednot warranted to to prevent catheter-related thrombosis, but prevent catheter-related thrombosis, but catheter patency rates/infections have not catheter patency rates/infections have not been studiedbeen studied

► Low-dose LMWH and fixed-dose warfarin Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for have not been shown to be effective for preventing symptomatic and asymptomatic preventing symptomatic and asymptomatic thrombosisthrombosis

SummarySummary► Recent studies demonstrate a low Recent studies demonstrate a low

incidence of symptomatic catheter-related incidence of symptomatic catheter-related thrombosis (~4%)thrombosis (~4%)

► Routine prophylaxis is Routine prophylaxis is not warrantednot warranted to to prevent catheter-related thrombosis, but prevent catheter-related thrombosis, but catheter patency rates/infections have not catheter patency rates/infections have not been studiedbeen studied

► Low-dose LMWH and fixed-dose warfarin Low-dose LMWH and fixed-dose warfarin have not been shown to be effective for have not been shown to be effective for preventing symptomatic and asymptomatic preventing symptomatic and asymptomatic thrombosisthrombosis

Prophylaxis for Central Venous Prophylaxis for Central Venous Access DevicesAccess Devices

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88thth ACCP Consensus Guidelines ACCP Consensus Guidelines

No routine prophylaxis to prevent No routine prophylaxis to prevent thrombosis secondary to central thrombosis secondary to central

venous catheters, including LMWH venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)(2B) and fixed-dose warfarin (1B)

ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S

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Primary Prophylaxis in Cancer RadiotherapyPrimary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient The Ambulatory Patient

► No recommendations from ACCPNo recommendations from ACCP

► No data from randomized trials (RCTs)No data from randomized trials (RCTs)

► Weak data from observational studies in Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian)pancreatic, lung, renal cell, ovarian)

► Recommendations extrapolated from Recommendations extrapolated from other groups of patients if additional risk other groups of patients if additional risk factors present (e.g., hemiparesis in brain factors present (e.g., hemiparesis in brain tumors, etc.)tumors, etc.)

► No recommendations from ACCPNo recommendations from ACCP

► No data from randomized trials (RCTs)No data from randomized trials (RCTs)

► Weak data from observational studies in Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian)pancreatic, lung, renal cell, ovarian)

► Recommendations extrapolated from Recommendations extrapolated from other groups of patients if additional risk other groups of patients if additional risk factors present (e.g., hemiparesis in brain factors present (e.g., hemiparesis in brain tumors, etc.)tumors, etc.)

Page 71: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Ambulatory Chemotherapy Ambulatory Chemotherapy PatientsPatients

Cancer and ThrombosisCancer and Thrombosis

Page 72: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Risk Factors for VTE inRisk Factors for VTE inMedical Oncology PatientsMedical Oncology Patients

► Tumor typeTumor type● Ovary, brain, pancreas, lung, colonOvary, brain, pancreas, lung, colon

► Stage, grade, and extent of cancerStage, grade, and extent of cancer● Metastatic disease, venous stasis due to Metastatic disease, venous stasis due to

bulky diseasebulky disease

► Type of antineoplastic treatmentType of antineoplastic treatment● Multiagent regimens, hormones,Multiagent regimens, hormones,

anti-VEGF, radiationanti-VEGF, radiation

► Miscellaneous VTE risk factorsMiscellaneous VTE risk factors● Previous VTE, Previous VTE, hospitalization, immobility, hospitalization, immobility,

infection, thrombophiliainfection, thrombophilia

► Tumor typeTumor type● Ovary, brain, pancreas, lung, colonOvary, brain, pancreas, lung, colon

► Stage, grade, and extent of cancerStage, grade, and extent of cancer● Metastatic disease, venous stasis due to Metastatic disease, venous stasis due to

bulky diseasebulky disease

► Type of antineoplastic treatmentType of antineoplastic treatment● Multiagent regimens, hormones,Multiagent regimens, hormones,

anti-VEGF, radiationanti-VEGF, radiation

► Miscellaneous VTE risk factorsMiscellaneous VTE risk factors● Previous VTE, Previous VTE, hospitalization, immobility, hospitalization, immobility,

infection, thrombophiliainfection, thrombophilia

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Independent Risk Factors for DVT/PEIndependent Risk Factors for DVT/PE

Risk Factor/CharacteristicRisk Factor/Characteristic O.R.O.R.

Recent surgery with institutionalizationRecent surgery with institutionalization 21.7221.72

TraumaTrauma 12.6912.69

Institutionalization without recent surgeryInstitutionalization without recent surgery 7.987.98

Malignancy with chemotherapyMalignancy with chemotherapy 6.536.53

Prior CVAD or pacemakerPrior CVAD or pacemaker 5.555.55

Prior superficial vein thrombosisPrior superficial vein thrombosis 4.324.32

Malignancy without chemotherapyMalignancy without chemotherapy 4.054.05

Neurologic disease w/ extremity paresisNeurologic disease w/ extremity paresis 3.043.04

Serious liver diseaseSerious liver disease 0.100.10

Heit JA et al. Heit JA et al. Thromb HaemostThromb Haemost. 2001;86:452-463. 2001;86:452-463

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VTE Incidence In Various TumorsVTE Incidence In Various Tumors

Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

Oncology SettingOncology Setting VTE VTE IncidenceIncidence

Breast cancer (Stage I & II) w/o further treatmentBreast cancer (Stage I & II) w/o further treatment 0.2%0.2%

Breast cancer (Stage I & II) w/ chemoBreast cancer (Stage I & II) w/ chemo 2%2%

Breast cancer (Stage IV) w/ chemoBreast cancer (Stage IV) w/ chemo 8%8%

Non-Hodgkin’s lymphomas w/ chemoNon-Hodgkin’s lymphomas w/ chemo 3%3%

Hodgkin’s disease w/ chemoHodgkin’s disease w/ chemo 6%6%

Advanced cancer (1-year survival=12%)Advanced cancer (1-year survival=12%) 9%9%

High-grade gliomaHigh-grade glioma 26%26%

Multiple myeloma (thalidomide + chemo)Multiple myeloma (thalidomide + chemo) 28%28%

Renal cell carcinoma Renal cell carcinoma 43%43%

Solid tumors (anti-VEGF + chemo)Solid tumors (anti-VEGF + chemo) 47%47%

Wilms tumor (cavoatrial extension) Wilms tumor (cavoatrial extension) 4%4%

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PrimaryPrimary VTE Prophylaxis VTE Prophylaxis

► Recommended for hospitalized Recommended for hospitalized cancer patientscancer patients

► Not recommended or generally used Not recommended or generally used for outpatientsfor outpatients● Very little dataVery little data● HeterogeneousHeterogeneous

► Recommended for hospitalized Recommended for hospitalized cancer patientscancer patients

► Not recommended or generally used Not recommended or generally used for outpatientsfor outpatients● Very little dataVery little data● HeterogeneousHeterogeneous

Need for risk stratificationNeed for risk stratification

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Ambulatory Cancer plus ChemotherapyAmbulatory Cancer plus Chemotherapy

Study MethodsStudy Methods

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

► 115 U.S. centers participated115 U.S. centers participated

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

Study MethodsStudy Methods

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

► 115 U.S. centers participated115 U.S. centers participated

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

Khorana, Cancer, 2005 Khorana, Cancer, 2005

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Ambulatory Cancer plus ChemotherapyAmbulatory Cancer plus Chemotherapy

► VTE events were recorded during mid-cycle or new-cycle VTE events were recorded during mid-cycle or new-cycle visitsvisits

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

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

► VTE events were recorded during mid-cycle or new-cycle VTE events were recorded during mid-cycle or new-cycle visitsvisits

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

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

Khorana, Cancer, 2005Khorana, Cancer, 2005

Study MethodsStudy Methods

Page 78: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Incidence of VTEIncidence of VTE

VTE / 2.4 monthsVTE / 2.4 months VTE/monthVTE/month VTE /cycleVTE /cycle Cumulative rate Cumulative rate (95% CI)(95% CI)

1.93%1.93% 0.8%0.8% 0.7%0.7% 2.2% (1.7-2.8)2.2% (1.7-2.8)

0.0%0.0%

0.5%0.5%

1.0%1.0%

1.5%1.5%

2.0%2.0%

2.5%2.5%

3.0%3.0%

BaselineBaseline Cycle 1Cycle 1 Cycle 2Cycle 2 Cycle 3Cycle 3

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Khorana, Cancer, 2005Khorana, Cancer, 2005

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Risk Factors: Site of CancerRisk Factors: Site of Cancer

0022446688

10101212

All pat

ients

All pat

ients

Breas

t

Breas

t

Colon

Colon

Lung

Lung

Upper

GI

Upper

GI

Hodgk

in’s

Hodgk

in’s

NHLNHL

Other

s

Other

s

Site of CancerSite of Cancer

VT

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/ 2.

4 m

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TE

(%

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2.4

mon

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Khorana, Cancer, 2005Khorana, Cancer, 2005

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Incidence of Venous Thromboembolism By Incidence of Venous Thromboembolism By Quartiles of Pre-chemotherapy Platelet CountQuartiles of Pre-chemotherapy Platelet Count

p for trend=0.005p for trend=0.005

0.0%0.0%

0.5%0.5%

1.0%1.0%

1.5%1.5%

2.0%2.0%

2.5%2.5%

3.0%3.0%

3.5%3.5%

4.0%4.0%

4.5%4.5%

5.0%5.0%

<217 <217 217-270 217-270 270-337270-337 >337>337

Pre-chemotherapy Platelet Count/mmPre-chemotherapy Platelet Count/mm 33 (x1000)(x1000)

Inci

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TE

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2.4

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Mon

ths(

%)

Khorana, Cancer, 2005Khorana, Cancer, 2005

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Risk Factors: Multivariate AnalysisRisk Factors: Multivariate Analysis

CharacteristicCharacteristic OROR P valueP value

Site of CancerSite of Cancer

Upper GIUpper GI

LungLung

LymphomaLymphoma

3.883.88

1.861.86

1.51.5

0.030.03

0.00760.0076

0.050.05

0.320.32

Pre-chemotherapy platelet count Pre-chemotherapy platelet count >> 350,000/mm350,000/mm33 2.812.81 0.00020.0002

Hgb < 10g/dL or use of red cell Hgb < 10g/dL or use of red cell growth factorgrowth factor 1.831.83 0.030.03

Use of white cell growth factor in high-Use of white cell growth factor in high-risk sitesrisk sites 2.092.09 0.0080.008

Khorana, Cancer, 2005Khorana, Cancer, 2005

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Predictive ModelPredictive Model

Patient CharacteristicPatient Characteristic ScoreScore

Site of CancerSite of Cancer

Very high risk (stomach, pancreas)Very high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, GU High risk (lung, lymphoma, gynecologic, GU excluding prostate)excluding prostate)

22

11

Platelet count Platelet count >> 350,000/mm 350,000/mm33 11

Hgb < 10g/dL or use of ESAHgb < 10g/dL or use of ESA 11

Leukocyte count > 11,000/mmLeukocyte count > 11,000/mm33 11

BMI BMI >> 35 35 11

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

Page 83: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Risk ScoreRisk Score 00 11 22 33 44

NN 1,3521,352 974974 476476 160160 3333

VTE(%) /2.4 mos.VTE(%) /2.4 mos. 0.80.8 1.81.8 2.72.7 6.36.3 13.213.2

Inci

denc

e of

VT

E O

ver

2.4

Mon

ths

Inci

denc

e of

VT

E O

ver

2.4

Mon

ths

0%0%

2%2%

4%4%

6%6%

8%8%

10%10%

12%12%

14%14%

16%16%

18%18%

00 11 22 33 44

Actual IncidenceActual IncidenceEstimated IncidenceEstimated Incidence95 % Confidence Limits95 % Confidence Limits

Predictive ModelPredictive Model

Page 84: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Predictive Model ValidationPredictive Model Validation

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

0%0%

1%1%

2%2%

3%3%

4%4%

5%5%

6%6%

7%7%

8%8%

Rat

e of

VT

E o

ver

2.5

mos

(%

)R

ate

of V

TE

ove

r 2.

5 m

os (

%)

n=734n=734 n=1627n=1627 n=340n=340

0.8%0.8%

1.8%1.8%

7.1%7.1%Development cohortDevelopment cohort

0.3%0.3%

2.0%2.0%

6.7%6.7%

Validation cohortValidation cohort

n=374n=374 n=842n=842 n=149n=149

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

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Oral Anticoagulant TherapyOral Anticoagulant Therapyin Cancer Patients: Problematicin Cancer Patients: Problematic

► Warfarin therapy is complicated by:Warfarin therapy is complicated by:

● Difficulty maintaining tight therapeutic control, due Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. to anorexia, vomiting, drug interactions, etc.

● Frequent interruptions for thrombocytopenia and Frequent interruptions for thrombocytopenia and proceduresprocedures

● Difficulty in venous access for monitoringDifficulty in venous access for monitoring● Increased risk of both recurrence and bleedingIncreased risk of both recurrence and bleeding

► Is it reasonable to substitute long-term LMWH Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?for warfarin ? When? How? Why?

► Warfarin therapy is complicated by:Warfarin therapy is complicated by:

● Difficulty maintaining tight therapeutic control, due Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. to anorexia, vomiting, drug interactions, etc.

● Frequent interruptions for thrombocytopenia and Frequent interruptions for thrombocytopenia and proceduresprocedures

● Difficulty in venous access for monitoringDifficulty in venous access for monitoring● Increased risk of both recurrence and bleedingIncreased risk of both recurrence and bleeding

► Is it reasonable to substitute long-term LMWH Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?for warfarin ? When? How? Why?

