Welcome to this Science-to-Strategy Summit

Welcome to this Science-to-Strategy SummitWelcome to this Science-to-Strategy Summit

Critical Challenges and Landmark Critical Challenges and Landmark Advances in Advances in Thrombosis ManagementThrombosis Management

The Evolving and Foundation Role of LMWHs in Cancer and VTE The Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, and Landmark Prophylaxis: Applying Science, Expert Analysis, and Landmark

Trials to the Front Lines of Oncology PracticeTrials to the Front Lines of Oncology Practice

Critical Challenges and Landmark Critical Challenges and Landmark Advances in Advances in Thrombosis ManagementThrombosis Management

The Evolving and Foundation Role of LMWHs in Cancer and VTE The Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, and Landmark Prophylaxis: Applying Science, Expert Analysis, and Landmark

Trials to the Front Lines of Oncology PracticeTrials to the Front Lines of Oncology Practice

Program ChairmanProgram ChairmanCharles W. Francis, MDCharles W. Francis, MD

Professor of Medicine and Pathology and Professor of Medicine and Pathology and Laboratory MedicineLaboratory Medicine

Department of MedicineDepartment of MedicineUniversity of RochesterUniversity of Rochester

School of Medicine and DentistrySchool of Medicine and DentistryRochester, New YorkRochester, New York





Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies

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

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

Program Educational ObjectivesProgram Educational Objectives

As a result of this session, physicians will:As a result of this session, physicians will: ► Review recent trials, research, and expert analysis of issues focused on Review recent trials, research, and expert analysis of issues focused on

thrombosis and cancer.thrombosis and cancer.

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

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

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

► Be able to describe how to risk stratify patients undergoing cancer surgery, and Be able to describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis.aimed at DVT prophylaxis.

As a result of this session, physicians will:As a result of this session, physicians will: ► Review recent trials, research, and expert analysis of issues focused on Review recent trials, research, and expert analysis of issues focused on

thrombosis and cancer.thrombosis and cancer.

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

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

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

► Be able to describe how to risk stratify patients undergoing cancer surgery, and Be able to describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis.aimed at DVT prophylaxis.

Program FacultyProgram Faculty

Program Chairman Program Chairman Charles W. Francis, MDCharles W. Francis, MDProfessor of Medicine and Pathology and Laboratory MedicineProfessor of Medicine and Pathology and Laboratory MedicineDepartment of MedicineDepartment of MedicineUniversity of RochesterUniversity of RochesterSchool of Medicine and DentistrySchool of Medicine and DentistryRochester, NYRochester, NY

Frederick Rickles, MDFrederick Rickles, MDProfessor of Medicine, Pediatrics, Pharmacology and PhysiologyProfessor of Medicine, Pediatrics, Pharmacology and PhysiologyDepartment of MedicineDepartment of MedicineDivision of Hematology-OncologyDivision of Hematology-OncologyThe George Washington UniversityThe George Washington UniversityWashington, DCWashington, DC

John Fanikos, RPh, MBAJohn Fanikos, RPh, MBAAssistant Director of PharmacyAssistant Director of PharmacyBrigham and Women’s HospitalBrigham and Women’s HospitalAssistant Clinical Professor of PharmacyAssistant Clinical Professor of PharmacyNortheastern UniversityNortheastern UniversityMassachusetts College of PharmacyMassachusetts College of PharmacyBoston, MABoston, MA

Program Chairman Program Chairman Charles W. Francis, MDCharles W. Francis, MDProfessor of Medicine and Pathology and Laboratory MedicineProfessor of Medicine and Pathology and Laboratory MedicineDepartment of MedicineDepartment of MedicineUniversity of RochesterUniversity of RochesterSchool of Medicine and DentistrySchool of Medicine and DentistryRochester, NYRochester, NY

Frederick Rickles, MDFrederick Rickles, MDProfessor of Medicine, Pediatrics, Pharmacology and PhysiologyProfessor of Medicine, Pediatrics, Pharmacology and PhysiologyDepartment of MedicineDepartment of MedicineDivision of Hematology-OncologyDivision of Hematology-OncologyThe George Washington UniversityThe George Washington UniversityWashington, DCWashington, DC

John Fanikos, RPh, MBAJohn Fanikos, RPh, MBAAssistant Director of PharmacyAssistant Director of PharmacyBrigham and Women’s HospitalBrigham and Women’s HospitalAssistant Clinical Professor of PharmacyAssistant Clinical Professor of PharmacyNortheastern UniversityNortheastern UniversityMassachusetts College of PharmacyMassachusetts College of PharmacyBoston, MABoston, MA

Faculty COI Financial DisclosuresFaculty COI Financial Disclosures

Charles Francis, MDCharles Francis, MDGrants/research support:Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai, Boehringer-Ingelheim, Eisai, Consultant: Eisai, Amgen, PfizerAmgen, Pfizer

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

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

Charles Francis, MDCharles Francis, MDGrants/research support:Grants/research support: Boehringer-Ingelheim, Eisai, Consultant: Eisai, Boehringer-Ingelheim, Eisai, Consultant: Eisai, Amgen, PfizerAmgen, Pfizer

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

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

Introduction and Chairman’s OverviewIntroduction and Chairman’s Overview

Clotting, Cancer, And Controversies: What Clotting, Cancer, And Controversies: What The Cascade Of Evidence And Current The Cascade Of Evidence And Current

Thinking Tell UsThinking Tell Us

The Evolving Science, Epidemiology, and Foundation Role The Evolving Science, Epidemiology, and Foundation Role of Low Molecular Weight Heparin in the Setting of Cancerof Low Molecular Weight Heparin in the Setting of Cancer









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 diseasesOncologyOncologyCardiology Cardiology Pulmonary medicinePulmonary medicineHematologyHematologyOncology/hematologyOncology/hematologyInterventional RadiologyInterventional RadiologyHospitalistHospitalistSurgeonsSurgeonsEMEMPCPPCP

SUBSPECIALISTSUBSPECIALISTSTAKEHOLDERSSTAKEHOLDERS

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

Comorbidity ConnectionComorbidity Connection

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

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.

Comorbidity ConnectionComorbidity Connection

ComorbidityComorbidityConnectionConnection

Overview Overview

Acute Medical Illness and VTEAcute Medical Illness and VTE

Among Patients Receiving Placebo orAmong Patients Receiving Placebo or Ineffective Antithrombotic TherapyIneffective Antithrombotic Therapy

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

Acute Medical Acute Medical IllnessIllness Relative RiskRelative Risk XX22 PP Value Value

Heart failureHeart failureNYHA class IIINYHA class IIINYHA class IVNYHA class IV

1.08 (0.72-1.62)1.08 (0.72-1.62)0.89 (0.55-1.43)0.89 (0.55-1.43)1.48 (0.84-2.60)1.48 (0.84-2.60)

0.050.050.120.121.231.23

.82.82

.72.72

.27.27

Acute respiratory Acute respiratory diseasedisease

1.26 (0.85-1.87)1.26 (0.85-1.87) 1.031.03 .31.31

Acute infectious Acute infectious diseasedisease

1.50 (1.00-2.26)1.50 (1.00-2.26) 3.543.54 .06.06

Acute rheumatic Acute rheumatic diseasedisease

1.45 (0.84-2.50)1.45 (0.84-2.50) 1.201.20 .27.27

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)

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

Chronic respiratory Chronic respiratory diseasedisease

0.60 (0.38-0.92)0.60 (0.38-0.92) 0.020.02

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 . 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study 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 . 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study