Page 86: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

CLOT: Landmark Cancer/VTE TrialCLOT: Landmark Cancer/VTE Trial

CANCER PATIENTS WITH CANCER PATIENTS WITH ACUTE DVT or PEACUTE DVT or PE RandomizationRandomization

[N = 677][N = 677]

► Primary Endpoints:Primary Endpoints: Recurrent VTE and Bleeding Recurrent VTE and Bleeding► Secondary EndpointSecondary Endpoint:: Survival Survival

Lee, Levine, Kakkar, Rickles et.al. Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, N Engl J Med, 2003;349:1462003;349:146

Dalteparin Dalteparin

Dalteparin Oral Anticoagulant

Page 87: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Landmark CLOT Cancer TrialLandmark CLOT Cancer TrialReduction in Recurrent VTEReduction in Recurrent VTE

00

55

1010

1515

2020

2525

Days Post RandomizationDays Post Randomization

00 3030 6060 9090 120120 150150 180180 210210

Pro

bab

ility

of R

ecu

rre

nt V

TE

, %P

roba

bili

ty o

f Re

curr

en

t VT

E, % Risk reduction = 52%Risk reduction = 52%

pp-value = 0.0017-value = 0.0017

DalteparinDalteparin

OACOAC

Recurrent VTERecurrent VTE

Lee, Levine, Kakkar, Rickles et.al. Lee, Levine, Kakkar, Rickles et.al. N N Engl J Med, Engl J Med, 2003;349:1462003;349:146

Page 88: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

DalteparinDalteparin N=338N=338

OACOACN=335N=335

P-value*P-value*

Major bleedMajor bleed 19 ( 5.6%) 19 ( 5.6%) 12 ( 3.6%)12 ( 3.6%) 0.270.27

Any bleedAny bleed 46 (13.6%)46 (13.6%) 62 (18.5%)62 (18.5%) 0.0930.093

* Fisher’s exact test* Fisher’s exact test

Bleeding Events in CLOTBleeding Events in CLOT

Lee, Levine, Kakkar, Rickles et.al. Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, N Engl J Med, 2003;349:1462003;349:146

Page 89: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Treatment of Cancer-Associated VTETreatment of Cancer-Associated VTE

StudyStudy DesignDesignLength of Length of TherapyTherapy(Months)(Months)

NNRecurrent Recurrent

VTE VTE (%)(%)

Major Major BleedingBleeding

(%)(%)

DeathDeath(%)(%)

CLOT TrialCLOT Trial(Lee 2003)(Lee 2003)

DalteparinDalteparinOACOAC

6 6 336336336336

991717

6644

39394141

CANTHENOXCANTHENOX(Meyer 2002)(Meyer 2002)

EnoxaparinEnoxaparinOACOAC

3367677171

11112121

771616

11112323

LITELITE(Hull ISTH 2003)(Hull ISTH 2003)

TinzaparinTinzaparinOACOAC

3380808787

661111

6688

23232222

ONCENOXONCENOX(Deitcher ISTH (Deitcher ISTH 2003)2003)

Enox (Low)Enox (Low)Enox (High)Enox (High)OACOAC

66323236363434

3.43.43.13.16.76.7

NS

NS0.03

NS

NS0.002

NS

NS

NR

0.09 0.030.09

Page 90: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Treatment and 2Treatment and 2° Prevention of VTE ° Prevention of VTE in Cancer – Bottom Linein Cancer – Bottom Line

► New standard of care is LMWH at therapeutic doses New standard of care is LMWH at therapeutic doses for a for a minimum of 3-6 monthsminimum of 3-6 months (Grade 1A (Grade 1A recommendation—ACCP)recommendation—ACCP)

► NOTENOTE:: Dalteparin is only LMWH approved (May, Dalteparin is only LMWH approved (May, 2007) for both the 2007) for both the treatment and secondary treatment and secondary preventionprevention of VTE in cancer of VTE in cancer

► Oral anticoagulant therapy to follow for as long as Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP)cancer is active (Grade 1C recommendation—ACCP)

► New standard of care is LMWH at therapeutic doses New standard of care is LMWH at therapeutic doses for a for a minimum of 3-6 monthsminimum of 3-6 months (Grade 1A (Grade 1A recommendation—ACCP)recommendation—ACCP)

► NOTENOTE:: Dalteparin is only LMWH approved (May, Dalteparin is only LMWH approved (May, 2007) for both the 2007) for both the treatment and secondary treatment and secondary preventionprevention of VTE in cancer of VTE in cancer

► Oral anticoagulant therapy to follow for as long as Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP)cancer is active (Grade 1C recommendation—ACCP)

ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S

New DevelopmentNew Development

Page 91: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

CLOT 12-month MortalityCLOT 12-month MortalityAll PatientsAll Patients

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

00 3030 6060 9090 120120 180180 240240 300300 360360

DalteparinDalteparin

OACOAC

HR 0.94 P-value = 0.40HR 0.94 P-value = 0.40

Days Post RandomizationDays Post Randomization

Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

Page 92: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

Days Post RandomizationDays Post Randomization

00 3030 6060 9090 120120 150150 180180 240240 300300 360360

Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

OACOAC

DalteparinDalteparin

HR = 0.50 P-value = 0.03HR = 0.50 P-value = 0.03

Anti-Tumor Effects of LMWHAnti-Tumor Effects of LMWH CLOT 12-month MortalityCLOT 12-month Mortality

Patients Without Metastases (N=150)Patients Without Metastases (N=150)

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

Page 93: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

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

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

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

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

LMWH for Small Cell Lung CancerLMWH for Small Cell Lung CancerTurkish StudyTurkish Study

Altinbas et al. J Thromb Haemost 2004;2:1266.Altinbas et al. J Thromb Haemost 2004;2:1266.

ChemotherapyChemotherapyplus Dalteparinplus Dalteparin Chemo aloneChemo alone P-valueP-value

1-y overall survival, %1-y overall survival, % 51.351.3 29.529.5 0.010.01

2-y overall survival, %2-y overall survival, % 17.217.2 0.00.0 0.010.01

Median survival, mMedian survival, m 13.013.0 8.08.0 0.010.01

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

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VTE Prophylaxis Is Underused VTE Prophylaxis Is Underused in Patients With Cancer in Patients With Cancer

1.Kakkar AK et al. Oncologist. 2003;8:381-3882.Stratton MA et al. Arch Intern Med. 2000;160:334-3403.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912

Cancer:Cancer:FRONTLINE SurveyFRONTLINE Survey11— — 3891 Clinician 3891 Clinician RespondentsRespondents

Rat

e of

App

ropr

iate

Pro

phyl

axis

, %R

ate

of A

ppro

pria

te P

roph

ylax

is, %

Major Surgery2

Major Abdominothoracic Surgery (Elderly)3 Medical

Inpatients4

Confirmed DVT (Inpatients)5

Cancer: Surgical

Cancer: Medical

4.Rahim SA et al. Thromb Res. 2003;111:215-2195.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

Page 95: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Conclusions and SummaryConclusions and Summary

► Risk factors for VTE in the setting of cancer have Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniasurgery, thrombocytopenia

► Long-term secondary prevention with LMWH has Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinbeen shown to produce better outcomes than warfarin

► Guidelines and landmark trials support administration Guidelines and landmark trials support administration of LMWH in at risk patientsof LMWH in at risk patients

► Cancer patients are under-prophylaxed for VTECancer patients are under-prophylaxed for VTE

► Health system pharmacists can play a pivotal role in Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient populationimproving clinical outcomes in this patient population

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Venous Thromboembolism (VTE) Venous Thromboembolism (VTE) Prophylaxis in the Prophylaxis in the

Cancer Patient and BeyondCancer Patient and Beyond

Guidelines and Implications for Clinical PracticeGuidelines and Implications for Clinical Practice

John Fanikos, RPh, MBAJohn Fanikos, RPh, MBAAssistant Director of PharmacyAssistant Director of PharmacyBrigham and Women’s HospitalBrigham and Women’s Hospital

Assistant Clinical Professor of PharmacyAssistant Clinical Professor of PharmacyNortheastern UniversityNortheastern University

Massachusetts College of PharmacyMassachusetts College of PharmacyBoston, MABoston, MA

Clotting, Cancer, and Clinical StrategiesClotting, Cancer, and Clinical Strategies

Page 97: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Outline of PresentationOutline of Presentation

► Guidelines for VTE preventionGuidelines for VTE prevention

► Performance to datePerformance to date

► Opportunities for improvementOpportunities for improvement

► Guidelines for VTE TreatmentGuidelines for VTE Treatment

► Performance to datePerformance to date

► Guidelines for VTE preventionGuidelines for VTE prevention

► Performance to datePerformance to date

► Opportunities for improvementOpportunities for improvement

► Guidelines for VTE TreatmentGuidelines for VTE Treatment

► Performance to datePerformance to date

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Amin A et al. Amin A et al. J Thromb Haemost. J Thromb Haemost. 2007; 5:1610-6.2007; 5:1610-6.

Prophylaxis Rates in Hospitalized PatientsProphylaxis Rates in Hospitalized Patients

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00 20 20 40 40 60 60 80 80 100 100 120 120 140 160 180 140 160 1800.000.00

0.200.20

0.400.40

1.001.00

0.800.80

0.600.60

DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease

Malignant DiseaseMalignant Disease

DVT/PE OnlyDVT/PE Only

Nonmalignant DiseaseNonmalignant Disease

Number of DaysNumber of Days

Pro

babi

lity

of

Pro

babi

lity

of

Dea

thD

eath

Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285

VTE, Cancer, and SurvivalVTE, Cancer, and Survival

N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancerN = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer

Page 100: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Time Distribution of VTE Events Time Distribution of VTE Events Following Cancer SurgeryFollowing Cancer Surgery

Agnelli G et al. Agnelli G et al. Ann SurgAnn Surg 2006; 243:89-95. 2006; 243:89-95.

@RISTOS Registry: prospective cohort N=2373@RISTOS Registry: prospective cohort N=2373

VTE EventsVTE Events

0

2

4

6

8

10

12

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

Page 101: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

• www.nccn.orgwww.nccn.org

• NCCN Clinical Practice Guidelines in NCCN Clinical Practice Guidelines in Oncology™ Oncology™

• “… “…The panel of experts includes medical The panel of experts includes medical and surgical oncologists, hematologists, and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a cardiologists, internists, radiologists. And a pharmacist.”pharmacist.”

• www.asco.orgwww.asco.org

•Recommendations for VTE Prophylaxis & Recommendations for VTE Prophylaxis & Treatment in Patients with CancerTreatment in Patients with Cancer

Page 102: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

2004 ACCP Recommendations2004 ACCP Recommendations

Cancer patients undergoing surgical procedures receive prophylaxis that is Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A)appropriate for their current risk state (Grade 1A)

● General, Gynecologic, Urologic SurgeryGeneral, Gynecologic, Urologic Surgery• Low Dose Unfractionated Heparin 5,000 units TIDLow Dose Unfractionated Heparin 5,000 units TID• LMWH > 3,400 units DailyLMWH > 3,400 units Daily

– Dalteparin 5,000 units Dalteparin 5,000 units – Enoxaparin 40 mg Enoxaparin 40 mg – Tinzaparin 4,500 unitsTinzaparin 4,500 units

• GCS and/or IPCGCS and/or IPC

Cancer patients with an acute medical illness receive prophylaxisCancer patients with an acute medical illness receive prophylaxisthat is appropriate for their current risk state (Grade 1Athat is appropriate for their current risk state (Grade 1A))

• Low Dose Unfractionated HeparinLow Dose Unfractionated Heparin• LMWHLMWH

Contraindication to anticoagulant prophylaxis (Grade 1C+)Contraindication to anticoagulant prophylaxis (Grade 1C+)• GCS or IPCGCS or IPC

Cancer patients undergoing surgical procedures receive prophylaxis that is Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A)appropriate for their current risk state (Grade 1A)

● General, Gynecologic, Urologic SurgeryGeneral, Gynecologic, Urologic Surgery• Low Dose Unfractionated Heparin 5,000 units TIDLow Dose Unfractionated Heparin 5,000 units TID• LMWH > 3,400 units DailyLMWH > 3,400 units Daily

– Dalteparin 5,000 units Dalteparin 5,000 units – Enoxaparin 40 mg Enoxaparin 40 mg – Tinzaparin 4,500 unitsTinzaparin 4,500 units

• GCS and/or IPCGCS and/or IPC

Cancer patients with an acute medical illness receive prophylaxisCancer patients with an acute medical illness receive prophylaxisthat is appropriate for their current risk state (Grade 1Athat is appropriate for their current risk state (Grade 1A))

• Low Dose Unfractionated HeparinLow Dose Unfractionated Heparin• LMWHLMWH

Contraindication to anticoagulant prophylaxis (Grade 1C+)Contraindication to anticoagulant prophylaxis (Grade 1C+)• GCS or IPCGCS or IPC

Geerts WH et al. Chest. 2004;126(suppl):338S-400S

1A is the highest possible grade1A is the highest possible gradeIndicates that benefits outweigh risks, burdens, and costs,Indicates that benefits outweigh risks, burdens, and costs,

with consistent RCT level of evidence with consistent RCT level of evidence

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NCCN Practice Guidelines in VTE DiseaseNCCN Practice Guidelines in VTE Disease

At Risk Population Initial ProphylaxisAt Risk Population Initial Prophylaxis

http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf

► Adult patientAdult patient► Diagnosis or Diagnosis or

clinical clinical suspicion of suspicion of cancercancer

► InpatientInpatient

Relative contra-Relative contra-indication to indication to anticoagulation anticoagulation treatmenttreatment

Prophylactic anticoagulation Prophylactic anticoagulation therapy (category 1) therapy (category 1) ++ sequential sequential compression device (SCD)compression device (SCD)

Mechanical prophylaxis (options)Mechanical prophylaxis (options)- SCD- SCD- Graduated compression stockings- Graduated compression stockings

NONO

YESYES

RISK FACTOR ASSESSMENTRISK FACTOR ASSESSMENT► AgeAge► Prior VTEPrior VTE► Familial thrombophiliaFamilial thrombophilia► Active cancerActive cancer► TraumaTrauma► Major surgical proceduresMajor surgical procedures► Acute or chronic medical illness requiring Acute or chronic medical illness requiring

hospitalization or prolonged bed resthospitalization or prolonged bed rest► Central venous catheter/IV catheterCentral venous catheter/IV catheter► Congestive heart failureCongestive heart failure► PregnancyPregnancy► Regional bulky lymphadenopathy with Regional bulky lymphadenopathy with

extrinsic vascular compressionextrinsic vascular compression

AGENTS ASSOCIATED AGENTS ASSOCIATED WITH INCREASED RISKWITH INCREASED RISK

► ChemotherapyChemotherapy► Exogenous estrogen Exogenous estrogen

compoundscompounds- HRT- HRT- Oral contraceptives- Oral contraceptives- Tamoxifen/Raloxifene- Tamoxifen/Raloxifene- Diethystilbestrol- Diethystilbestrol

► Thalidomide/lenalidomideThalidomide/lenalidomide

Modifiable risk factors: Lifestyle, Modifiable risk factors: Lifestyle, smoking, tobacco, obesity, smoking, tobacco, obesity, activity level/exerciseactivity level/exercise

Continue Continue Prophylaxis Prophylaxis

After After Discharge ?Discharge ?

Continue Continue Prophylaxis Prophylaxis

After After Discharge ?Discharge ?