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 neoplasmNoneNone

With chemotherapyWith chemotherapyWithout chemotherapyWithout chemotherapy

1.001.004.24 (2.58-6.95)4.24 (2.58-6.95)2.21 (1.60-3.06)2.21 (1.60-3.06)

Cancer, Thrombosis, and the Cancer, Thrombosis, and the Biology of MalignancyBiology of Malignancy

Scientific Foundations for the Role ofScientific Foundations for the Role ofLow-Molecular-Weight HeparinLow-Molecular-Weight Heparin

Cancer, Thrombosis, and the Cancer, Thrombosis, and the Biology of MalignancyBiology of Malignancy

Scientific Foundations for the Role ofScientific Foundations for the Role ofLow-Molecular-Weight HeparinLow-Molecular-Weight Heparin

Frederick R. Rickles, MDFrederick R. Rickles, MDProfessor of Medicine, Pediatrics, Professor of Medicine, Pediatrics,

Pharmacology and PhysiologyPharmacology and PhysiologyThe George Washington UniversityThe George Washington University

Washington, DCWashington, DC

Frederick R. Rickles, MDFrederick R. Rickles, MDProfessor of Medicine, Pediatrics, Professor of Medicine, Pediatrics,

Pharmacology and PhysiologyPharmacology and PhysiologyThe George Washington UniversityThe George Washington University

Washington, DCWashington, DC

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

Professor Armand TrousseauProfessor Armand TrousseauLectures in Clinical MedicineLectures in Clinical Medicine

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

New Syndenham Society – 1865New Syndenham Society – 1865

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

New Syndenham Society – 1865New Syndenham Society – 1865

Professor Armand TrousseauProfessor Armand TrousseauMore Observations About Cancer and ThrombosisMore Observations About Cancer and Thrombosis

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

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

Lectures in Clinical Medicine, 1865Lectures in Clinical Medicine, 1865

Trousseau’s SyndromeTrousseau’s Syndrome

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

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

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

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

Trousseau’s SyndromeTrousseau’s Syndrome

► Occult cancerOccult cancer in patients with idiopathic in patients with idiopathic venous thromboembolismvenous thromboembolism

► ThrombophlebitisThrombophlebitis in patientsin patientswith cancerwith cancer

► Occult cancerOccult cancer in patients with idiopathic in patients with idiopathic venous thromboembolismvenous thromboembolism

► ThrombophlebitisThrombophlebitis in patientsin patientswith cancerwith cancer

Silver Silver In: In: The Hematologist - modified from Blom et. al. The Hematologist - modified from Blom et. al. JAMAJAMA 2005;293:715 2005;293:715

• Population-based case-control (MEGA) study

• N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects

• CA patients = OR 7x VTE risk vs. non-CA patients

• Population-based case-control (MEGA) study

• N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects

• CA patients = OR 7x VTE risk vs. non-CA patients

Effect of Malignancy on Risk of Effect of Malignancy on Risk of Venous Thromboembolism (VTE)Venous Thromboembolism (VTE)

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Type of cancerType of cancer Time since cancer diagnosis Time since cancer diagnosis

2828

22.222.220.320.3

4.94.9

19.819.8

53.553.5

14.314.3

2.62.61.11.13.63.6

Cancer, Mortality, and VTECancer, Mortality, and VTEEpidemiology and RiskEpidemiology and Risk

► Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patients

► Patients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patients

► Cancer patients undergoing surgery have a 2-fold increased risk for postoperative VTE

► Death rate from cancer is four-fold higher if patient has concurrent VTE

► VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection))

► Patients with cancer have a 4- to 6-fold increased risk for VTE vs. non-cancer patients

► Patients with cancer have a 3-fold increased risk for recurrence of VTE vs. non-cancer patients

► Cancer patients undergoing surgery have a 2-fold increased risk for postoperative VTE

► Death rate from cancer is four-fold higher if patient has concurrent VTE

► VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection))

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

Mechanisms of Cancer-Induced Thrombosis: Mechanisms of Cancer-Induced Thrombosis: The InterfaceThe Interface

1.1. PathogenesisPathogenesis??

2.2. Biological significance?Biological significance?

3.3. Potential importance for cancer therapy?Potential importance for cancer therapy?

1.1. PathogenesisPathogenesis??


3.3. Potential importance for cancer therapy?Potential importance for cancer therapy?

““There appears in the cachexiae…a There appears in the cachexiae…a

particular condition of the blood that particular condition of the blood that

predisposes it to spontaneouspredisposes it to spontaneous

coagulation.”coagulation.”


““There appears in the cachexiae…a There appears in the cachexiae…a

particular condition of the blood that particular condition of the blood that

predisposes it to spontaneouspredisposes it to spontaneous

coagulation.”coagulation.”


Trousseau’s Observations (continued)Trousseau’s Observations (continued)

Fibrinolytic activities:t-PA, u-PA, u-PAR, PAI-1, PAI-2

Procoagulant Activities

FIBRIN

Endothelial cells

IL-1, TNF-VEGF

Tumor cells

Monocyte

PMN leukocyte

Activation of coagulation

Platelets

Angiogenesis,Basement matrix degradation.

Falanga and Rickles, Falanga and Rickles, New Oncology:ThrombosisNew Oncology:Thrombosis, 2005; , 2005; Hematology, Hematology, 20072007

Interface of Biology and CancerInterface of Biology and Cancer

Pathogenesis of Thrombosis in Cancer Pathogenesis of Thrombosis in Cancer A Modification of Virchow’s TriadA Modification of Virchow’s Triad

1.1. StasisStasis● Prolonged bed restProlonged bed rest● Extrinsic compression of blood vessels by tumorExtrinsic compression of blood vessels by tumor

2.2. Vascular InjuryVascular Injury● Direct invasion by tumorDirect invasion by tumor● Prolonged use of central venous cathetersProlonged use of central venous catheters● Endothelial damage by chemotherapy drugsEndothelial damage by chemotherapy drugs● Effect of tumor cytokines on vascular endotheliumEffect of tumor cytokines on vascular endothelium

3.3. HypercoagulabilityHypercoagulability● Tumor-associated procoagulants and cytokines (tissue factor, CP, Tumor-associated procoagulants and cytokines (tissue factor, CP,

TNFTNF, IL-1, IL-1, VEGF, etc.), VEGF, etc.)● Impaired endothelial cell defense mechanisms (APC resistance; Impaired endothelial cell defense mechanisms (APC resistance;

deficiencies of AT, Protein C and S) deficiencies of AT, Protein C and S) ● Enhanced selectin/integrin-mediated, adhesive interactions Enhanced selectin/integrin-mediated, adhesive interactions

between tumor cells,vascular endothelial cells, platelets and host between tumor cells,vascular endothelial cells, platelets and host macrophagesmacrophages

1.1. StasisStasis● Prolonged bed restProlonged bed rest● Extrinsic compression of blood vessels by tumorExtrinsic compression of blood vessels by tumor

2.2. Vascular InjuryVascular Injury● Direct invasion by tumorDirect invasion by tumor● Prolonged use of central venous cathetersProlonged use of central venous catheters● Endothelial damage by chemotherapy drugsEndothelial damage by chemotherapy drugs● Effect of tumor cytokines on vascular endotheliumEffect of tumor cytokines on vascular endothelium

3.3. HypercoagulabilityHypercoagulability● Tumor-associated procoagulants and cytokines (tissue factor, CP, Tumor-associated procoagulants and cytokines (tissue factor, CP,

TNFTNF, IL-1, IL-1, VEGF, etc.), VEGF, etc.)● Impaired endothelial cell defense mechanisms (APC resistance; Impaired endothelial cell defense mechanisms (APC resistance;

deficiencies of AT, Protein C and S) deficiencies of AT, Protein C and S) ● Enhanced selectin/integrin-mediated, adhesive interactions Enhanced selectin/integrin-mediated, adhesive interactions

between tumor cells,vascular endothelial cells, platelets and host between tumor cells,vascular endothelial cells, platelets and host macrophagesmacrophages

Mechanisms of Cancer-Induced Thrombosis: Mechanisms of Cancer-Induced Thrombosis: Clot and Cancer InterfaceClot and Cancer Interface

1.1. Pathogenesis?Pathogenesis?


3.3. Potential importance for cancer therapyPotential importance for cancer therapy??



3.3. Potential importance for cancer therapyPotential importance for cancer therapy??

Activation of Blood Coagulation in CancerActivation of Blood Coagulation in CancerBiological Significance?Biological Significance?

► EpiphenomenonEpiphenomenon? ?

Is this a generic secondary event where Is this a generic secondary event where thrombosis is an incidental findingthrombosis is an incidental finding

oor, is clotting activation . . .r, is clotting activation . . .

► A Primary Event?A Primary Event?

Linked to malignant transformation Linked to malignant transformation

► EpiphenomenonEpiphenomenon? ?

Is this a generic secondary event where Is this a generic secondary event where thrombosis is an incidental findingthrombosis is an incidental finding

oor, is clotting activation . . .r, is clotting activation . . .

► A Primary Event?A Primary Event?

Linked to malignant transformation Linked to malignant transformation

TF

VEGF

AngiogenesisAngiogenesis

Endothelial cells

IL-8IL-8

Blood CoagulationBlood CoagulationActivationActivation

FIBRINFIBRIN

PAR-2PAR-2

AngiogenesisAngiogenesis

FVII/FVIIaFVII/FVIIa

THROMBINTHROMBIN

Tumor Tumor CCellell

TF

Falanga and Rickles, New Oncology:Thrombosis, 2005

Interface of Clotting Activation Interface of Clotting Activation and Tumor Biology and Tumor Biology

Coagulation Cascade and Tumor BiologyCoagulation Cascade and Tumor Biology

TFTFTFTF ThrombinThrombinThrombinThrombin

Clotting-Clotting-dependentdependentClotting-Clotting-

dependentdependentClotting-Clotting-

dependentdependentClotting-Clotting-

dependentdependent

Clotting-Clotting-independentindependent


Clotting-Clotting-dependentdependent

FibrinFibrinFibrinFibrin



PARsPARsPARsPARs

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

VIIaVIIaVIIaVIIa XaXaXaXa

Angiogenesis, Tumor Angiogenesis, Tumor Growth and MetastasisGrowth and MetastasisAngiogenesis, Tumor Angiogenesis, Tumor Growth and MetastasisGrowth and Metastasis

VEGF and AngiogenesisVEGF and Angiogenesis

1.1. TF regulates VEGF expression in human cancer TF regulates VEGF expression in human cancer cell linescell lines

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

1.1. TF regulates VEGF expression in human cancer TF regulates VEGF expression in human cancer cell linescell lines

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

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

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

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

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

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

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

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

VEGF and AngiogenesisVEGF and Angiogenesis

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

Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Alok A. Khorana, Steven A. Ahrendt, Charlotte K. Ryan, Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter, Charles W. Francis, Ralph H. Hruban, Ying Chuan Hu, Galen Hostetter,

Jennifer Harvey and Mark B.TaubmanJennifer Harvey and Mark B.Taubman (U Rochester, U Pitt, Johns Hopkins, (U Rochester, U Pitt, Johns Hopkins,

Translational Genomics)Translational Genomics)

Clin Cancer ResClin Cancer Res 2007;13:2870 2007;13:2870

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

► SurvivalSurvival

► VTE RateVTE Rate

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

► SurvivalSurvival

► VTE RateVTE Rate

Tissue Factor Expression, Angiogenesis, and Tissue Factor Expression, Angiogenesis, and Thrombosis in Pancreatic CancerThrombosis in Pancreatic Cancer

Correlation of Tissue Factor Expression with theCorrelation of Tissue Factor Expression with theExpression of Other Angiogenesis Cariables in Resected Expression of Other Angiogenesis Cariables in Resected

Pancreatic CancerPancreatic Cancer

Khorana et.al. Clin CA Res 2007:13:2870

High TF High TF expressionexpression

Low TF Low TF expressionexpression PP

VEGF expressionVEGF expression NegativeNegative PositivePositive

13135353

41411515

<0.0001<0.0001

Microvessel densityMicrovessel density V6 per tissue coreV6 per tissue core >6 per tissue core>6 per tissue core MedianMedian

2727393988

3333232366

0.0470.047

0.010.01

0

5

10

15

20

25

30

Low TF High TF

Symptomatic VTE in Pancreatic CancerSymptomatic VTE in Pancreatic Cancer

1/22; 4.5%1/22; 4.5%

5/19; 26.3%5/19; 26.3%

Khorana et.al. Khorana et.al. Clin CA Res Clin CA Res 2007:13:2870 2007:13:2870

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Activation of Blood Coagulation Activation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation

► Epiphenomenon? Epiphenomenon?

► Linked to malignant transformation?Linked to malignant transformation?

1.1. METMET oncogene induction produces DIC in oncogene induction produces DIC in human liver carcinomahuman liver carcinoma

(Boccaccio et. al. (Boccaccio et. al. NatureNature 2005;434:396-400) 2005;434:396-400)

2.2. PtenPten loss produces TF activation and loss produces TF activation and pseudopalisading necrosis in human pseudopalisading necrosis in human glioblastomaglioblastoma

(Rong et.al. (Rong et.al. Ca ResCa Res 2005;65:1406-1413) 2005;65:1406-1413)

3. 3. K-K-rasras oncogene, p53 inactivation and TF oncogene, p53 inactivation and TF induction in human colorectal carcinomainduction in human colorectal carcinoma

(Yu et.al. (Yu et.al. BloodBlood 2005;105:1734-1741) 2005;105:1734-1741)

► Epiphenomenon? Epiphenomenon?

► Linked to malignant transformation?Linked to malignant transformation?