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http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf

NCCN Practice Guidelines NCCN Practice Guidelines in VTE Diseasein VTE Disease

Inpatient Prophylactic Anticoagulation TherapyInpatient Prophylactic Anticoagulation Therapy

► LMWHLMWH- Dalteparin 5,000 units subcutaneous daily- Dalteparin 5,000 units subcutaneous daily- Enoxaparin 40 mg subcutaneous daily- Enoxaparin 40 mg subcutaneous daily- Tinzaparin 4,500 units (fixed dose) subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily

or or 75 units/kg subcutaneous daily 75 units/kg subcutaneous daily

► PentasaccharidePentasaccharide- Fondaparinux 2.5 mg subcutaneous daily- Fondaparinux 2.5 mg subcutaneous daily

► Unfractionated heparin 5,000 units subcutaneous 3 Unfractionated heparin 5,000 units subcutaneous 3 times dailytimes daily

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http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf

NCCN Practice Guidelines NCCN Practice Guidelines in VTE Diseasein VTE Disease

Relative Contraindications to Prophylactic or Relative Contraindications to Prophylactic or Therapeutic AnticoagulationTherapeutic Anticoagulation

► Recent CNS bleed, intracranial or spinal lesion at high risk for bleedingRecent CNS bleed, intracranial or spinal lesion at high risk for bleeding► Active bleeding (major): more than 2 units transfused in 24 hoursActive bleeding (major): more than 2 units transfused in 24 hours► Chronic, clinically significant measurable bleeding > 48 hoursChronic, clinically significant measurable bleeding > 48 hours► Thrombocytopenia (platelets < 50,000/mcL)Thrombocytopenia (platelets < 50,000/mcL)► Severe platelet dysfunction (uremia, medications, dysplastic Severe platelet dysfunction (uremia, medications, dysplastic

hematopoiesis)hematopoiesis)► Recent major operation at high risk for bleedingRecent major operation at high risk for bleeding► Underlying coagulopathyUnderlying coagulopathy► Clotting factor abnormalitiesClotting factor abnormalities

- Elevated PT or aPTT (excluding lupus inhibitors)- Elevated PT or aPTT (excluding lupus inhibitors)

- Spinal anesthesia/lumbar puncture- Spinal anesthesia/lumbar puncture► High risk for fallsHigh risk for falls

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► Should hospitalized patients with cancer Should hospitalized patients with cancer receive anticoagulation for VTE receive anticoagulation for VTE prophylaxis ?prophylaxis ?

● ““Hospitalized patients with cancer should be Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in considered candidates for VTE prophylaxis in the absence of bleeding or other the absence of bleeding or other contraindications to anticoagulation”contraindications to anticoagulation”

► Should hospitalized patients with cancer Should hospitalized patients with cancer receive anticoagulation for VTE receive anticoagulation for VTE prophylaxis ?prophylaxis ?

● ““Hospitalized patients with cancer should be Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in considered candidates for VTE prophylaxis in the absence of bleeding or other the absence of bleeding or other contraindications to anticoagulation”contraindications to anticoagulation”

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

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Incidence and Relative Risk of High-Grade VTE Incidence and Relative Risk of High-Grade VTE with Bevacizumabwith Bevacizumab

Tumor Tumor TypeType

No. No. StudiesStudies

BevacizumabBevacizumab ControlControl IncidenceIncidence RR RR

OverallOverall 1313 235/3795235/3795 134/3167134/3167 6.36.3 1.381.38

Colo-rectalColo-rectal 44 96/131596/1315 50/112850/1128 7.37.3 1.561.56

NSCLCNSCLC 44 78/122878/1228 41/86241/862 6.66.6 1.241.24

Breast Breast CancerCancer

22 20/59420/594 13/56113/561 3.93.9 1.471.47

Renal CellRenal Cell 11 7/3377/337 2/3042/304 2.02.0 2.862.86

MesotheliomaMesothelioma 11 9/539/53 5/555/55 17.017.0 1.891.89

Pancreatic Pancreatic CancerCancer

11 24/26824/268 23/25723/257 9.09.0 1.001.00

SR Nalluri et al. JAMA 2008;300(19):2277-2285SR Nalluri et al. JAMA 2008;300(19):2277-2285

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► Should ambulatory patients with cancer Should ambulatory patients with cancer receive anticoagulation for VTE receive anticoagulation for VTE prophylaxis during systemic prophylaxis during systemic chemotherapy?chemotherapy?

● ““Routine prophylaxis is not recommended.”Routine prophylaxis is not recommended.”

● ““Patients receiving thalidomide or lenalidomide Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.”risk for thrombosis and warrant prophylaxis.”

► Should ambulatory patients with cancer Should ambulatory patients with cancer receive anticoagulation for VTE receive anticoagulation for VTE prophylaxis during systemic prophylaxis during systemic chemotherapy?chemotherapy?

● ““Routine prophylaxis is not recommended.”Routine prophylaxis is not recommended.”

● ““Patients receiving thalidomide or lenalidomide Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.”risk for thrombosis and warrant prophylaxis.”

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

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► Should hospitalized patients with cancer Should hospitalized patients with cancer undergoing surgery receive perioperative VTE undergoing surgery receive perioperative VTE prophylaxis ?prophylaxis ?

● All patients should be considered for All patients should be considered for thromboprophylaxis.thromboprophylaxis.

● Procedures greater than 30 minutes should receive Procedures greater than 30 minutes should receive pharmacologic prophylaxis.pharmacologic prophylaxis.

● Mechanical methods should not be used as Mechanical methods should not be used as monotherapy.monotherapy.

● Prophylaxis should continue for at least 7-10 days Prophylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be considered post-op. Prolonged prophylaxis may be considered for cancer with high risk features.for cancer with high risk features.

► Should hospitalized patients with cancer Should hospitalized patients with cancer undergoing surgery receive perioperative VTE undergoing surgery receive perioperative VTE prophylaxis ?prophylaxis ?

● All patients should be considered for All patients should be considered for thromboprophylaxis.thromboprophylaxis.

● Procedures greater than 30 minutes should receive Procedures greater than 30 minutes should receive pharmacologic prophylaxis.pharmacologic prophylaxis.

● Mechanical methods should not be used as Mechanical methods should not be used as monotherapy.monotherapy.

● Prophylaxis should continue for at least 7-10 days Prophylaxis should continue for at least 7-10 days post-op. Prolonged prophylaxis may be considered post-op. Prolonged prophylaxis may be considered for cancer with high risk features.for cancer with high risk features.

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

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Compliance With ACCP VTE Compliance With ACCP VTE Prophylaxis Guidelines Is PoorProphylaxis Guidelines Is Poor

9.9% 6.7%

35,124

62,012

0

5,000

10,000

70,000

Nu

mb

er

of

pa

tie

nts

At risk for DVT/PE

Received compliant care

15.3% 12.7%52.4%

2324

9175

1388

OrthopedicSurgery

At-risk Medical Conditions

General Surgery

UrologicSurgery

Gynecologic 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

Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient GroupCompliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group

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HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76

Started LateStarted Late Started late & Started late & Ended EarlyEnded Early Ended EarlyEnded Early

At-Risk Medical At-Risk Medical (n=5,994)(n=5,994)

1,347 (22.5)1,347 (22.5) 2,961 (49.4)2,961 (49.4) 1,686 (28.1)1,686 (28.1)

Abdominal Surgery Abdominal Surgery (n=3,240)(n=3,240)

824 (25.4)824 (25.4) 1,764 (54.4)1,764 (54.4) 652 (20.1)652 (20.1)

Urologic surgery Urologic surgery (n=158)(n=158)

18 (11.4)18 (11.4) 73 (46.2)73 (46.2) 67 (42.4)67 (42.4)

Gynecologic surgery Gynecologic surgery (n=163)(n=163)

13 (8.0)13 (8.0) 43 (26.4)43 (26.4) 107 (65.6)107 (65.6)

Neurosurgery Neurosurgery (n=250)(n=250)

66 (26.4)66 (26.4) 125 (50.0)125 (50.0) 59 (23.6)59 (23.6)

Reasons for Inadequate DurationReasons for Inadequate Durationof VTE Prophylaxisof VTE Prophylaxis

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Odds Ratio

Malignancy 0.40

Others 0.58

Infection 0.83

Bleeding Risk 0.91

Gender 0.92

Hospital Size 0.93

Age 1.00

LOS 1.05

Cardiovascular Disease 1.06

Internal Medicine 1.33

Respiratory 1.35

AMC 1.46

Duration of Immobility 1.60

VTE Risk Factors 1.78

Malignancy 0.40

Others 0.58

Infection 0.83

Bleeding Risk 0.91

Gender 0.92

Hospital Size 0.93

Age 1.00

LOS 1.05

Cardiovascular Disease 1.06

Internal Medicine 1.33

Respiratory 1.35

AMC 1.46

Duration of Immobility 1.60

VTE Risk Factors 1.78

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Effect Odds Ratio (95% CI)Effect Odds Ratio (95% CI)

Predictors of the Predictors of the Use of ThromboprophylaxisUse of Thromboprophylaxis

Kahn SR et Al. Thromb Res 2007; 119:145-155Kahn SR et Al. Thromb Res 2007; 119:145-155

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Unfractionated Heparin Prophylaxis:Unfractionated Heparin Prophylaxis:BID vs TID—What Works, What Doesn’t?BID vs TID—What Works, What Doesn’t?

Meta-analysis: Meta-analysis: 12 RCTs12 RCTs► DVT, PE, all VTE events, BleedingDVT, PE, all VTE events, Bleeding

► Proximal DVT plus PEProximal DVT plus PE● BID VTE event rate: BID VTE event rate:

2.34 events per 1,0002.34 events per 1,000patient dayspatient days

● TID event rate: TID event rate:

0.86 events per 1,0000.86 events per 1,000patient dayspatient days

P=0.05P=0.05

► NNTNNT● 676 hospital prophylaxis days 676 hospital prophylaxis days

with UFH TID to preventwith UFH TID to prevent● 1 major bleed with 1,649 hospital 1 major bleed with 1,649 hospital

prophylaxis days of TID dosingprophylaxis days of TID dosing

Meta-analysis: Meta-analysis: 12 RCTs12 RCTs► DVT, PE, all VTE events, BleedingDVT, PE, all VTE events, Bleeding

► Proximal DVT plus PEProximal DVT plus PE● BID VTE event rate: BID VTE event rate:

2.34 events per 1,0002.34 events per 1,000patient dayspatient days

● TID event rate: TID event rate:

0.86 events per 1,0000.86 events per 1,000patient dayspatient days

P=0.05P=0.05

► NNTNNT● 676 hospital prophylaxis days 676 hospital prophylaxis days

with UFH TID to preventwith UFH TID to prevent● 1 major bleed with 1,649 hospital 1 major bleed with 1,649 hospital

prophylaxis days of TID dosingprophylaxis days of TID dosing

King CS et al. CHEST 2007;131:507-516King CS et al. CHEST 2007;131:507-516

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Heparin, Low Molecular Heparin, Low Molecular Weight Heparin ProphylaxisWeight Heparin Prophylaxis

Wein L et al. Wein L et al. Arch Intern Med.Arch Intern Med. 2007;167:1476-86. 2007;167:1476-86.

LMWH vs UFHLMWH vs UFH

DVT Risk DVT Risk

Study Reduction (95% CI) Weight %Study Reduction (95% CI) Weight %

Harenberg et al, 1990Harenberg et al, 1990 0.70 (0.16-3.03) 3.4 0.70 (0.16-3.03) 3.4

Turpie et al, 1992Turpie et al, 1992 0.29 (0.10-0.81) 11.4 0.29 (0.10-0.81) 11.4

Dumas et al, 1994 0.74 (0.38-1.43) 14.4Dumas et al, 1994 0.74 (0.38-1.43) 14.4

Bergmann & Neuhart 0.94 (0.39-2.26) 8.1Bergmann & Neuhart 0.94 (0.39-2.26) 8.1

et al, 1996et al, 1996

Harenberg et al, 1996 2.89 (0.30-27.71) 0.8Harenberg et al, 1996 2.89 (0.30-27.71) 0.8

Lechler et al, 1996 0.25 (0.03-2.23) 3.3Lechler et al, 1996 0.25 (0.03-2.23) 3.3

Hillbom et al, 2002 0.55 (0.31-0.98) 20.5Hillbom et al, 2002 0.55 (0.31-0.98) 20.5

Kleber, et al 2003 0.77 (0.43-1.38) 19.4Kleber, et al 2003 0.77 (0.43-1.38) 19.4

Diener et al, 2006 0.76 (0.42-1.38) 18.9Diener et al, 2006 0.76 (0.42-1.38) 18.9

Overall (95% CI) 0.68 (0.52-0.88)Overall (95% CI) 0.68 (0.52-0.88)

LMWH Better LMWH WorseLMWH Better LMWH Worse

0.1 1.0 100.1 1.0 10Risk RatioRisk Ratio

► Meta-analysis Meta-analysis ► 36 randomized 36 randomized

controlled trialscontrolled trials► 23,000 hospitalized 23,000 hospitalized

medical patients medical patients ► UFH 5,000 units TID is UFH 5,000 units TID is

more effective in more effective in preventing DVT than preventing DVT than UFH BID UFH BID

► Low molecular weight Low molecular weight heparin is 33% more heparin is 33% more effective than effective than unfractionated heparin unfractionated heparin in preventing DVTin preventing DVT

● RR for DVT 0.68 RR for DVT 0.68 (p=0.004(p=0.004))

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BWH/DFCI Partners BWH/DFCI Partners Cancer Care ExperienceCancer Care Experience

• Consecutive patients, < 60 daysConsecutive patients, < 60 days

• 2 Nursing units 2 Nursing units

• LOS ranged from 3 days to 31 daysLOS ranged from 3 days to 31 days

• Number of days where doses were omitted ranged from Number of days where doses were omitted ranged from 1 to 6 days1 to 6 days

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VTE Incidence: More CommonVTE Incidence: More Commonin the Outpatient Settingin the Outpatient Setting

► Medical records of residents (n=477,800)Medical records of residents (n=477,800)

► 587 VTE events (104 per 100,000 population)587 VTE events (104 per 100,000 population)

► 30 Day recurrence 4.8 %30 Day recurrence 4.8 %

► Medical records of residents (n=477,800)Medical records of residents (n=477,800)

► 587 VTE events (104 per 100,000 population)587 VTE events (104 per 100,000 population)

► 30 Day recurrence 4.8 %30 Day recurrence 4.8 %

VTE Event LocationVTE Event Location

Patients receiving prophylaxis Patients receiving prophylaxis during high risk periodsduring high risk periods

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

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Thrombosis in MalignancyThrombosis in Malignancy77THTH ACCP Consensus Conference Recommendations ACCP Consensus Conference Recommendations

Initial Phase

5-7 daysDalteparin 200/kg q24h

(GRADE 1A)

Subacute Phase Subacute Phase 3 - 6 months3 - 6 months

Dalteparin* 150 units/kg q24hDalteparin* 150 units/kg q24h(GRADE 1A)(GRADE 1A)

Chronic Phase Continue anticoagulation

(warfarin or LMWH) long-term or until malignancy resolves

(GRADE 1C)

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

Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428sBuller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s

* Dalteparin Approved for Extended Treatment to Reduce the * Dalteparin Approved for Extended Treatment to Reduce the Recurrence of Blood Clots in Patients with CancerRecurrence of Blood Clots in Patients with Cancer

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Recurrent ThrombosisRecurrent Thrombosis

Dalteparin: 9.0% of 336Dalteparin: 9.0% of 336Warfarin: 17% of 336Warfarin: 17% of 336

Dalteparin: 200 units/kg/dayDalteparin: 200 units/kg/dayx 1 mo, then 150 units/kg/dayx 1 mo, then 150 units/kg/day

Warfarin dosed to INR 2-3Warfarin dosed to INR 2-3

Duration: 6 months Duration: 6 months

Warfarin vs. Dalteparin for Warfarin vs. Dalteparin for VTE Treatment in MalignancyVTE Treatment in Malignancy

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

2525

2020

1515

1010

55

00

0 30 60 90 120 150 180 2100 30 60 90 120 150 180 210

DalteparinDalteparin

Oral anticoagulantOral anticoagulant

P=0.002P=0.002

Pro

ba

bil

ity

of

Re

cu

rre

nt

Ve

no

us

Pro

ba

bil

ity

of

Re

cu

rre

nt

Ve

no

us

Th

rom

bo

em

bo

lis

m (

%)

Th

rom

bo

em

bo

lis

m (

%)

Days after RandomizationDays after Randomization

No. at RiskNo. at Risk

Dalteparin 336 301 264 235 227 210 164Dalteparin 336 301 264 235 227 210 164

Oral anticoagulant 336 280 242 221 200 194 154Oral anticoagulant 336 280 242 221 200 194 154

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Subgroup AnalysisSubgroup Analysis

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

12-month Cumulative Mortality Rate12-month Cumulative Mortality Rate

DalteparinDalteparin WarfarinWarfarin P ValueP Value

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

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

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Dalteparin Cost Effectiveness Dalteparin Cost Effectiveness in Recurrent VTEin Recurrent VTE

Cost Cost ParameterParameter

Dalteparin Dalteparin (n=338)(n=338)

Warfarin Warfarin (n=338)(n=338)

Drug 2852 269

Laboratory 303 437

Diagnostic Tests

253 267

Unscheduled Visits

286 300

Transfusions 143 208

Major bleeding 97.5 92.3

VTE Recurrence

228 429

Mean Cost Per Patient

4162 2003

Dranitsaris G. Pharmacoeconomics 2006; 24(6):5093-607Dranitsaris G. Pharmacoeconomics 2006; 24(6):5093-607

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http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf

NCCN Practice Guidelines—Venous NCCN Practice Guidelines—Venous Thromboembolic DiseaseThromboembolic Disease

Therapeutic Anticoagulation Treatment for Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated ThrombosisDVT, PE, and Catheter-Associated Thrombosis

ImmediateImmediate► LMWHLMWH

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

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

subcutaneous dailysubcutaneous daily

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

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http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf

NCCN Practice Guidelines—Venous NCCN Practice Guidelines—Venous Thromboembolic DiseaseThromboembolic Disease

Therapeutic Anticoagulation Treatment for Therapeutic Anticoagulation Treatment for DVT, PE, and Catheter-Associated ThrombosisDVT, PE, and Catheter-Associated Thrombosis

Long TermLong Term► LMWH is preferred as monotherapy without warfarin in patients with LMWH is preferred as monotherapy without warfarin in patients with

proximal DVT or PE and prevention of recurrent VTE in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic canceradvanced or metastatic cancer

► Warfarin (2.5-5 mg every day initially, subsequent dosing based on Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2.0-3.0)INR value; target INR 2.0-3.0)

Duration of Long Term TherapyDuration of Long Term Therapy► Minimum time of 3-6 mo for DVT and 6-12 mo for PEMinimum time of 3-6 mo for DVT and 6-12 mo for PE► Consider indefinite anticoaugulation if active cancer or persistent risk Consider indefinite anticoaugulation if active cancer or persistent risk

factorsfactors► For catheter associated thrombosis, anticoagulate as long as catheter For catheter associated thrombosis, anticoagulate as long as catheter

is in place and for 1-3 mo after catheter removalis in place and for 1-3 mo after catheter removal

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► What is the best treatment for patients with What is the best treatment for patients with cancer with established VTE to prevent recurrent cancer with established VTE to prevent recurrent VTE ?VTE ?

● LMWH is the preferred approach for the initial 5-10 LMWH is the preferred approach for the initial 5-10 days.days.

● LMWH, given for at least 6 months, is the preferred LMWH, given for at least 6 months, is the preferred for long-term anticoagulant therapy.for long-term anticoagulant therapy.

● After 6 months, anticoagulation therapy should be After 6 months, anticoagulation therapy should be considered for select patients.considered for select patients.

● For CNS malignancies, elderly patients For CNS malignancies, elderly patients anticoagulation is recommended with careful anticoagulation is recommended with careful monitoring and dose adjustment.monitoring and dose adjustment.

► What is the best treatment for patients with What is the best treatment for patients with cancer with established VTE to prevent recurrent cancer with established VTE to prevent recurrent VTE ?VTE ?

● LMWH is the preferred approach for the initial 5-10 LMWH is the preferred approach for the initial 5-10 days.days.

● LMWH, given for at least 6 months, is the preferred LMWH, given for at least 6 months, is the preferred for long-term anticoagulant therapy.for long-term anticoagulant therapy.

● After 6 months, anticoagulation therapy should be After 6 months, anticoagulation therapy should be considered for select patients.considered for select patients.

● For CNS malignancies, elderly patients For CNS malignancies, elderly patients anticoagulation is recommended with careful anticoagulation is recommended with careful monitoring and dose adjustment.monitoring and dose adjustment.

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

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► Should patients with cancer receive Should patients with cancer receive anticoagulants in the absence of anticoagulants in the absence of established VTE to improve survival?established VTE to improve survival?

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

► Should patients with cancer receive Should patients with cancer receive anticoagulants in the absence of anticoagulants in the absence of established VTE to improve survival?established VTE to improve survival?

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

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

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Tapson V et al. Arch Intern Med 2005Tapson V et al. Arch Intern Med 2005

►Survey of 38 U.S. Hospitals

►n=939 DVT or PE

►50% patients reached INR >2 for 2 consecutive days

►Survey of 38 U.S. Hospitals

►n=939 DVT or PE

►50% patients reached INR >2 for 2 consecutive days

TherapyTherapy n (%)n (%)

LMWHLMWH 527 (56.1%)527 (56.1%)

UFHUFH 562 (59.8%)562 (59.8%)

UFH SCUFH SC 78 (8.3%)78 (8.3%)

DTIDTI 6 (0.6%)6 (0.6%)

Antithrombotic Therapy PracticesAntithrombotic Therapy Practicesin U.S. Hospitalsin U.S. Hospitals

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Self-Managed Long Term LMWH TherapySelf-Managed Long Term LMWH Therapy

737 Randomized

737 Randomized

Hull R. Am Jour Med 2007; 120:72-82Hull R. Am Jour Med 2007; 120:72-82Hull R. Am Jour Med 2007; 120:72-82Hull R. Am Jour Med 2007; 120:72-82

2212 patients with proximal vein thrombosis assessed for eligibility

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

3 lost to follow-up

1 withdrew consent

369 included in analysis

3 lost to follow-up

5 withdrew consent

369 included in analysis

1475 excluded for anticoagulant violations or

inability to give written consent

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Self-Managed Long Term LMWH TherapySelf-Managed Long Term LMWH Therapy

OutcomesOutcomes Tinzaparin Tinzaparin (n=369)(n=369)

Usual Care Usual Care (n=368)(n=368)

Absolute DifferenceAbsolute Difference(95% CI)(95% CI)

p-valuep-value

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

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

All BleedingAll Bleeding 48 (13.0)48 (13.0) 73 (19.8)73 (19.8) -6.8 (-12.4--6.8 (-12.4---1.5)1.5) p=.011p=.011

Major BleedingMajor Bleeding 12 (3.3)12 (3.3) 17 (4.6)17 (4.6) -1.4 (-4.3-1.4)-1.4 (-4.3-1.4) NSNS

Minor BleedingMinor Bleeding 36 (9.8)36 (9.8) 56 (15.2)56 (15.2) -5.5 (-10.4--5.5 (-10.4---0.6)0.6) p=.022p=.022

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

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

Thrombocytopenia Thrombocytopenia (<150)(<150) 21 (5.7)21 (5.7) 9 (2.4)9 (2.4) 1.6 (-3.6-0.3)1.6 (-3.6-0.3) NSNS

Bone FractureBone Fracture 4 (1.1)4 (1.1) 7 (1.9)7 (1.9) -0.8 (-0.9-2.6)-0.8 (-0.9-2.6) NSNS

Hull R. Am Jour Med 2007; 120:72-82Hull R. Am Jour Med 2007; 120:72-82

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LMWHs and Bleeding in PatientsLMWHs and Bleeding in Patientswith Renal Dysfunctionwith Renal Dysfunction

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

Dosage adjustmentsfor renal dysfunction

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Barriers to Long-term Use of LMWH forBarriers to Long-term Use of LMWH forTreatment of Cancer-associated VTETreatment of Cancer-associated VTE

Wittkowsky AK. Wittkowsky AK. J Thromb Haemost.J Thromb Haemost. 2006; 4:2090-1. 2006; 4:2090-1.

Initial treatmentInitial treatment

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

Reasons LMWH not used long-termReasons LMWH not used long-term

Not covered by medical insuranceNot covered by medical insurance 49.4% 49.4%Physician preferencePhysician preference 32.0% 32.0%Patient refused long-term injectionsPatient refused long-term injections 13.6% 13.6%History of HITHistory of HIT 2.5% 2.5%Severe renal insufficiencySevere renal insufficiency 2.5% 2.5%

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ConclusionsConclusions

Examine your current practices of VTE Examine your current practices of VTE prophylaxis and treatmentprophylaxis and treatment

► Review available guidelines as a benchmarkReview available guidelines as a benchmark► Consider the use of a pharmacologic or Consider the use of a pharmacologic or

mechanical interventionmechanical intervention► Evaluate use of Reminder or Risk Scoring Evaluate use of Reminder or Risk Scoring

SystemsSystems► Utilize the regimen providing the best efficacy in Utilize the regimen providing the best efficacy in

reducing events and offering best compliancereducing events and offering best compliance► Follow-up with patients to monitor and avoid Follow-up with patients to monitor and avoid

adverse events and to ensure optimal outcomesadverse events and to ensure optimal outcomes

Examine your current practices of VTE Examine your current practices of VTE prophylaxis and treatmentprophylaxis and treatment

► Review available guidelines as a benchmarkReview available guidelines as a benchmark► Consider the use of a pharmacologic or Consider the use of a pharmacologic or

mechanical interventionmechanical intervention► Evaluate use of Reminder or Risk Scoring Evaluate use of Reminder or Risk Scoring

SystemsSystems► Utilize the regimen providing the best efficacy in Utilize the regimen providing the best efficacy in

reducing events and offering best compliancereducing events and offering best compliance► Follow-up with patients to monitor and avoid Follow-up with patients to monitor and avoid

adverse events and to ensure optimal outcomesadverse events and to ensure optimal outcomes

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Pharmacologic Prophylaxis of DVT in Pharmacologic Prophylaxis of DVT in Special PopulationsSpecial Populations

Edith Nutescu, PharmD, FCCPClinical Associate Professor

Pharmacy PracticeAffiliate Faculty, Center for

Pharmacoeconomic ResearchDirector, Antithrombosis Center

The University of Illinois at Chicago College of Pharmacy & Medical Center

Chicago, IL

Edith Nutescu, PharmD, FCCPClinical Associate Professor

Pharmacy PracticeAffiliate Faculty, Center for

Pharmacoeconomic ResearchDirector, Antithrombosis Center

The University of Illinois at Chicago College of Pharmacy & Medical Center

Chicago, IL

A Year 2009 Update for A Year 2009 Update for The Health System PharmacistThe Health System Pharmacist

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ObjectivesObjectives

1.1. Differentiate data with various LMWHs in special Differentiate data with various LMWHs in special populationspopulations

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

3.3. Discuss cautions of using emerging agents in Discuss cautions of using emerging agents in special special populationspopulations

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Risk of Inadequate Therapy Risk of Inadequate Therapy in High Risk Patientsin High Risk Patients

► 524 VTE Patients524 VTE Patients● Active Cancer in 26%Active Cancer in 26%

• Only 1/3Only 1/3rdrd on LMWH monotherapy on LMWH monotherapy

● Weight > 100Kg in 15%Weight > 100Kg in 15%• Under-dosing of LMWH by > 10%Under-dosing of LMWH by > 10%

– 36% of > pts 100Kg36% of > pts 100Kg– 8% of pts < 100Kg (p < 0.001)8% of pts < 100Kg (p < 0.001)

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

► 524 VTE Patients524 VTE Patients● Active Cancer in 26%Active Cancer in 26%

• Only 1/3Only 1/3rdrd on LMWH monotherapy on LMWH monotherapy

● Weight > 100Kg in 15%Weight > 100Kg in 15%• Under-dosing of LMWH by > 10%Under-dosing of LMWH by > 10%

– 36% of > pts 100Kg36% of > pts 100Kg– 8% of pts < 100Kg (p < 0.001)8% of pts < 100Kg (p < 0.001)

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

Cook LM, et.al. J Thromb Hemost 2007;5;937-41.Cook LM, et.al. J Thromb Hemost 2007;5;937-41.

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88thth ACCP Conference on Antithrombotic Therapy ACCP Conference on Antithrombotic Therapy

““In obese patients given LMWH prophylaxis or In obese patients given LMWH prophylaxis or treatment, we suggest weight-based dosing treatment, we suggest weight-based dosing

(Grade 2C).”(Grade 2C).”

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

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

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

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

Hirsh J et al. Hirsh J et al. ChestChest. 2008;133(suppl):141S-159S.. 2008;133(suppl):141S-159S.