1.1. METMET oncogene induction produces DIC in oncogene induction produces DIC in human liver carcinomahuman liver carcinoma

(Boccaccio et. al. (Boccaccio et. al. NatureNature 2005;434:396-400) 2005;434:396-400)

2.2. PtenPten loss produces TF activation and loss produces TF activation and pseudopalisading necrosis in human pseudopalisading necrosis in human glioblastomaglioblastoma

(Rong et.al. (Rong et.al. Ca ResCa Res 2005;65:1406-1413) 2005;65:1406-1413)

3. 3. K-K-rasras oncogene, p53 inactivation and TF oncogene, p53 inactivation and TF induction in human colorectal carcinomainduction in human colorectal carcinoma

(Yu et.al. (Yu et.al. BloodBlood 2005;105:1734-1741) 2005;105:1734-1741)

► METMET encodes a tyrosine kinase receptor for hepatocyte encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) growth factor/scatter factor (HGF/SF) ● Drives physiologicalDrives physiological cellular program of “invasive cellular program of “invasive

growth” (tissue morphogenesis, angiogenesis growth” (tissue morphogenesis, angiogenesis and repair)and repair)

● Aberrant execution (e.g. hypoxia-induced Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transcription) is associated with neoplastic transformation, invasion, and metastasistransformation, invasion, and metastasis

► METMET encodes a tyrosine kinase receptor for hepatocyte encodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) growth factor/scatter factor (HGF/SF) ● Drives physiologicalDrives physiological cellular program of “invasive cellular program of “invasive

growth” (tissue morphogenesis, angiogenesis growth” (tissue morphogenesis, angiogenesis and repair)and repair)

● Aberrant execution (e.g. hypoxia-induced Aberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastic transcription) is associated with neoplastic transformation, invasion, and metastasistransformation, invasion, and metastasis

Boccaccio et al Boccaccio et al Nature Nature 2005;434:396-4002005;434:396-400

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

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


► Mouse model of Trousseau’s SyndromeMouse model of Trousseau’s Syndrome

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

● Preceded and accompanied by a thrombohemorrhagic Preceded and accompanied by a thrombohemorrhagic syndrome syndrome

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

● Syndrome characterized by Syndrome characterized by d-dimer and PT and d-dimer and PT and platelet count (DIC)platelet count (DIC)


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

● Preceded and accompanied by a thrombohemorrhagic Preceded and accompanied by a thrombohemorrhagic syndrome syndrome

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

● Syndrome characterized by Syndrome characterized by d-dimer and PT and d-dimer and PT and platelet count (DIC)platelet count (DIC)

““METMET Oncogene Drives a Genetic Programme Oncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Linking Cancer to Haemostasis”


Blood Coagulation Parameters in Mice Blood Coagulation Parameters in Mice Transduced with the Transduced with the MET MET OncogeneOncogene

TransgeneTransgene ParameterParameter

Time after Transduction (days)Time after Transduction (days)

0 30 900 30 90

GFPGFP

__________________

MET MET

Platelets (x10Platelets (x1033))

D-dimer (D-dimer (µg/ml)µg/ml)

PT (s)PT (s)

________________________________

Platelets (x10Platelets (x1033))

D-dimer (µg/ml)D-dimer (µg/ml)

PT (s)PT (s)

968 656 800 968 656 800

<0.05 <0.05 <0.05<0.05 <0.05 <0.05

12.4 11.6 11.412.4 11.6 11.4

______________________________________________________________

974 350 150974 350 150

<0.05 0.11 0.22<0.05 0.11 0.22

12.9 11.8 25.112.9 11.8 25.1

Boccaccio et al Boccaccio et al Nature Nature 2005;434:396-4002005;434:396-400


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

● Using either XR5118 (Using either XR5118 (PAI-1 inhibitorPAI-1 inhibitor) or Rofecoxib ) or Rofecoxib (Vioxx;(Vioxx; COX-2 inhibitorCOX-2 inhibitor) resulted in inhibition of ) resulted in inhibition of clinical and laboratory evidence for DIC in miceclinical and laboratory evidence for DIC in mice


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

● Using either XR5118 (Using either XR5118 (PAI-1 inhibitorPAI-1 inhibitor) or Rofecoxib ) or Rofecoxib (Vioxx;(Vioxx; COX-2 inhibitorCOX-2 inhibitor) resulted in inhibition of ) resulted in inhibition of clinical and laboratory evidence for DIC in miceclinical and laboratory evidence for DIC in mice




2. “2. “PtenPten and Hypoxia Regulate Tissue Factor and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Expression and Plasma Coagulation By

Glioblastoma”Glioblastoma”► PtenPten = Tumor suppressor with lipid and protein = Tumor suppressor with lipid and protein

phosphatase activityphosphatase activity

► Loss or inactivation of Loss or inactivation of Pten Pten (70-80% of (70-80% of glioblastomas) leads to Akt activation and glioblastomas) leads to Akt activation and upregulation of upregulation of Ras/MEK/ERKRas/MEK/ERK signaling cascade signaling cascade

2. “2. “PtenPten and Hypoxia Regulate Tissue Factor and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Expression and Plasma Coagulation By

Glioblastoma”Glioblastoma”► PtenPten = Tumor suppressor with lipid and protein = Tumor suppressor with lipid and protein

phosphatase activityphosphatase activity

► Loss or inactivation of Loss or inactivation of Pten Pten (70-80% of (70-80% of glioblastomas) leads to Akt activation and glioblastomas) leads to Akt activation and upregulation of upregulation of Ras/MEK/ERKRas/MEK/ERK signaling cascade signaling cascade

Rong, Brat et.al. Rong, Brat et.al. Ca ResCa Res 2005;65:1406-1413 2005;65:1406-1413

► Glioblastomas characterized histologically by Glioblastomas characterized histologically by “pseudopalisading necrosis” “pseudopalisading necrosis”

► Thought to be wave of tumor cells migrating away Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by from a central hypoxic zone, perhaps created by thrombosisthrombosis

► Pseudopalisading cells produce VEGF and IL-8 Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growth and drive angiogenesis and rapid tumor growth

► TF expressed by >90% of grade 3 and 4 malignant TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2)astrocytomas (but only 10% of grades 1 and 2)

► Glioblastomas characterized histologically by Glioblastomas characterized histologically by “pseudopalisading necrosis” “pseudopalisading necrosis”

► Thought to be wave of tumor cells migrating away Thought to be wave of tumor cells migrating away from a central hypoxic zone, perhaps created by from a central hypoxic zone, perhaps created by thrombosisthrombosis

► Pseudopalisading cells produce VEGF and IL-8 Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growth and drive angiogenesis and rapid tumor growth

► TF expressed by >90% of grade 3 and 4 malignant TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of grades 1 and 2)astrocytomas (but only 10% of grades 1 and 2)

““PtenPten and Hypoxia Regulate Tissue Factor Expression and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”and Plasma Coagulation By Glioblastoma”

Results:Results:

1.1. Hypoxia and Hypoxia and PTEN PTEN loss loss TF (mRNA, Ag and TF (mRNA, Ag and procoagulant activity); partially reversed with procoagulant activity); partially reversed with induction of induction of PTEN PTEN

2.2. Both Both AktAkt and and RasRas pathways modulated TF in pathways modulated TF in sequentially transformed astrocytes.sequentially transformed astrocytes.

3.3. Ex vivo Ex vivo data: data: TF (by immunohistochemical TF (by immunohistochemical staining) in pseudopalisades of # 7 human staining) in pseudopalisades of # 7 human glioblastoma specimensglioblastoma specimens

Results:Results:

1.1. Hypoxia and Hypoxia and PTEN PTEN loss loss TF (mRNA, Ag and TF (mRNA, Ag and procoagulant activity); partially reversed with procoagulant activity); partially reversed with induction of induction of PTEN PTEN

2.2. Both Both AktAkt and and RasRas pathways modulated TF in pathways modulated TF in sequentially transformed astrocytes.sequentially transformed astrocytes.