Obese PatientsObese Patients

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Pharmacokinetic Characteristics of Pharmacokinetic Characteristics of Low Molecular Weight HeparinsLow Molecular Weight Heparins

Lipid solubilityLipid solubility LOWLOW

Plasma protein bindingPlasma protein binding HIGHHIGH

Tissue bindingTissue binding LOWLOW

Volume of DistributionVolume of Distribution 5-7 L5-7 L

Lipid solubilityLipid solubility LOWLOW

Plasma protein bindingPlasma protein binding HIGHHIGH

Tissue bindingTissue binding LOWLOW

Volume of DistributionVolume of Distribution 5-7 L5-7 L

Logical conclusion:Logical conclusion:

IBW may be a better predictor of LMWH dosing than TBWIBW may be a better predictor of LMWH dosing than TBW

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LMWH: Maximum Weights StudiedLMWH: Maximum Weights Studied

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

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

Kinetic Kinetic StudiesStudies Clinical TrialsClinical Trials

DalteparinDalteparin 190 kg190 kg 128 kg*128 kg*

EnoxaparinEnoxaparin 144 kg144 kg 194 kg194 kg

TinzaparinTinzaparin 165 kg165 kg 88 kg88 kg

FondaparinuxFondaparinux 175.5 kg175.5 kg

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LMWH Pharmacokinetics in ObesityLMWH Pharmacokinetics in Obesity

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

Clin PharmacolPharmacol Ther 2002;72:308-18. Thromb Haemost 2002;87:817-23.

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DalteparinDalteparinPharmacokinetics in Obesity Pharmacokinetics in Obesity

Yee JYV, Duffull SB. Yee JYV, Duffull SB. Eur J Clin PharmacolEur J Clin Pharmacol 2000; 56:293-7. 2000; 56:293-7.Yee JYV, Duffull SB. Yee JYV, Duffull SB. Eur J Clin PharmacolEur J Clin Pharmacol 2000; 56:293-7. 2000; 56:293-7.

Dose: 200 U/kg qd

Duration: routine

Obese (BMI > 30)Obese (BMI > 30) Normal (BMI < 30)Normal (BMI < 30)

NN 1010 1010

TBW (mean +/- SD)TBW (mean +/- SD) 106.4 +/- 22.1106.4 +/- 22.1 69.7 +/- 9.369.7 +/- 9.3

LBW (mean +/- SD)LBW (mean +/- SD) 64.1 +/- 12.364.1 +/- 12.3 66.1 +/- 8.766.1 +/- 8.7

Mean Vd (l)Mean Vd (l) 12.3912.39 8.368.36

Mean CI (l/hr)Mean CI (l/hr) 1.301.30 1.111.11

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DalteparinDalteparinPharmacokinetics In Obesity Pharmacokinetics In Obesity

Correlation Coefficient Between Vd and:Correlation Coefficient Between Vd and:

LBWLBW 0.050.05

ABWABW 0.520.52

TBWTBW 0.550.55

Correlation Coefficient Between Cl and:Correlation Coefficient Between Cl and:

LBWLBW 0.010.01

ABWABW 0.320.32

TBWTBW 0.390.39

Yee JYV et al. Yee JYV et al. Eur J Clin PharmacolEur J Clin Pharmacol 2000; 56:293-7. 2000; 56:293-7.

Correlation Coefficient Between Vd and:Correlation Coefficient Between Vd and:

LBWLBW 0.050.05

ABWABW 0.520.52

TBWTBW 0.550.55

Correlation Coefficient Between Cl and:Correlation Coefficient Between Cl and:

LBWLBW 0.010.01

ABWABW 0.320.32

TBWTBW 0.390.39

Yee JYV et al. Yee JYV et al. Eur J Clin PharmacolEur J Clin Pharmacol 2000; 56:293-7. 2000; 56:293-7.

Conclusion:Conclusion:

TBW may be a better predictor of LMWH dose than IBWTBW may be a better predictor of LMWH dose than IBW

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

Wilson SJ et al. Wilson SJ et al. HemostasisHemostasis 2001; 31:42-8. 2001; 31:42-8.

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

Wilson SJ et al. Wilson SJ et al. HemostasisHemostasis 2001; 31:42-8. 2001; 31:42-8.

DalteparinDalteparinPharmacokinetics In Obesity Pharmacokinetics In Obesity

Dose: 200 U/kg qd

Duration: 5 Days

Max TBW: 190kg <20% of <20% of IBWIBW

20-40% of 20-40% of IBWIBW

> 40% of > 40% of IBWIBW

NN 1313 1414 1010

Mean Dose (U)Mean Dose (U) 14,03014,030 17,64617,646 23,56523,565

Ant-Xa Activity (u/ml)Ant-Xa Activity (u/ml)

Day 3 PeakDay 3 Peak 1.011.01 0.970.97 1.12 NS1.12 NS

Day 3 TroughDay 3 Trough 0.120.12 0.110.11 0.11 NS0.11 NS

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LMWH Safety and Effectiveness Using TBWLMWH Safety and Effectiveness Using TBWEnoxaparin In ACS (ESSENCE/TIMI IIb)Enoxaparin In ACS (ESSENCE/TIMI IIb)

14.3%14.3%

16.1%16.1%

P=0.39P=0.39

P=0.13P=0.13

Obese: BMI Obese: BMI >> 30mg/m2 30mg/m2

Enox max weight 158 kgEnox max weight 158 kg

Spinler SA et al. Spinler SA et al. Am Heart JAm Heart J 2003; 146:33-41 2003; 146:33-41

0.4%0.4%1.6%1.6%

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Safety Of TBW-based Dosing of DalteparinSafety Of TBW-based Dosing of Dalteparinfor Treatment of Acute VTE in Obese Patientsfor Treatment of Acute VTE in Obese Patients

Al-Yaseen E et al. Al-Yaseen E et al. J Thromb HaemostJ Thromb Haemost 2004; 3:100-2. 2004; 3:100-2.

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

WEIGHTWEIGHT(kg) (kg) NN

MeanMeanDoseDose

Full dose Full dose +/- 5%+/- 5%

QD QD DosingDosing

BIDBIDDosingDosing

90-9990-99 4040 19,30019,300 3939 2424 1616

100-109100-109 5252 20,85020,850 4949 2525 1717

110-119110-119 4141 21,47021,470 2121 2626 1515

120-129120-129 2525 24,30024,300 2222 1616 99

130-139130-139 1616 25,25025,250 88 1010 66

140-149140-149 99 26,92026,920 66 55 44

>> 150 150 1010 28,28028,280 66 66 44

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Fondaparinux In ObesityFondaparinux In ObesityResults From the Matisse TrialsResults From the Matisse Trials

Davidson BL et al. J Thrombosis Haemost 2007; 5:1191-4.

Fondaparinux:Fondaparinux:< 50kg: 5mg qd< 50kg: 5mg qd

50-100kg: 7.5mg qd50-100kg: 7.5mg qd> 100kg: 10mg qd> 100kg: 10mg qd

Enoxaparin: Enoxaparin: (Matisse DVT)(Matisse DVT)1mg/kg q12h1mg/kg q12h

Heparin:Heparin:(Matisse PE)(Matisse PE)

Adjusted per aPTT Adjusted per aPTT

No weight-dependentdifference in

efficacy or safety

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Body Weight and Anti-Xa ActivityBody Weight and Anti-Xa Activityfor Prophylactic Doses of LMWHfor Prophylactic Doses of LMWH

N = 17 patients and 2 volunteersN = 17 patients and 2 volunteersEnoxaparin 40mg SQ x1 doseEnoxaparin 40mg SQ x1 doseAntiXa levels hourly x10 hoursAntiXa levels hourly x10 hours

Frederiksen SG et al. Frederiksen SG et al. Br J SurgeryBr J Surgery 2003; 90:547-8 2003; 90:547-8

40 60 80 100 120 140 16040 60 80 100 120 140 160

Body Weight (kg)Body Weight (kg)

Are

a un

der

the

curv

e fo

r 10

hA

rea

unde

r th

e cu

rve

for

10 h 200

150

100

50

0

200

150

100

50

0

Regression line95% CI for line95% CI for data points

Regression line95% CI for line95% CI for data points

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Kucher N et al. Kucher N et al. Arch Int MedArch Int Med 2005;165:341-5. 2005;165:341-5.

0.010.01 0.10.1 0.550.55 1.01.0 10.010.0

Favors Dalteparin Favor Placebo Favors Dalteparin Favor Placebo

Relative RiskRelative Risk

< 25 37.5< 25 37.5

25-29.925-29.9 33.1 33.1

30-34.930-34.9 18.9 18.9

35-39.935-39.9 7.1 7.1

>> 40 3.3 40 3.3

Overall Prevent TrialOverall Prevent Trial

Dalteparin: Dalteparin: Fixed Dosing For VTE PreventionFixed Dosing For VTE Prevention

Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)

BMI (kg/m2) Patients %BMI (kg/m2) Patients %

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

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Enoxaparin VTE Prophylaxis in Enoxaparin VTE Prophylaxis in TKA/THA/TraumaTKA/THA/Trauma

Samama MM et al. Thromb Haemost 1995; 73:977.Samama MM et al. Thromb Haemost 1995; 73:977.Samama MM et al. Thromb Haemost 1995; 73:977.Samama MM et al. Thromb Haemost 1995; 73:977.

N: 807 Dose: 40 mg qd Obese : BMI>32kg/mN: 807 Dose: 40 mg qd Obese : BMI>32kg/m22

31.8%31.8%

16.7%16.7%

p<0.001p<0.001

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Enoxaparin: Enoxaparin: VTE Prophylaxis in Bariatric SurgeryVTE Prophylaxis in Bariatric Surgery

Scholten Obes Surg 2002; 12:19-24.Scholten Obes Surg 2002; 12:19-24.Scholten Obes Surg 2002; 12:19-24.Scholten Obes Surg 2002; 12:19-24.

30mg bid: n=9230mg bid: n=92BMI 51.7kg/mBMI 51.7kg/m22

5.4%5.4%

0.6%0.6%

p<0.01p<0.01

40mg bid: n=38940mg bid: n=389 BMI 50.3kg/mBMI 50.3kg/m22

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Anti-factor Xa levelAnti-factor Xa level Number of patient Number of patient (%)(%) Body weight (kg)Body weight (kg)

Below target value (<0.2 UI/ml)Below target value (<0.2 UI/ml) 41 (30.4%)41 (30.4%) 159.4 ± 35.8159.4 ± 35.8

Target value (0.2–0.5 UI/ml)Target value (0.2–0.5 UI/ml) 81 (60.0%)81 (60.0%) 145.7 ± 28.4145.7 ± 28.4

Above target value (>0.5 UI/ml)Above target value (>0.5 UI/ml) 13 (9.6%)13 (9.6%) 134.6 ± 24.2134.6 ± 24.2

pp value value    0.0152 0.0152

N=135N=135

Bariatric SurgeryBariatric Surgery

Mean Weight: 148.8KgMean Weight: 148.8Kg

Mean BMI: 53.7Mean BMI: 53.7

Dalteparin: 7,500 IU dailyDalteparin: 7,500 IU daily

Dalteparin in Morbid Obesity: Bariatric SurgeryDalteparin in Morbid Obesity: Bariatric Surgery

Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print] Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]

P=0.031P=0.031

P=0.052P=0.052P=0.444P=0.444

Under target value<0.2 IU/mL

n-=41

Under target value<0.2 IU/mL

n-=41

Target value<0.2-0.5 IU/mL

n-=81

Target value<0.2-0.5 IU/mL

n-=81

Over target value<>0.5 IU/mL

n=13

Over target value<>0.5 IU/mL

n=13

200

180

160

140

120

0

200

180

160

140

120

0B

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Wei

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Bod

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LMWH in Obesity: Summary LMWH in Obesity: Summary

► Treatment: Treatment: in controlled trials, LMWH dosing has been based on TBW in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg)(max 160-190 kg)

● DalteparinDalteparin • Dose based on TBWDose based on TBW• PI recommends dose capping PI recommends dose capping • Recent clinical data supports TBW dosingRecent clinical data supports TBW dosing

– QD or BID dosing QD or BID dosing

● EnoxaparinEnoxaparin• Dose based on TBWDose based on TBW• Dose capping NOT recommendedDose capping NOT recommended• BID dosing preferredBID dosing preferred

● TinzaparinTinzaparin • Dose based on TBW, NO dose adjustment or cappingDose based on TBW, NO dose adjustment or capping

● Anti-Xa monitoring not necessary for TBW < 190kgAnti-Xa monitoring not necessary for TBW < 190kg► Prophylaxis: Prophylaxis: a 25-30% dose increase (a 25-30% dose increase (or 50IU/kg in high risk patientsor 50IU/kg in high risk patients))

► Treatment: Treatment: in controlled trials, LMWH dosing has been based on TBW in controlled trials, LMWH dosing has been based on TBW (max 160-190 kg)(max 160-190 kg)

● DalteparinDalteparin • Dose based on TBWDose based on TBW• PI recommends dose capping PI recommends dose capping • Recent clinical data supports TBW dosingRecent clinical data supports TBW dosing

– QD or BID dosing QD or BID dosing

● EnoxaparinEnoxaparin• Dose based on TBWDose based on TBW• Dose capping NOT recommendedDose capping NOT recommended• BID dosing preferredBID dosing preferred

● TinzaparinTinzaparin • Dose based on TBW, NO dose adjustment or cappingDose based on TBW, NO dose adjustment or capping

● Anti-Xa monitoring not necessary for TBW < 190kgAnti-Xa monitoring not necessary for TBW < 190kg► Prophylaxis: Prophylaxis: a 25-30% dose increase (a 25-30% dose increase (or 50IU/kg in high risk patientsor 50IU/kg in high risk patients))

Nutescu E, et.al. Ann Pharmacother; 2009; in press.Nutescu E, et.al. Ann Pharmacother; 2009; in press.

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88thth ACCP Conference on Antithrombotic Therapy ACCP Conference on Antithrombotic TherapyRenal ImpairmentRenal Impairment

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

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

► Options for patients with renal impairment (Grade 1B)Options for patients with renal impairment (Grade 1B)

● Avoid agents that renal accumulateAvoid agents that renal accumulate● Use a lower doseUse a lower dose● Monitor the drug level or anticoagulant effectMonitor the drug level or anticoagulant effect

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

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

► Options for patients with renal impairment (Grade 1B)Options for patients with renal impairment (Grade 1B)

● Avoid agents that renal accumulateAvoid agents that renal accumulate● Use a lower doseUse a lower dose● Monitor the drug level or anticoagulant effectMonitor the drug level or anticoagulant effect

Geerts WH. Geerts WH. ChestChest 2008;133(suppl):381S-453S. 2008;133(suppl):381S-453S.

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LMWH in Renal DysfunctionLMWH in Renal DysfunctionManufacturer RecommendationsManufacturer Recommendations

DalteparinDalteparin● ““should be should be used with cautionused with caution in patients with severe kidney in patients with severe kidney

insufficiency.”insufficiency.”• Monitor anti-Factor Xa for dose guiding with therapeutic dosesMonitor anti-Factor Xa for dose guiding with therapeutic doses

EnoxaparinEnoxaparin● ““adjustment of dose is adjustment of dose is recommendedrecommended for patients with severe for patients with severe

renal impairment (CrCL < 30 mL/min).”renal impairment (CrCL < 30 mL/min).”