3.3. Ex vivo Ex vivo data: data: TF (by immunohistochemical TF (by immunohistochemical staining) in pseudopalisades of # 7 human staining) in pseudopalisades of # 7 human glioblastoma specimensglioblastoma specimens


Both Akt and Ras Pathways Modulate TF Both Akt and Ras Pathways Modulate TF Expression By Transformed AstrocytesExpression By Transformed Astrocytes

Rong, Brat et.al. Rong, Brat et.al. Ca ResCa Res 2005;65:1406-1413 2005;65:1406-1413

N=NormoxiaN=Normoxia

H=hypoxiaH=hypoxia

pseudopalisadingnecrosis

Vascular Endothelium

H&E

TF Immuno-histochemistry


Rong, Brat et.al. Ca Res 2005;65:1406-1413


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

► Activation of K-Activation of K-ras ras oncogene and inactivation of oncogene and inactivation of p53 p53 tumor tumor suppressor suppressor TF expression in TF expression in human human colorectal cancer cellscolorectal cancer cells

► Transforming events dependent on MEK/MAPK and PI3KTransforming events dependent on MEK/MAPK and PI3K► Cell-associated and MP-associated TF activity linked to Cell-associated and MP-associated TF activity linked to

genetic status of cancer cellsgenetic status of cancer cells► TF siRNA reduced cell surface TF expression, tumor growth TF siRNA reduced cell surface TF expression, tumor growth

and angiogenesis and angiogenesis

► TF may be required for K-TF may be required for K-ras-ras-driven phenotypedriven phenotype

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

► Activation of K-Activation of K-ras ras oncogene and inactivation of oncogene and inactivation of p53 p53 tumor tumor suppressor suppressor TF expression in TF expression in human human colorectal cancer cellscolorectal cancer cells

► Transforming events dependent on MEK/MAPK and PI3KTransforming events dependent on MEK/MAPK and PI3K► Cell-associated and MP-associated TF activity linked to Cell-associated and MP-associated TF activity linked to

genetic status of cancer cellsgenetic status of cancer cells► TF siRNA reduced cell surface TF expression, tumor growth TF siRNA reduced cell surface TF expression, tumor growth

and angiogenesis and angiogenesis

► TF may be required for K-TF may be required for K-ras-ras-driven phenotypedriven phenotype

Yu, Mackman, Rak et.al. Yu, Mackman, Rak et.al. Blood Blood 2005;105:1734-412005;105:1734-41

““Oncogenic Events Regulate Tissue Factor Expression In Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression Colorectal Cancer Cells: Implications For Tumor Progression

And Angiogenesis”And Angiogenesis”TF expression in cancer cells parallels genetic tumor progression

with an impact of K-ras and p53 status

““Oncogenic Events Regulate Tissue Factor Expression In Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Progression Colorectal Cancer Cells: Implications For Tumor Progression

And Angiogenesis”And Angiogenesis”TF expression in cancer cells parallels genetic tumor progression

with an impact of K-ras and p53 status



0

50

100

150

200

250

300

350

400

450

HKh-2 HCT116 379.2

0

20

40

60

80

100

120

140

160

HKh-2 HCT116 379.2Mea

n C

ha

nn

el T

F F

lou

res

cen

ce

Mea

n C

ha

nn

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F F

lou

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cen

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TF

Ac

tiv

ity

(U

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TF

Ac

tiv

ity

(U

/1066

cell

s)

cel

ls)

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

““Oncogenic Events Regulate Tissue Factor Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Expression In Colorectal Cancer Cells:

Implications For Tumor Progression And Implications For Tumor Progression And Angiogenesis”Angiogenesis”

Effect of TF si mRNA on tumor growth in vitro and in vivo

““Oncogenic Events Regulate Tissue Factor Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Expression In Colorectal Cancer Cells:

Implications For Tumor Progression And Implications For Tumor Progression And Angiogenesis”Angiogenesis”

Effect of TF si mRNA on tumor growth in vitro and in vivo



0

2

4

6

8

10

12

14

HCT116 SI-2 SI-3 MG only

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

““Oncogenic Events Regulate Tissue Factor Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells”Expression In Colorectal Cancer Cells”


%V

WF

-Pos

itive

Are

a%

VW

F-P

ositi

ve A

rea

““Oncogenic Events Regulate Tissue Factor Expression In Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Colorectal Cancer Cells: Implications For Tumor

Progression And Angiogenesis”Progression And Angiogenesis”

Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology

““Oncogenic Events Regulate Tissue Factor Expression In Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For Tumor Colorectal Cancer Cells: Implications For Tumor

Progression And Angiogenesis”Progression And Angiogenesis”

Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology



Mechanisms of Cancer-Induced Thrombosis: Mechanisms of Cancer-Induced Thrombosis: ImplicationsImplications



3.3. Potential importance for cancer Potential importance for cancer therapy?therapy?



3.3. Potential importance for cancer Potential importance for cancer therapy?therapy?

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

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

3. Can anticoagulation alter the biology of cancer?3. Can anticoagulation alter the biology of cancer?

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

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

3. Can anticoagulation alter the biology of cancer?3. Can anticoagulation alter the biology of cancer?

Cancer and Thrombosis Cancer and Thrombosis Year 2008 State-of-the-Science UpdateYear 2008 State-of-the-Science Update


Key QuestionsKey Questions Key QuestionsKey Questions

1. 1. Epidemiologic evidence is Epidemiologic evidence is suggestivesuggestive that VTE is a that VTE is a bad prognostic sign in cancerbad prognostic sign in cancer

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

3. Results of recent, randomized clinical trials of LMWH 3. Results of recent, randomized clinical trials of LMWH in cancer patients indicate superiority in preventing in cancer patients indicate superiority in preventing recurrent VTE and suggest increased survival (not recurrent VTE and suggest increased survival (not due to just preventing VTE)— due to just preventing VTE)— “Titillating”“Titillating”

1. 1. Epidemiologic evidence is Epidemiologic evidence is suggestivesuggestive that VTE is a that VTE is a bad prognostic sign in cancerbad prognostic sign in cancer

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

3. Results of recent, randomized clinical trials of LMWH 3. Results of recent, randomized clinical trials of LMWH in cancer patients indicate superiority in preventing in cancer patients indicate superiority in preventing recurrent VTE and suggest increased survival (not recurrent VTE and suggest increased survival (not due to just preventing VTE)— due to just preventing VTE)— “Titillating”“Titillating”

Tentative AnswersTentative AnswersTentative AnswersTentative Answers



Coagulation Cascade and Tumor BiologyCoagulation Cascade and Tumor Biology

TFTF ThrombinThrombin




Clotting-dependent

FibrinFibrin


PARsPARs

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

VIIaVIIaXaXa

Angiogenesis, Tumor Angiogenesis, Tumor Growth and MetastasisGrowth and Metastasis

??

LMWH LMWH (e.g. dalteparin)(e.g. dalteparin)

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

Linking Science to Clinical PracticeLinking Science to Clinical Practice

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

Linking Science to Clinical PracticeLinking Science to Clinical Practice

Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies









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

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 deathVTE is the second leading cause of death in in hospitalized cancer patientshospitalized cancer patients1,21,2

► The risk of VTE in cancer patients undergoing The risk of VTE in cancer patients undergoing surgery is surgery is 3- to 5-fold higher3- to 5-fold higher than those without than those without cancercancer22

► Up to Up to 50% of cancer patients50% 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 for recurrent DVT/PE that persists for high risk for recurrent DVT/PE that persists for many yearsmany years44

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

► The risk of VTE in cancer patients undergoing The risk of VTE in cancer patients undergoing surgery is surgery is 3- to 5-fold higher3- to 5-fold higher than those without than those without cancercancer22

► Up to Up to 50% of cancer patients50% 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 for recurrent DVT/PE that persists for high risk for recurrent DVT/PE that persists for many yearsmany years44

Clinical Features of VTE in CancerClinical Features of VTE in Cancer

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

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

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

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

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

within 2 yearswithin 2 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

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

Hospital Mortality With or Without VTEHospital Mortality With or Without VTE

Khorana, JCO, 2006Khorana, JCO, 2006

7.98

10.59

8.67

14.8516.13 16.41

02468

1012141618

All Non-metastatic Metastatic

No VTE VTE

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

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.

Thrombosis Risk In CancerThrombosis Risk In Cancer

Primary ProphylaxisPrimary Prophylaxis

► Medical InpatientsMedical Inpatients

► SurgerySurgery

► RadiotherapyRadiotherapy

► Central Venous CathetersCentral Venous Catheters

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

● Systemic therapySystemic therapy● Central venous cathetersCentral venous catheters (~4% generate clinically (~4% generate clinically

relevant VTE)relevant VTE)

► PatientPatient● Prior VTEPrior VTE● Co-morbitiesCo-morbities● Genetic backgroudGenetic backgroud

► 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

● Systemic therapySystemic therapy● Central venous cathetersCentral venous catheters (~4% generate clinically (~4% generate clinically

relevant VTE)relevant VTE)

► PatientPatient● Prior VTEPrior VTE● Co-morbitiesCo-morbities● Genetic backgroudGenetic backgroud

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

Medical InpatientsMedical Inpatients

Cancer and ThrombosisCancer and Thrombosis

Thromboembolism in Hospitalized Thromboembolism in Hospitalized Neutropenic Cancer PatientsNeutropenic Cancer Patients

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

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

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

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


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)


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.

PharmacologicPharmacologic(Prophylaxis & Treatment)(Prophylaxis & Treatment)

Low MolecularLow MolecularWeight HeparinWeight Heparin

(LMWH)(LMWH)

NonpharmacologicNonpharmacologic(Prophylaxis)(Prophylaxis)

UnfractionatedUnfractionatedHeparin (UH)Heparin (UH)

OralOral AnticoagulantsAnticoagulants

ElasticElasticStockingsStockings

InferiorInferiorVena CavaVena Cava

FilterFilter

IntermittentIntermittentPneumaticPneumatic

CompressionCompression

Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices

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

Prophylaxis Studies in Medical PatientsProphylaxis Studies in Medical Patients

Francis, NEJM, 2007Francis, NEJM, 2007

14.9

5

10.5

5.5

2.8

5.6

0

5

10

15

20

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%





ASCO GuidelinesASCO Guidelines

1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITH

CANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FOR

VTE PROPHYLAXISVTE PROPHYLAXIS??

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

1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITH

CANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FOR

VTE PROPHYLAXISVTE PROPHYLAXIS??

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

Lyman, JCO, 2007Lyman, JCO, 2007

Surgical PatientsSurgical Patients


► 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

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, abstract OC191, ISTH 2003Agnelli, abstract OC191, ISTH 2003

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


0%

5%

10%

15%

20%

UFH 5000 U tid

enoxaparin 40 mg

VTE Major Bleeding

In

cid

ence

of

Ou

tco

me

Eve

nt

ENOXACAN ENOXACAN 14.7%14.7%

2.9% 4.1%2.9% 4.1%

18.2%

N=319N=319

N=312N=312

ENOXACAN Study Group. Br J Surg 1997;84:1099–103

P>0.05P>0.05

0%

5%

10%

15%

20%

UFH 5000 U tid

enoxaparin 40 mg

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

cid

ence

of

Ou

tco

me

Eve

nt

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


Extended prophylaxisExtended prophylaxis► Abdominal or pelvic surgery for cancerAbdominal or pelvic surgery for cancer

► LMWH for ~ 7 days vs. 28 days post-opLMWH for ~ 7 days vs. 28 days post-op

► Routine bilateral venography at ~day 28Routine bilateral venography at ~day 28

Extended prophylaxisExtended prophylaxis► Abdominal or pelvic surgery for cancerAbdominal or pelvic surgery for cancer

► LMWH for ~ 7 days vs. 28 days post-opLMWH for ~ 7 days vs. 28 days post-op

► Routine bilateral venography at ~day 28Routine bilateral venography at ~day 28

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


StudyStudy NN DesignDesign RegimensRegimens

ENOXACAN IIENOXACAN II 332332 Double-blindDouble-blind Enoxaparin vs. placeboEnoxaparin vs. placebo

FAME FAME (subgroup)(subgroup) 198198 Open-labelOpen-label Dalteparin vs. no prophylaxisDalteparin vs. no prophylaxis

0%

5%

10%

15%

placebo

enoxaparin 40 mg

VTE Prox Any Major DVT 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

cide

nce

of O

utco

me

Eve

nt

N=167

N=165

0% 0.4%

12.0%

4.8%

NNT = 140.6%

3.6%

Extended Prophylaxis inExtended Prophylaxis inSurgical PatientsSurgical Patients

► 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 Investigators—Major Abdominal Surgery: FAME Investigators—Dalteparin ExtendedDalteparin Extended

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

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, JCO, 2007Lyman, JCO, 2007

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)

• • Incidence up to 60% from historical dataIncidence up to 60% from historical data

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

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)

• • Incidence up to 60% from historical dataIncidence up to 60% from historical data

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

Central Venous CathetersCentral Venous Catheters

Geerts W, et al. Geerts W, et al. ChestChest 2001;119:132S-175S 2001;119:132S-175S

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

StudyStudy RegimenRegimen NN CRT (%)CRT (%)

Reichardt* Reichardt* 20022002

Dalteparin 5000 U odDalteparin 5000 U odplaceboplacebo

285285140140

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

Couban*Couban*20022002

Warfarin 1mg odWarfarin 1mg odplaceboplacebo

130130125125

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

ETHICSETHICS††

20042004Enoxaparin 40 mg odEnoxaparin 40 mg od

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 al. 2002;100:703a; Agnelli G, et al. Proc ASCOProc ASCO 2004;23:7302004;23:730

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

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

77thth ACCP Consensus Guidelines ACCP Consensus Guidelines

Geerts W, et al. Geerts W, et al. ChestChest 2004; 126: 338S-400S 2004; 126: 338S-400S

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

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

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.)

Ambulatory Chemotherapy PatientsAmbulatory Chemotherapy PatientsAmbulatory Chemotherapy PatientsAmbulatory Chemotherapy Patients


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

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

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%

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 stratificationNeed for risk stratificationNeed for risk stratification

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


► 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

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


Patient CharacteristicsPatient Characteristics

CharacteristicCharacteristic No. (%)No. (%)

All patientsAll patients 3,1963,196

Age Age >> 65 65 1,243 (39)1,243 (39)

FemaleFemale 2,136 (67)2,136 (67)

Stage IVStage IV 1,150 (37)1,150 (37)

Performance status 0-1Performance status 0-1 2,912 (91)2,912 (91)

Pre-chemotherapy platelet count Pre-chemotherapy platelet count >> 350,000/mm350,000/mm33 691 (22)691 (22)


Site of CancerSite of Cancer No. (%)No. (%)

All patientsAll patients 3,1963,196

BreastBreast 1,137 (36)1,137 (36)

LungLung 612 (19)612 (19)

ColonColon 353 (11)353 (11)

OvaryOvary 225 (7)225 (7)

Upper GIUpper GI 91 (3)91 (3)

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma 287 (9)287 (9)

Hodgkin’s diseaseHodgkin’s disease 53 (2)53 (2)

OthersOthers 438 (14)438 (14)

Patient Characteristics (2)Patient Characteristics (2)


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 (

%)


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


VT

E (

%)

/ 2.