TinzaparinTinzaparin● ““patients with severe renal impairment should be dosed patients with severe renal impairment should be dosed with with

cautioncaution.”.”

FondaparinuxFondaparinux- Contraindicated in CrCL < 30mL/min- Contraindicated in CrCL < 30mL/min

DalteparinDalteparin● ““should be should be used with cautionused with caution in patients with severe kidney in patients with severe kidney

insufficiency.”insufficiency.”• Monitor anti-Factor Xa for dose guiding with therapeutic dosesMonitor anti-Factor Xa for dose guiding with therapeutic doses

EnoxaparinEnoxaparin● ““adjustment of dose is adjustment of dose is recommendedrecommended for patients with severe for patients with severe

renal impairment (CrCL < 30 mL/min).”renal impairment (CrCL < 30 mL/min).”

TinzaparinTinzaparin● ““patients with severe renal impairment should be dosed patients with severe renal impairment should be dosed with with

cautioncaution.”.”

FondaparinuxFondaparinux- Contraindicated in CrCL < 30mL/min- Contraindicated in CrCL < 30mL/min

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Study; yearStudy; yearPatients w/ Patients w/ renal insuff. renal insuff.

(n/n)(n/n)

Patients w/ no Patients w/ no renal insuff.renal insuff.

(n/n)(n/n)

Peto ORPeto OR(95%, CI)(95%, CI)

Weight Weight (%)(%)

Peto ORPeto OR(95%, CI)(95%, CI)

Collet, et al; 2001Collet, et al; 2001 0/280/28 1/831/83 2.012.01 0.26 (0.00 – 23.94)0.26 (0.00 – 23.94)Paulas, et al; 2002Paulas, et al; 2002 0/510/51 3/1493/149 6.026.02 0.26 (0.02 – 3.50)0.26 (0.02 – 3.50)Siguret, et al; 2000Siguret, et al; 2000 0/170/17 0/130/13 Not estimableNot estimable

Chow, et al; 2003Chow, et al; 2003 0/50/5 0/130/13 Not estimableNot estimable

Khazan, et al. (adj.); 2003Khazan, et al. (adj.); 2003 0/100/10 3/423/42 4.784.78 0.28 (0.01 – 5.16)0.28 (0.01 – 5.16)(Prophylactic) 2003(Prophylactic) 2003 3/363/36 3/473/47 14.7714.77 1.33 (0.25 – 7.05)1.33 (0.25 – 7.05)(Therapeutic) 2003(Therapeutic) 2003 2/172/17 3/613/61 8.628.62 3.09 (0.35 – 27.31)3.09 (0.35 – 27.31)

Spinler, et al; 2003Spinler, et al; 2003 5/695/69 74/3,43274/3,432 15.9315.93 10.05 (2.02 – 49.98)10.05 (2.02 – 49.98)

Green, et al; 2005Green, et al; 2005 1/181/18 0/200/20 2.662.66 8.26 (0.16 – 418.42)8.26 (0.16 – 418.42)

Kruse & Lee; 2004Kruse & Lee; 2004 0/500/50 1/1201/120 2.222.22 0.24 (0.00 – 17.90)0.24 (0.00 – 17.90)

Macie, et al; 2004Macie, et al; 2004 2/72/7 6/2016/201 2.682.68 977.78 (19.61 – 48,752.07)977.78 (19.61 – 48,752.07)

Peng, et al; 2004Peng, et al; 2004 0/70/7 0/430/43 Not estimableNot estimable

Thorevska, et al; 2004Thorevska, et al; 2004 7/657/65 11/17111/171 35.5635.56 1.85 (0.63 – 5.40)1.85 (0.63 – 5.40)

Bazinet, et al; 2005Bazinet, et al; 2005 1/361/36 2/1602/160 4.754.75 2.74 (0.15 – 51.73)2.74 (0.15 – 51.73)

Total (95%, CI)Total (95%, CI) 21/41621/416 107/4,555107/4,555 100.00100.00 2.25 (1.19 – 4.27)2.25 (1.19 – 4.27)

Recent Meta-Analysis of LMWHs and Bleeding Recent Meta-Analysis of LMWHs and Bleeding In Patients With Severe Renal DysfunctionIn Patients With Severe Renal Dysfunction

Lim W, et al. Lim W, et al. Ann Intern Med.Ann Intern Med. 2006;144:673-684. 2006;144:673-684.

Dosage adjustmentsDosage adjustments

for renal dysfunctionfor renal dysfunction

0.010.01 0.1 0.1 11 1010 100100

Favors ↓’edFavors ↓’ed Favors ↑’edFavors ↑’ed

bleeding bleeding

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Sanderink GJCM. Thromb Res 2002;105:225-31.Sanderink GJCM. Thromb Res 2002;105:225-31.

Enoxaparin PK and PD in Renal ImpairmentEnoxaparin PK and PD in Renal Impairment

Result:Tmax: 3-4 hoursAmax: 10-35% higher in RI groupsCI/F”linearly correlated with CrCl

Result:Tmax: 3-4 hoursAmax: 10-35% higher in RI groupsCI/F”linearly correlated with CrCl

Day 4Day 4 CL/FCL/F(L/h)(L/h)

Half-lifeHalf-life(h)(h)

AUC (0-24)AUC (0-24)(h(h●●IU/mL)IU/mL)

NormalsNormals 0.980.98 6.876.87

Mild RIMild RI 0.870.87 9.949.94 20% 20% ↑↑

Moderate RIModerate RI 0.760.76 11.311.3 21% 21% ↑↑

Severe RISevere RI 0.580.58 15.915.9 65% 65% ↑↑

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LMWH Renal Dosing in NSTE ACS PatientsLMWH Renal Dosing in NSTE ACS Patients

► 56 UA pts with CrCl <60 56 UA pts with CrCl <60 ml/minml/min

► Enoxaparin dose empirically Enoxaparin dose empirically and anti-Xa level measured and anti-Xa level measured after 3after 3rdrd dose dose

► 56 UA pts with CrCl <60 56 UA pts with CrCl <60 ml/minml/min

► Enoxaparin dose empirically Enoxaparin dose empirically and anti-Xa level measured and anti-Xa level measured after 3after 3rdrd dose dose

CrClCrCl (ml/min)(ml/min)

<30 <30 (n = 28)(n = 28)

>30 and <60>30 and <60 (n =28)(n =28)

AgeAge 76+/-376+/-3 73+/-373+/-3

Enoxaparin (mg/kg/12h)Enoxaparin (mg/kg/12h) 0.640.64 0.840.84

Anti-Xa (IU/ml)Anti-Xa (IU/ml) 0.950.95 0.950.95

Collet JP et al. International J Cardiol 2001;80:81-2.Collet JP et al. International J Cardiol 2001;80:81-2.

• Dose may be Dose may be to 0.6mg/kg/ to 0.6mg/kg/ q12h if CrCL <30mL/min; or 0.8 q12h if CrCL <30mL/min; or 0.8 mg/kg/q12h if CrCl 30-60 ml/minmg/kg/q12h if CrCl 30-60 ml/min

• Anti-Xa monitoring Anti-Xa monitoring

• Doses “appeared safe”Doses “appeared safe”

• Further prospective evaluation Further prospective evaluation neededneeded

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Clinical Use Of Recommended Clinical Use Of Recommended Enoxaparin Dosage in Renal ImpairmentEnoxaparin Dosage in Renal Impairment

Lachish T et al. Lachish T et al. PharmacotherapyPharmacotherapy 2007; 27:1347-52. 2007; 27:1347-52.

PEAK ANTI-Xa LEVELSPEAK ANTI-Xa LEVELS TROUGH ANTI-Xa LEVELSTROUGH ANTI-Xa LEVELS

N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24hN = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h

First doseFirst dose Subsequent doses(second and third)Subsequent doses(second and third)

1.0.

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

1.0.

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Median 25-75% interquartile rangeMedian 25-75% interquartile range

Ant

ifact

or

X1

Leve

l (U

/mL)

Ant

ifact

or

X1

Leve

l (U

/mL)

6

5

4

3

2

1

0

6

5

4

3

2

1

0

0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.550.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55

Trough Antifactor Xa Level (U/mL)Trough Antifactor Xa Level (U/mL)Trough Antifactor Xa Level (U/mL)Trough Antifactor Xa Level (U/mL)

Num

ber

of

Pat

ien

tsN

umb

er o

f P

atie

nts

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Tinzaparin 175 U/kgTinzaparin 175 U/kgPeak Anti-Xa Levels According to Renal FunctionPeak Anti-Xa Levels According to Renal Function

Siguret V et al. Siguret V et al. Thromb HaemostThromb Haemost 2000;84:800-4. 2000;84:800-4.

No correlation between peak anti-Xa activity and Clcr No correlation between peak anti-Xa activity and Clcr No accumulation of Anti-Xa activity after 10 days of therapyNo accumulation of Anti-Xa activity after 10 days of therapy

Page 157: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Pharmacokinetics of ProphylacticPharmacokinetics of ProphylacticEnoxaparin vs TinzaparinEnoxaparin vs Tinzaparin

Mahe I et al. Thromb Haemost 2007; 97:581-6.Mahe I et al. Thromb Haemost 2007; 97:581-6.

Enoxaparin 40mg qdEnoxaparin 40mg qd or or Tinazaparin 4500 IU qdTinazaparin 4500 IU qd

N = 52 patientsN = 52 patients

Mean age = 87.7 yrsMean age = 87.7 yrsMean wt = 52.3kgMean wt = 52.3kgMean Clcr = 34.7ml/minMean Clcr = 34.7ml/min

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Shprecher AR et al. Shprecher AR et al. PharmacotherapyPharmacotherapy 2005; 25:817-22. 2005; 25:817-22.

No difference in peak anti-Xa activity between normal patients and No difference in peak anti-Xa activity between normal patients and patients with renal impairement patients with renal impairement

ClcrClcr > 80> 80 < 40< 40

Mean peakMean peak 0.47 0.47 0.55 0.55anti-Xa levelanti-Xa levelafter 5-6 dosesafter 5-6 doses

N=11N=11N=11N=11

Dalteparin 100 U/kg q12hDalteparin 100 U/kg q12hPeak Anti-Xa Levels According to Renal FunctionPeak Anti-Xa Levels According to Renal Function

1.5

1.0

0.5

0

1.5

1.0

0.5

0Subjects withoutSubjects withoutRenal impairmentRenal impairment

Subjects withSubjects withRenal impairmentRenal impairment

Ant

ifact

or

Xa

Leve

l (U

/mL)

Ant

ifact

or

Xa

Leve

l (U

/mL)

xxxx

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Pharmacokinetics ofPharmacokinetics ofProphylactic Doses of DalteparinProphylactic Doses of Dalteparin

Tincani E et al. Tincani E et al. HaematologicaHaematologica 2006; 91:976-9. 2006; 91:976-9.

N = 115 elderly (age > 65) pts with acute medical illness and elevated SCrN = 115 elderly (age > 65) pts with acute medical illness and elevated SCrTx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxisTx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxis

Renal FailureRenal Failure MildMild(n=12)(n=12)

ModerateModerate(n=73)(n=73)

SevereSevere(n=24)(n=24)

CrCL (ml/min)CrCL (ml/min) 60-8960-89 30-5930-59 <30<30

Day 6 peak anti-XaDay 6 peak anti-Xa 0.0300.030 0.0330.033 0.0480.048

Minor BleedingMinor Bleeding 00 33 00

Major BleedingMajor Bleeding 00 00 00

P=0.72P=0.72P=0.72P=0.72

► No evidence of accumulation of anti-Xa activity► No relationship between the degree of renal impairment and peak

anti-Xa level on Day 6► No association between creatinine clearance and anti-Xa levels

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Dalteparin Thromboprophylaxis in Critically Ill Patients Dalteparin Thromboprophylaxis in Critically Ill Patients with Severe Renal Insufficiency: The Direct Studywith Severe Renal Insufficiency: The Direct Study

● N=138 critically ill patientsN=138 critically ill patients● CrCl < 30 ml/min CrCl < 30 ml/min

• Mean CrCL 18.9ml/minMean CrCL 18.9ml/min● Dalteparin 5000 IU sc daily Dalteparin 5000 IU sc daily ● Serial anti Xa levels measured on days 3, 10, and 17Serial anti Xa levels measured on days 3, 10, and 17● Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL

Results:Results:• The median duration of dalteparin exposure was 7 (4-12) The median duration of dalteparin exposure was 7 (4-12)

days days • No patient had a trough anti Xa level > 0.4 IU/mlNo patient had a trough anti Xa level > 0.4 IU/ml• Based on serial measurementsBased on serial measurements

• peak anti-Xa levels were 0.29 to 0.34 IU/mLpeak anti-Xa levels were 0.29 to 0.34 IU/mL• trough levels were lower than 0.06 IU/mLtrough levels were lower than 0.06 IU/mL

● N=138 critically ill patientsN=138 critically ill patients● CrCl < 30 ml/min CrCl < 30 ml/min

• Mean CrCL 18.9ml/minMean CrCL 18.9ml/min● Dalteparin 5000 IU sc daily Dalteparin 5000 IU sc daily ● Serial anti Xa levels measured on days 3, 10, and 17Serial anti Xa levels measured on days 3, 10, and 17● Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL

Results:Results:• The median duration of dalteparin exposure was 7 (4-12) The median duration of dalteparin exposure was 7 (4-12)

days days • No patient had a trough anti Xa level > 0.4 IU/mlNo patient had a trough anti Xa level > 0.4 IU/ml• Based on serial measurementsBased on serial measurements

• peak anti-Xa levels were 0.29 to 0.34 IU/mLpeak anti-Xa levels were 0.29 to 0.34 IU/mL• trough levels were lower than 0.06 IU/mLtrough levels were lower than 0.06 IU/mL

Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12. Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12.

Page 161: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Dosing of LMWHs In Renal Impairment Dosing of LMWHs In Renal Impairment RecommendationsRecommendations

FOR CrCL < 30 ml/minFOR CrCL < 30 ml/min► Enoxaparin:Enoxaparin:

● Prophylaxis doses: 30 mg sq QDProphylaxis doses: 30 mg sq QD● Treatment doses: 1mg/Kg sq QDTreatment doses: 1mg/Kg sq QD

► Dalteparin and Tinzaparin:Dalteparin and Tinzaparin:● no specific dosing guidelinesno specific dosing guidelines● No or lower degree of accumulation expectedNo or lower degree of accumulation expected● Anti-Factor Xa activity monitoringAnti-Factor Xa activity monitoring

FOR CrCL 30-50 mL/minFOR CrCL 30-50 mL/min► No specific recommendations No specific recommendations ► Concern with prolonged use > 10 days with enoxaparin (15-25% Concern with prolonged use > 10 days with enoxaparin (15-25%

dose decrease ?)dose decrease ?)► Monitoring anti-Xa ?Monitoring anti-Xa ?