4 m

onth

sV

TE

(%

) /

2.4

mon

ths


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

denc

e O

f V

TE

Ove

r 2.

4 In

cide

nce

Of

VT

E O

ver

2.4

Mon

ths(

%)

Mon

ths(

%)


Risk Factors: Multivariate AnalysisRisk Factors: Multivariate Analysis

CharacteristicCharacteristic OROR P valueP value


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


Predictive ModelPredictive Model

Patient CharacteristicPatient Characteristic ScoreScore


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

Risk ScoreRisk Score 00 11 22 33 44

NN 1,3521,352 974974 476476 160160 3333

VTE(%) /2.4 mo.sVTE(%) /2.4 mo.s 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

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

VTE Treatment VTE Treatment


Vitamin K antagonist (INR 2.0 - 3.0)Vitamin K antagonist (INR 2.0 - 3.0)

>> 3 months 3 months

LMWH or UFH LMWH or UFH

5 to 7 days5 to 7 daysInitial treatment

Long-term therapy

Standard Treatment of VTEStandard Treatment of VTECan We Do Better Than This?Can We Do Better Than This?

Recurrent VTE in CancerRecurrent VTE in Cancer

Recurrent VTERecurrent VTEEvents per 100 patient yearsEvents per 100 patient years P valueP value

MalignantMalignant Non- MalignantNon- Malignant

27.127.1 9.09.0 0.0030.003

Hutten et.al. Hutten et.al. J Clin Oncol J Clin Oncol 2000;18:3078 2000;18:3078

Subset Analysis of the Home Treatment Studies Subset Analysis of the Home Treatment Studies

(UH/VKA vs. LMWH/VKA)(UH/VKA vs. LMWH/VKA)

Recurrent VTE in CancerRecurrent VTE in Cancer

Major BleedingMajor BleedingEvents per 100 patient yearsEvents per 100 patient years P-valueP-value

MalignantMalignant Non-Non-malignantmalignant

13.313.3 2.12.1 0.0020.002

Hutten et.al. Hutten et.al. J Clin Oncol J Clin Oncol 2000;18:3078 2000;18:3078

Subset Analysis of the Home Treatment StudiesSubset Analysis of the Home Treatment Studies

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?

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

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

DalteparinDalteparin

DalteparinDalteparin Oral AnticoagulantOral Anticoagulant


[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

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


OACOAC

Recurrent VTERecurrent VTE

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

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

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 336336

336336991717

6644

39394141

CANTHENOXCANTHENOX(Meyer 2002)(Meyer 2002)

EnoxaparinEnoxaparinOACOAC 33

67677171

11112121

771616

11112323

LITELITE(Hull ISTH 2003)(Hull ISTH 2003)

TinzaparinTinzaparinOACOAC 33

80808787

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

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)

Buller et.al. Chest Suppl 2004;126:401S-428SBuller et.al. Chest Suppl 2004;126:401S-428S

New DevelopmentNew Development

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


OACOAC

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


Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

Lee A, et al. ASCO. 2003Lee A, et al. ASCO. 2003

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100


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


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

Lee A, et al. ASCO. 2003Lee A, et al. ASCO. 2003

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

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

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

5

89

3833

42

52

0

10

20

30

40

50

60

70

80

90

100

FRONTLINESurgical

FRONTLINE:Medical

Stratton Bratzler Rahim DVT FREE

5

89

3833

42

52

0

10

20

30

40

50

60

70

80

90

100

FRONTLINESurgical

FRONTLINE:Medical

Stratton Bratzler Rahim DVT FREE

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 o

f A

pp

rop

riat

e P

rop

hyl

axis

, %

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

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

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

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

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


► Guidelines for VTE preventionGuidelines for VTE prevention


► Opportunities for improvementOpportunities for improvement

► Guidelines for VTE TreatmentGuidelines for VTE Treatment


• 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

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 1A)that 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 1A)that 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 gradeIndicates that benefits outweigh risks, burdens, and costs,

with consistent RCT level of evidence

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 VTE► Familial thrombophilia► Active cancer► Trauma► Major surgical procedures► Acute or chronic medical illness requiring

hospitalization or prolonged bed rest► Central venous catheter/IV catheter► Congestive heart failure► Pregnancy► Regional bulky lymphadenopathy with

extrinsic vascular compression

AGENTS ASSOCIATED 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 ?

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 times dailyUnfractionated heparin 5,000 units subcutaneous 3 times daily

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 times dailyUnfractionated heparin 5,000 units subcutaneous 3 times daily


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

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

► 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.

► 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.

► 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.


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

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

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 Use of Predictors of the Use of ThromboprophylaxisThromboprophylaxis

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

Computer Reminder SystemComputer Reminder System

► Computer program linked to patient database to identify Computer program linked to patient database to identify consecutive hospitalized patients at risk for VTEconsecutive hospitalized patients at risk for VTE

► Patients randomized to intervention group or control groupPatients randomized to intervention group or control group

► In the intervention group the physicians were alerted to the VTE In the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxisrisk and offered the option to order VTE prophylaxis

► Point scale for VTE riskPoint scale for VTE risk● Major riskMajor risk: : CancerCancer, prior VTE, hypercoagulability, prior VTE, hypercoagulability

(3 points)(3 points)● Intermediate riskIntermediate risk: Major surgery (2 points): Major surgery (2 points)● Minor riskMinor risk: Advanced age, obesity, bedrest, HRT,: Advanced age, obesity, bedrest, HRT,

use of oral contraceptives (1 point)use of oral contraceptives (1 point)

► VTE prophylaxis (VTE prophylaxis (graduated elastic stockingsgraduated elastic stockings, IPC, UFH, , IPC, UFH, LMWH, warfarin)LMWH, warfarin)

► Computer program linked to patient database to identify Computer program linked to patient database to identify consecutive hospitalized patients at risk for VTEconsecutive hospitalized patients at risk for VTE

► Patients randomized to intervention group or control groupPatients randomized to intervention group or control group

► In the intervention group the physicians were alerted to the VTE In the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxisrisk and offered the option to order VTE prophylaxis

► Point scale for VTE riskPoint scale for VTE risk● Major riskMajor risk: : CancerCancer, prior VTE, hypercoagulability, prior VTE, hypercoagulability

(3 points)(3 points)● Intermediate riskIntermediate risk: Major surgery (2 points): Major surgery (2 points)● Minor riskMinor risk: Advanced age, obesity, bedrest, HRT,: Advanced age, obesity, bedrest, HRT,

use of oral contraceptives (1 point)use of oral contraceptives (1 point)

► VTE prophylaxis (VTE prophylaxis (graduated elastic stockingsgraduated elastic stockings, IPC, UFH, , IPC, UFH, LMWH, warfarin)LMWH, warfarin)

Kucher N, et al. N Engl J Med. 2005;352:969-77Kucher N, et al. N Engl J Med. 2005;352:969-77

MD Computer AlertMD Computer Alert

Electronic Alerts to Prevent VTEElectronic Alerts to Prevent VTE

88

90

92

94

96

98

100

0 30 60 90

88

90

92

94

96

98

100

0 30 60 90

Fre

edom

fro

m

DV

T o

r P

E (

%)

Number at riskIntervention group 1,255 977 900 853Control group 1,251 876 893 839

Control groupControl group

Intervention groupIntervention group

P<0.001

Time (days)

Kucher N, et al. N Engl J Med. 2005;352:969-77Kucher N, et al. N Engl J Med. 2005;352:969-77

Mechanical Thromboprophylaxis In Critically Ill Patients: Mechanical Thromboprophylaxis In Critically Ill Patients: Review And Meta-analysisReview And Meta-analysis

RESULTSRESULTS: 21 relevant studies (5 randomized controlled trials, 13 : 21 relevant studies (5 randomized controlled trials, 13 observational studies, and 3 surveys) were found. A total of 811 patients observational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patients were randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies. participated in the observational studies.

Trauma patients only were enrolled in 4 randomized controlled trials and 4 Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. Meta-analysis of 2 randomized controlled trials with observational studies. Meta-analysis of 2 randomized controlled trials with similar populations and outcomes revealed that use of compression and similar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venous pneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).

A range of methodological issues, including bias and confounding variables, A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult. make meaningful interpretation of the observational studies difficult.

CONCLUSIONSCONCLUSIONS: The role of mechanical approaches to : The role of mechanical approaches to thromboprophylaxis for intensive care patients remains thromboprophylaxis for intensive care patients remains uncertainuncertain

RESULTSRESULTS: 21 relevant studies (5 randomized controlled trials, 13 : 21 relevant studies (5 randomized controlled trials, 13 observational studies, and 3 surveys) were found. A total of 811 patients observational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patients were randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies. participated in the observational studies.

Trauma patients only were enrolled in 4 randomized controlled trials and 4 Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. Meta-analysis of 2 randomized controlled trials with observational studies. Meta-analysis of 2 randomized controlled trials with similar populations and outcomes revealed that use of compression and similar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venous pneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90).

A range of methodological issues, including bias and confounding variables, A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult. make meaningful interpretation of the observational studies difficult.

CONCLUSIONSCONCLUSIONS: The role of mechanical approaches to : The role of mechanical approaches to thromboprophylaxis for intensive care patients remains thromboprophylaxis for intensive care patients remains uncertainuncertain

Limbus A et al. Am J Crit Care, 2006;15:402-10Limbus A et al. Am J Crit Care, 2006;15:402-10

Dahan et al, 1986 (41) 1/132 3/131 0.33 (0.03 to 3.14)

Garlund at al, 1996 (35) 3/5776 12/5917 0.26 (0.07 to 0.91)

Leizorovic et al, 2004 (23) 0/1829 2/1807 0.20 (0.01 to 4.11)

Mahe et al, 2005 (22) 10/1230 17/1244 0.59 (0.27 to 1.29)

Cohen at, 2006 (42) 0/321 5/323 0.09 (0.01 to 1.65)

Total (95% CI) 0.38 (0.21 to 0.69)

Total events 14 39

Dahan et al, 1986 (41) 1/132 3/131 0.33 (0.03 to 3.14)

Garlund at al, 1996 (35) 3/5776 12/5917 0.26 (0.07 to 0.91)

Leizorovic et al, 2004 (23) 0/1829 2/1807 0.20 (0.01 to 4.11)

Mahe et al, 2005 (22) 10/1230 17/1244 0.59 (0.27 to 1.29)

Cohen at, 2006 (42) 0/321 5/323 0.09 (0.01 to 1.65)

Total (95% CI) 0.38 (0.21 to 0.69)

Total events 14 39

Dentali, F. et. al. Ann Intern Med 2007;146:278-288Dentali, F. et. al. Ann Intern Med 2007;146:278-288Dentali, F. et. al. Ann Intern Med 2007;146:278-288Dentali, F. et. al. Ann Intern Med 2007;146:278-288

Fatal Pulmonary Embolism During Fatal Pulmonary Embolism During Anticoagulant ProphylaxisAnticoagulant Prophylaxis

0.001 0.01 0.1 1.0 10 100 1000Favors Treatment Favors PlaceboFavors Treatment Favors Placebo

Study,

Year (Reference)

Study,

Year (Reference)

Prophylaxis

n/n

Prophylaxis

n/n

Placebo

n/n

Placebo

n/n

RR Fixed

(95% CI)

RR Fixed

(95% CI)

RR Fixed

(95% CI)

RR Fixed

(95% CI)

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

Meta-analysis: 12 Meta-analysis: 12 RCTsRCTs

► 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:


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: 12 Meta-analysis: 12 RCTsRCTs

► 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:


● TID event rate: TID event rate:


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

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 UFH

DVT Risk

Study Reduction (95% CI) Weight %

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

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

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

Bergmann & Neuhart 0.94 (0.39-2.26) 8.1

et al, 1996

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

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

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

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

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

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 UFH 5,000 units TID

is more effective in is 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)

► 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 UFH 5,000 units TID

is more effective in is 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)

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

Reasons for Non-Compliance

4

28

68

0

10

20

30

40

50

60

70

80

Off Floor Refused Unknown

Per

cent

Reasons for Non-Compliance

4

28

68

0

10

20

30

40

50

60

70

80

Off Floor Refused Unknown

Per

cent

Compliance with UFH TID

9582

29

0102030405060708090

100

< 3dosesDay 1

< 3DosesDay 2+

4 doses

Per

cent

Compliance with UFH TID

9582

29

0102030405060708090

100

< 3dosesDay 1

< 3DosesDay 2+

4 doses

Per

cent

• 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

• 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

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 %

25%

75%

Inpatient Outpatient

25%

75%

Inpatient Outpatient

VTE Event Location

48%

49%49%

50%

50%

51%51%

52%

Prophylaxis None

48%

49%49%

50%

50%

51%51%

52%

Prophylaxis None

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

DVT, PE Diagnosis and TreatmentDVT, PE Diagnosis and Treatment


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

PRESS RELEASE: May 2, 2007PRESS RELEASE: May 2, 2007

FDA Approves Dalteparin as First Low-Molecular Weight Heparin for Extended FDA Approves Dalteparin as First Low-Molecular Weight Heparin for Extended Treatment to Reduce the Recurrence of Blood Clots in Patients with CancerTreatment to Reduce the Recurrence of Blood Clots in Patients with Cancer


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)


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)


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


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


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

► 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.


► 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.”


6.1

4

8.1

12.7

0

2

4

6

8

10

12

14

Acute(n=72)

Bridge(n=241)

Long term(n=460)

Other(n=134)

LOS

, Day

s

7.9%

26.6%

50.7%

14.8%

0%

10%

20%

30%

40%

50%

60%

70%

Acute (n=72) Bridge (n=241) Long Term(n=460)

Other (n=134)

Therapy

Per

cen

t (%

)

7.9%

26.6%

50.7%

14.8%

0%

10%

20%

30%

40%

50%

60%

70%

Acute (n=72) Bridge (n=241) Long Term(n=460)

Other (n=134)

Therapy

Per

cen

t (%

)

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

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

2212 patients with proximal vein thrombosis assessed for eligibility

2212 patients with proximal vein thrombosis assessed for eligibility

737 Randomized

737 Randomized

1475 excluded for anticoagulant violations

or inability to give written consent

1475 excluded for anticoagulant violations

or inability to give written consent

369 assigned to LMWH369 assigned to LMWH 369 assigned to usual care with heparin & warfarin369 assigned to usual care with heparin & warfarin

3 lost to follow=up

1 withdrew consent

3 lost to follow=up

1 withdrew consent

3 lost to follow-up

5 withdrew consent

3 lost to follow-up

5 withdrew consent

369 included in Analysis369 included in Analysis 369 included in Analysis369 included in Analysis

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

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

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

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

Documents

Welcome to this Science-to-Strategy Summit