FOR CrCL < 30 ml/minFOR CrCL < 30 ml/min► Enoxaparin:Enoxaparin:

● Prophylaxis doses: 30 mg sq QDProphylaxis doses: 30 mg sq QD● Treatment doses: 1mg/Kg sq QDTreatment doses: 1mg/Kg sq QD

► Dalteparin and Tinzaparin:Dalteparin and Tinzaparin:● no specific dosing guidelinesno specific dosing guidelines● No or lower degree of accumulation expectedNo or lower degree of accumulation expected● Anti-Factor Xa activity monitoringAnti-Factor Xa activity monitoring

FOR CrCL 30-50 mL/minFOR CrCL 30-50 mL/min► No specific recommendations No specific recommendations ► Concern with prolonged use > 10 days with enoxaparin (15-25% Concern with prolonged use > 10 days with enoxaparin (15-25%

dose decrease ?)dose decrease ?)► Monitoring anti-Xa ?Monitoring anti-Xa ?

Nutescu E, et.al. Ann Pharmacother; 2009; in press.Nutescu E, et.al. Ann Pharmacother; 2009; in press.

Page 162: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Unresolved Issues in Unresolved Issues in Renal Dosing of LMWHsRenal Dosing of LMWHs

CrCl (mL/min)CrCl (mL/min) RecommendationsRecommendations

< 30< 30 Dose of enoxaparin should be adjusted; dalteparin and Dose of enoxaparin should be adjusted; dalteparin and tinzaparin no short term accumulation expected.tinzaparin no short term accumulation expected.

< 20-15< 20-15LMWHs have not been adequately studied as repeated doses LMWHs have not been adequately studied as repeated doses for prophylaxis and treatment indications; UFH is preferred in for prophylaxis and treatment indications; UFH is preferred in these patients.these patients.

Issues with anti-factor Xa testing include: Issues with anti-factor Xa testing include: true therapeutic range, standardization, availability, true therapeutic range, standardization, availability,

recommendations for dose adjustmentrecommendations for dose adjustment

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Anti-Xa Activity Level MonitoringAnti-Xa Activity Level Monitoring

Enoxaparin 1mg/kg SQ pharmacokinetic profileEnoxaparin 1mg/kg SQ pharmacokinetic profile

Peak (goal ~ 0.5-1 U/ml) at 3-4 hrs

Trough (goal < 0.5 U/ml) at 11-12 hrs

Laposata et al. Laposata et al. Arch Pathol Lab MedArch Pathol Lab Med. 1998;122:799-807.. 1998;122:799-807.

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ANTI-Xa MONITORING: RecommendationsANTI-Xa MONITORING: Recommendations

Level 3 Evidence: (isolated anecdotal studies or the consensus of experts)Level 3 Evidence: (isolated anecdotal studies or the consensus of experts)

► Laboratory monitoring using an anti-Xa assay Laboratory monitoring using an anti-Xa assay MAYMAY be of value in certain be of value in certain clinical settings clinical settings

► Use peak levels 4 hrs after SQ doseUse peak levels 4 hrs after SQ dose

► Through levels in renal impairment maybe preferredThrough levels in renal impairment maybe preferred

► Use chromogenic, not clot-based assaysUse chromogenic, not clot-based assays

► Peak:Peak:• for BID dosing: 0.5-1.1U/mlfor BID dosing: 0.5-1.1U/ml

• for QD dosing: 1.0-2.0 U/mlfor QD dosing: 1.0-2.0 U/ml

• Through: < 0.4 U/mlThrough: < 0.4 U/ml

Level 3 Evidence: (isolated anecdotal studies or the consensus of experts)Level 3 Evidence: (isolated anecdotal studies or the consensus of experts)

► Laboratory monitoring using an anti-Xa assay Laboratory monitoring using an anti-Xa assay MAYMAY be of value in certain be of value in certain clinical settings clinical settings

► Use peak levels 4 hrs after SQ doseUse peak levels 4 hrs after SQ dose

► Through levels in renal impairment maybe preferredThrough levels in renal impairment maybe preferred

► Use chromogenic, not clot-based assaysUse chromogenic, not clot-based assays

► Peak:Peak:• for BID dosing: 0.5-1.1U/mlfor BID dosing: 0.5-1.1U/ml

• for QD dosing: 1.0-2.0 U/mlfor QD dosing: 1.0-2.0 U/ml

• Through: < 0.4 U/mlThrough: < 0.4 U/ml

Laposata et al. Arch Pathol Lab Med. 1998;122:799-807.Laposata et al. Arch Pathol Lab Med. 1998;122:799-807.Nutescu E, et.al. Ann Pharmacother; 2009; in press.Nutescu E, et.al. Ann Pharmacother; 2009; in press.

Page 165: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

00

0.050.05

0.10.1

0.150.15

0.20.2

0.250.25

0.30.3

0.350.35

Pen

tasa

ccha

ride*

P

enta

sacc

harid

e*

conc

entr

atio

n (µ

g/m

L)co

ncen

trat

ion

(µg/

mL)

00 44 88 1212 1616 2020 2424 2828 3232 3636

Donat F, et al. Donat F, et al. Clin PharmacokineticsClin Pharmacokinetics 2002; 41 (suppl 2):1-9. 2002; 41 (suppl 2):1-9.

Time (h)Time (h)

Fondaparinux PharmacokineticsFondaparinux Pharmacokinetics

100% bioavailable

Cmax = 0.34 µg/mL (SD: 0.04)

Tmax = 1.7 h (SD: 0.4)

T1/2 = 17.2 h (SD: 3.2)

Elimination = RENAL

Page 166: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Fondaparinux Use in Patients Fondaparinux Use in Patients with with Impaired Renal FunctionImpaired Renal Function

► Total clearance lower than in patients Total clearance lower than in patients with normal renal functionwith normal renal function

● Mild impairmentMild impairment ~25%~25%

● Moderate impairmentModerate impairment ~40%~40%

● Severe impairmentSevere impairment ~55%~55%

► Total clearance lower than in patients Total clearance lower than in patients with normal renal functionwith normal renal function

● Mild impairmentMild impairment ~25%~25%

● Moderate impairmentModerate impairment ~40%~40%

● Severe impairmentSevere impairment ~55%~55%

Fondaparinux: PIFondaparinux: PI

Page 167: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Full-dose FondaparinuxFull-dose FondaparinuxRisk Of Major BleedingRisk Of Major Bleeding

ClcrClcr80 80

mL/minmL/min

Inci

denc

e (%

)In

cide

nce

(%)

Data on file, GlaxoSmithKlineData on file, GlaxoSmithKline

ClcrClcr30–50 30–50 mL/minmL/min

ClcrClcr50–80 50–80 mL/minmL/min

1.6%1.6%

3.8%3.8%

2.4%2.4%

n=1565n=1565n=1288n=1288

n=504n=504

ClcrClcr< 30 < 30

ml/minml/min

4.8%4.8%

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Influence of Renal Function Influence of Renal Function Fondaparinux vs Enoxaparin in ACSFondaparinux vs Enoxaparin in ACS

Fox KAA et al. Fox KAA et al. Ann Intern MedAnn Intern Med 2007; 147:304-10. 2007; 147:304-10.

OASIS-5:OASIS-5:

Fondaparinux 2.5mg qdFondaparinux 2.5mg qd

vs enoxaparin 1mg/kg q12hvs enoxaparin 1mg/kg q12h

for 2-8 daysfor 2-8 days

Page 169: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

Electronic Alerts: Electronic Alerts: Future HorizonsFuture Horizons

Karen Fiumara, PharmDMedication Safety Officer

Brigham and Women’s HospitalAdjunct Assistant Professor of Pharmacy Practice

Massachusetts College of Pharmacy and Allied Health SciencesAdjunct Assistant Professor of Pharmacy Practice

Bouve’ College of Health Sciences Northeastern UniversityBoston, MA

Karen Fiumara, PharmDMedication Safety Officer

Brigham and Women’s HospitalAdjunct Assistant Professor of Pharmacy Practice

Massachusetts College of Pharmacy and Allied Health SciencesAdjunct Assistant Professor of Pharmacy Practice

Bouve’ College of Health Sciences Northeastern UniversityBoston, MA

A Year 2009 Update for A Year 2009 Update for The Health System PharmacistThe Health System Pharmacist

Page 170: The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer The Pharmacologic Foundations of DVT Prophylaxis in the Setting of Cancer Edith

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

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

► The IOM report “To Err is Human” have led to The IOM report “To Err is Human” have led to increased research and development of both increased research and development of both medical informatics and computerized alerting medical informatics and computerized alerting systemssystems

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

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

► The IOM report “To Err is Human” have led to The IOM report “To Err is Human” have led to increased research and development of both increased research and development of both medical informatics and computerized alerting medical informatics and computerized alerting systemssystems

BackgroundBackground

Bates DW et al. JAMA 1995;274:1311-16Bates DW et al. JAMA 1995;274:1311-16

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CPOE : Friend or Foe?CPOE : Friend or Foe?

► Recently, institutions are beginning to critically Recently, institutions are beginning to critically assess electronic systems, such as CPOE assess electronic systems, such as CPOE

► VA Medical Center in Salt Lake City: VA Medical Center in Salt Lake City: ● 74% of medication errors occur during prescribing 74% of medication errors occur during prescribing ● 11% during administration 11% during administration ● 0% during transcription0% during transcription

► Bates et al. study:Bates et al. study:● 56% of medication errors - prescribing56% of medication errors - prescribing● 24% of medication errors – administration24% of medication errors – administration● 6% of medication errors – transcription6% of medication errors – transcription

► Recently, institutions are beginning to critically Recently, institutions are beginning to critically assess electronic systems, such as CPOE assess electronic systems, such as CPOE

► VA Medical Center in Salt Lake City: VA Medical Center in Salt Lake City: ● 74% of medication errors occur during prescribing 74% of medication errors occur during prescribing ● 11% during administration 11% during administration ● 0% during transcription0% during transcription

► Bates et al. study:Bates et al. study:● 56% of medication errors - prescribing56% of medication errors - prescribing● 24% of medication errors – administration24% of medication errors – administration● 6% of medication errors – transcription6% of medication errors – transcription

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

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► VA Medical Center attributed low error rates VA Medical Center attributed low error rates during the transcription and administration to during the transcription and administration to information system upgrades such as:information system upgrades such as:

● Bar code technology during administration, EMAR and Bar code technology during administration, EMAR and computerized drug-drug interaction and allergy computerized drug-drug interaction and allergy screeningscreening

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

► VA Medical Center attributed low error rates VA Medical Center attributed low error rates during the transcription and administration to during the transcription and administration to information system upgrades such as:information system upgrades such as:

● Bar code technology during administration, EMAR and Bar code technology during administration, EMAR and computerized drug-drug interaction and allergy computerized drug-drug interaction and allergy screeningscreening

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

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

CPOE : Friend or Foe?CPOE : Friend or Foe?

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

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

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

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

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

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

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

CPOE AlertsCPOE Alerts

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Saving CPOE from ExtinctionSaving CPOE from Extinction

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

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

► One area in which CPOE has proven beneficial is One area in which CPOE has proven beneficial is VTE prophylaxisVTE prophylaxis

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

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

► One area in which CPOE has proven beneficial is One area in which CPOE has proven beneficial is VTE prophylaxisVTE prophylaxis

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Medical Error RatesMedical Error Rates

► Two errors per day = 99% proficiency levelTwo errors per day = 99% proficiency level

► If 99% was good enough:If 99% was good enough:

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

► Two errors per day = 99% proficiency levelTwo errors per day = 99% proficiency level

► If 99% was good enough:If 99% was good enough:

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

Leape LL. Leape LL. JAMAJAMA. 1994;272:1851-7.. 1994;272:1851-7.

–Airline industry = 2 unsafe landings per dayAirline industry = 2 unsafe landings per day

–Banking industry = 32,000 checks deducted from the wrong Banking industry = 32,000 checks deducted from the wrong account per houraccount per hour

–Mail industry = 16,000 pieces of mail lost every hourMail industry = 16,000 pieces of mail lost every hour

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BackgroundBackground

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

prophylaxis strategiesprophylaxis strategies

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

prophylaxis strategiesprophylaxis strategies

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Types of InterventionsTypes of Interventions

► Electronic computer generated alerting Electronic computer generated alerting systemssystems

► Efficacy of these alerting systems have Efficacy of these alerting systems have been studied in:been studied in:● RCT trial of a 1-screen alertRCT trial of a 1-screen alert● Cohort study of a 3-screen alertCohort study of a 3-screen alert

► Electronic computer generated alerting Electronic computer generated alerting systemssystems

► Efficacy of these alerting systems have Efficacy of these alerting systems have been studied in:been studied in:● RCT trial of a 1-screen alertRCT trial of a 1-screen alert● Cohort study of a 3-screen alertCohort study of a 3-screen alert

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First Generation Electronic AlertsFirst Generation Electronic Alerts

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

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

► VTE group utilized computer system to screen VTE group utilized computer system to screen all patients admitted to the hospital for High Risk all patients admitted to the hospital for High Risk VTE statusVTE status

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

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

► VTE group utilized computer system to screen VTE group utilized computer system to screen all patients admitted to the hospital for High Risk all patients admitted to the hospital for High Risk VTE statusVTE status

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First Generation Alert: DevelopmentFirst Generation Alert: Development

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

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

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

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

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

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

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Study SchemaStudy Schema

NO

YES

All Adult Patients

DVT Risk Score > 4

Presence ofProphylaxis

Generate Alert

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Definition of “High Risk”Definition of “High Risk”

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 33 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 33 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

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RandomizationRandomization

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

VTE Risk Score > 4

No Prophylaxis

N = 2506

Intervention

Single Alert

n = 1255

Control

No Alert

n = 1251

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Physician Notification of AlertsPhysician Notification of Alerts

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First GenerationFirst GenerationComputerized Alerts for VTE PreventionComputerized Alerts for VTE Prevention

► Utilization of computer Utilization of computer generated alerts to house generated alerts to house staff reduced the staff reduced the incidence of VTE by 41%incidence of VTE by 41%

► VTE prophylaxis was VTE prophylaxis was prescribed in 33.5% of prescribed in 33.5% of patients in the patients in the intervention groupintervention group

► Following study Following study conclusion a follow up conclusion a follow up cohort study was cohort study was conductedconducted

► Utilization of computer Utilization of computer generated alerts to house generated alerts to house staff reduced the staff reduced the incidence of VTE by 41%incidence of VTE by 41%

► VTE prophylaxis was VTE prophylaxis was prescribed in 33.5% of prescribed in 33.5% of patients in the patients in the intervention groupintervention group

► Following study Following study conclusion a follow up conclusion a follow up cohort study was cohort study was conductedconducted

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

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Second Generation: Second Generation: Electronic Computer Electronic Computer

Generated AlertsGenerated Alerts

AlertsAlerts

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BWH VTE Alerts: The FutureBWH VTE Alerts: The Future

► Goals:Goals:● Engage the house officer with an Engage the house officer with an

interactive alert to increase acceptance interactive alert to increase acceptance and gain feedbackand gain feedback

● Update the DVT prophylaxis template to Update the DVT prophylaxis template to meet current practice guidelinesmeet current practice guidelines

● Provide real-time knowledge linksProvide real-time knowledge links

► Goals:Goals:● Engage the house officer with an Engage the house officer with an

interactive alert to increase acceptance interactive alert to increase acceptance and gain feedbackand gain feedback

● Update the DVT prophylaxis template to Update the DVT prophylaxis template to meet current practice guidelinesmeet current practice guidelines

● Provide real-time knowledge linksProvide real-time knowledge links

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Interactive TechniquesInteractive Techniques

► Provide objective data to the house officer Provide objective data to the house officer that this alert positively impacts patient that this alert positively impacts patient outcomeoutcome

► Create opportunity to capture rationale for Create opportunity to capture rationale for declining alertdeclining alert● Hypothesized that many physicians fear a risk Hypothesized that many physicians fear a risk

of bleeding with anticoagulationof bleeding with anticoagulation

► Provide a final opportunity to order Provide a final opportunity to order mechanical prophylaxismechanical prophylaxis

► Alert attending physician if alert is not Alert attending physician if alert is not acknowledged after 24 hoursacknowledged after 24 hours

► Provide objective data to the house officer Provide objective data to the house officer that this alert positively impacts patient that this alert positively impacts patient outcomeoutcome

► Create opportunity to capture rationale for Create opportunity to capture rationale for declining alertdeclining alert● Hypothesized that many physicians fear a risk Hypothesized that many physicians fear a risk

of bleeding with anticoagulationof bleeding with anticoagulation

► Provide a final opportunity to order Provide a final opportunity to order mechanical prophylaxismechanical prophylaxis

► Alert attending physician if alert is not Alert attending physician if alert is not acknowledged after 24 hoursacknowledged after 24 hours

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DVT Alert ScreenDVT Alert Screen

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Rule Logic – Alert DetailsRule Logic – Alert Details

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Option AOption A

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Option C or “Done”Option C or “Done”

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Escalation and Timing of AlertsEscalation and Timing of Alerts

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

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

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

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

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Quality AssuranceQuality Assurance

► Weekly reports are reviewedWeekly reports are reviewed

► Allows core team to review all aspects of the Allows core team to review all aspects of the alerts including:alerts including:● Type of action takenType of action taken● Rate of overridesRate of overrides● Rational for declining the alertsRational for declining the alerts

► Results coming soonResults coming soon

► Weekly reports are reviewedWeekly reports are reviewed

► Allows core team to review all aspects of the Allows core team to review all aspects of the alerts including:alerts including:● Type of action takenType of action taken● Rate of overridesRate of overrides● Rational for declining the alertsRational for declining the alerts

► Results coming soonResults coming soon

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Human AlertsHuman Alerts

Pharmacy/Physician Pharmacy/Physician Collaboration Collaboration

AlertsAlerts

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VTE Prophylaxis: hALERTVTE Prophylaxis: hALERT

► Multicentered RCT of human alerts (hALERT). Multicentered RCT of human alerts (hALERT).

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

► Can a Can a humanhuman alert be more effective than an alert be more effective than an electronielectronicc alert? alert?

► Multicentered RCT of human alerts (hALERT). Multicentered RCT of human alerts (hALERT).

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

► Can a Can a humanhuman alert be more effective than an alert be more effective than an electronielectronicc alert? alert?

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MethodologyMethodology

► Patients admitted to the hospital are screen by Patients admitted to the hospital are screen by human for increased VTE riskhuman for increased VTE risk

► High risk patients are randomized to alert or no High risk patients are randomized to alert or no alert alert

► Physicians of patients in alert group receive Physicians of patients in alert group receive page alerting them of high risk statuspage alerting them of high risk status

► Records are checked for prophylaxis order 48 Records are checked for prophylaxis order 48 hours after alerthours after alert

► 90 day follow up for clinically significant VTE 90 day follow up for clinically significant VTE and clinically importing bleedingand clinically importing bleeding

► Patients admitted to the hospital are screen by Patients admitted to the hospital are screen by human for increased VTE riskhuman for increased VTE risk

► High risk patients are randomized to alert or no High risk patients are randomized to alert or no alert alert

► Physicians of patients in alert group receive Physicians of patients in alert group receive page alerting them of high risk statuspage alerting them of high risk status

► Records are checked for prophylaxis order 48 Records are checked for prophylaxis order 48 hours after alerthours after alert

► 90 day follow up for clinically significant VTE 90 day follow up for clinically significant VTE and clinically importing bleedingand clinically importing bleeding

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hALERT: Capturing New hALERT: Capturing New Prophylaxis OrdersProphylaxis Orders

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

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

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

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

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Human Alert TrialHuman Alert Trial

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

2.2. The attending physician, not the intern, The attending physician, not the intern, receives the Alertreceives the Alert

3.3. Diversity of centers: community, suburban, Diversity of centers: community, suburban, throughout the USAthroughout the USA

4.4. Will attendings pay more attention than house Will attendings pay more attention than house staff?staff?

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

2.2. The attending physician, not the intern, The attending physician, not the intern, receives the Alertreceives the Alert

3.3. Diversity of centers: community, suburban, Diversity of centers: community, suburban, throughout the USAthroughout the USA

4.4. Will attendings pay more attention than house Will attendings pay more attention than house staff?staff?

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ConclusionsConclusions

► Changing behavior is challengingChanging behavior is challenging

► Multi-disciplinary team involvement is critical to Multi-disciplinary team involvement is critical to successful implementationsuccessful implementation

► Need to engage providers and obtain feedbackNeed to engage providers and obtain feedback

► Designing “smart alerts” that include decision Designing “smart alerts” that include decision support functionality or “human alerts” that require support functionality or “human alerts” that require face to face contact may be effective face to face contact may be effective

► Changing behavior is challengingChanging behavior is challenging

► Multi-disciplinary team involvement is critical to Multi-disciplinary team involvement is critical to successful implementationsuccessful implementation

► Need to engage providers and obtain feedbackNeed to engage providers and obtain feedback

► Designing “smart alerts” that include decision Designing “smart alerts” that include decision support functionality or “human alerts” that require support functionality or “human alerts” that require face to face contact may be effective face to face contact may be effective

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Electronic Alerts to Electronic Alerts to Prevent Infusion ErrorsPrevent Infusion Errors

AlertsAlerts

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Patient Case—Infusion Pump ErrorPatient Case—Infusion Pump Error

Error DescriptionError Description► 57 YOM endstage CMP57 YOM endstage CMP► EF = 10%EF = 10%► Heart transplant candidate Heart transplant candidate

with BIVADwith BIVAD► Receiving UFH 900 units Receiving UFH 900 units

per hour (9 mls/hr)per hour (9 mls/hr)► New order to reduce New order to reduce

Heparin 800 units per hour Heparin 800 units per hour @ 10:22 PM@ 10:22 PM

► Infusion pump set for 800 Infusion pump set for 800 mls per hourmls per hour

Error DescriptionError Description► 57 YOM endstage CMP57 YOM endstage CMP► EF = 10%EF = 10%► Heart transplant candidate Heart transplant candidate

with BIVADwith BIVAD► Receiving UFH 900 units Receiving UFH 900 units

per hour (9 mls/hr)per hour (9 mls/hr)► New order to reduce New order to reduce

Heparin 800 units per hour Heparin 800 units per hour @ 10:22 PM@ 10:22 PM

► Infusion pump set for 800 Infusion pump set for 800 mls per hourmls per hour

► 8:45 PM aPTT = 75.18:45 PM aPTT = 75.1

► 1:13 AM Protamine 25mg1:13 AM Protamine 25mg

► 1:28 AM aPTT = >1501:28 AM aPTT = >150

► 3:13 AM aPTT = >150 3:13 AM aPTT = >150

► 3:32 AM Protamine 26mg3:32 AM Protamine 26mg

► 2 Units PRBC2 Units PRBC

► 4:08 AM aPTT = >1504:08 AM aPTT = >150

► 8:21 AM aPTT = 44.48:21 AM aPTT = 44.4

► 8:45 PM aPTT = 75.18:45 PM aPTT = 75.1

► 1:13 AM Protamine 25mg1:13 AM Protamine 25mg

► 1:28 AM aPTT = >1501:28 AM aPTT = >150

► 3:13 AM aPTT = >150 3:13 AM aPTT = >150

► 3:32 AM Protamine 26mg3:32 AM Protamine 26mg

► 2 Units PRBC2 Units PRBC

► 4:08 AM aPTT = >1504:08 AM aPTT = >150

► 8:21 AM aPTT = 44.48:21 AM aPTT = 44.4

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BackgroundBackground

RankRank Medications Causing Medications Causing HarmHarm

1.1. InsulinInsulin

2.2. MorphineMorphine

3.3. HeparinHeparin

4.4. WarfarinWarfarin

5.5. PotassiumPotassium

6.6. FurosemideFurosemide

7.7. VancomycinVancomycin

8.8. HydromorphoneHydromorphone

9.9. MeperidineMeperidine

10.10. DiltiazemDiltiazem

MEDMARXSM 2001. The United States Pharmacopoeia MEDMARXSM 2001. The United States Pharmacopoeia (USP)Convention Inc. (USP)Convention Inc.

•Heparin has been identified both Heparin has been identified both nationally and internally at BWH as a nationally and internally at BWH as a medication frequently associated with medication frequently associated with ADE ADE

•Removed access to different formulationsRemoved access to different formulations

•Standardized UFH ConcentrationStandardized UFH Concentration

•Calculate infusion rates in OECalculate infusion rates in OE

National DataNational Data

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UFH Error Analysis: BWHUFH Error Analysis: BWH

► 1 event per 1,000 patients1 event per 1,000 patients● 52% - Administration related52% - Administration related● 31% - Equipment failure, rate or dosing error31% - Equipment failure, rate or dosing error● 23% - Infusion Pump 23% - Infusion Pump

► 6% - Prolonged LOS or significant harm6% - Prolonged LOS or significant harm

► 1 event per 1,000 patients1 event per 1,000 patients● 52% - Administration related52% - Administration related● 31% - Equipment failure, rate or dosing error31% - Equipment failure, rate or dosing error● 23% - Infusion Pump 23% - Infusion Pump

► 6% - Prolonged LOS or significant harm6% - Prolonged LOS or significant harm

Fanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol Fanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol 2004;94:532-5352004;94:532-535

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

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ObjectivesObjectives

► Evaluate impact of “smart” infusion Evaluate impact of “smart” infusion technology on anticoagulation technology on anticoagulation administration administration

► To determine if infusion technology To determine if infusion technology equipped with drug libraries may equipped with drug libraries may reduce medication errors reduce medication errors

► Evaluate impact of “smart” infusion Evaluate impact of “smart” infusion technology on anticoagulation technology on anticoagulation administration administration

► To determine if infusion technology To determine if infusion technology equipped with drug libraries may equipped with drug libraries may reduce medication errors reduce medication errors

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Features of the “Smart” PumpsFeatures of the “Smart” Pumps

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

► ““Smart” pumps also equipped with a drug librarySmart” pumps also equipped with a drug library● Provide dose and rate limits on commonly used Provide dose and rate limits on commonly used

medicationsmedications● Provide users with overdose and underdose Provide users with overdose and underdose

alerts based on predetermined limits defined by alerts based on predetermined limits defined by the drug librarythe drug library

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

► ““Smart” pumps also equipped with a drug librarySmart” pumps also equipped with a drug library● Provide dose and rate limits on commonly used Provide dose and rate limits on commonly used

medicationsmedications● Provide users with overdose and underdose Provide users with overdose and underdose

alerts based on predetermined limits defined by alerts based on predetermined limits defined by the drug librarythe drug library

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MethodsMethods

► We programmed the drug We programmed the drug library to alert for overdoses library to alert for overdoses or underdosesor underdoses

► Alerts where subsequently Alerts where subsequently recorded in the device’s recorded in the device’s electronic memory, along electronic memory, along with the user’s next actionwith the user’s next action

► We retrospectively We retrospectively reviewed all anticoagulant reviewed all anticoagulant alerts and the user’s next alerts and the user’s next action for all devices from action for all devices from 10/2003 through 1/200510/2003 through 1/2005

► We programmed the drug We programmed the drug library to alert for overdoses library to alert for overdoses or underdosesor underdoses

► Alerts where subsequently Alerts where subsequently recorded in the device’s recorded in the device’s electronic memory, along electronic memory, along with the user’s next actionwith the user’s next action

► We retrospectively We retrospectively reviewed all anticoagulant reviewed all anticoagulant alerts and the user’s next alerts and the user’s next action for all devices from action for all devices from 10/2003 through 1/200510/2003 through 1/2005

MedicationMedication Underdose Underdose AlertAlert

Overdose Overdose AlertAlert

UFHUFH <300 units/hour<300 units/hour >2,800 >2,800 units/hourunits/hour

ArgatrobanArgatroban <0.5 mcg/kg/min<0.5 mcg/kg/min >10 mcg/kg/min>10 mcg/kg/min

LepirudinLepirudin <5 mg/hour<5 mg/hour >16.5 mg/hour>16.5 mg/hour

BivalirudinBivalirudin <0.2 mg/kg/hour<0.2 mg/kg/hour >1.8 >1.8 mg/kg/hourmg/kg/hour

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Dosing Errors and their MagnitudeDosing Errors and their Magnitude

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Data Entry Errors Frequently Data Entry Errors Frequently Repeated with UFHRepeated with UFH

27.2 % entry errors User 27.2 % entry errors User repeated the errorrepeated the error

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Alerts by Time of DayAlerts by Time of Day

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ConclusionsConclusions

► The drug library and its alerting system The drug library and its alerting system intercept programming errorsintercept programming errors

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

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

► The drug library and its alerting system The drug library and its alerting system intercept programming errorsintercept programming errors

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

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