new frontiers and evolving paradigms in cancer and thrombosis optimizing prevention, risk...

New Frontiers and Evolving New Frontiers and Evolving Paradigms Paradigms inin Cancer Cancer andand

ThrombosisThrombosis

Optimizing Prevention, Risk Assessment, and Optimizing Prevention, Risk Assessment, and Management of Thrombotic Complications in Management of Thrombotic Complications in

Malignancy: What Do the Trials Teach Us? Malignancy: What Do the Trials Teach Us? How Should the Science Guide Us?How Should the Science Guide Us?

Program ChairmanProgram ChairmanSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MD

Cardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s Hospital

Professor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School

A Year 2010 Milestone SummitA Year 2010 Milestone Summit

Program FacultyProgram Faculty

Program ChairmanProgram ChairmanSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School Craig Kessler, MDCraig Kessler, MDProfessor of MedicineProfessor of MedicineDepartment of HematologyDepartment of HematologyAnticoagulation ServicesAnticoagulation ServicesGeorgetown University Medical Georgetown University Medical CenterCenterWashington, DCWashington, DC

Alok A. Khorana, MD, FACPAlok A. Khorana, MD, FACPVice-Chief, Division of Vice-Chief, Division of Hematology/Oncology Associate Hematology/Oncology Associate Professor of Medicine and Oncology Professor of Medicine and Oncology James P. Wilmot Cancer CenterJames P. Wilmot Cancer CenterUniversity of RochesterUniversity of RochesterRochester, NYRochester, NY Frederick R. Rickles, MDFrederick R. Rickles, MDClinical Professor of Medicine, Pediatrics, Clinical Professor of Medicine, Pediatrics, Pharmacology and PhysiologyPharmacology and PhysiologyDivision of Hematology-OncologyDivision of Hematology-OncologyDepartment of MedicineDepartment of MedicineThe George Washington University The George Washington University School of School of Medicine and Health SciencesMedicine and Health SciencesWashington, DCWashington, DC

Program AgendaProgram Agenda

8:15 PM — 8:30 PM8:15 PM — 8:30 PMProgram Chairman’s Concluding Vision Program Chairman’s Concluding Vision Statement: Current and Near Future Statement: Current and Near Future Perspectives of VTE Management in the Perspectives of VTE Management in the Setting of Malignancy Setting of Malignancy Translating Scientific Advances into Clinical PracticeTranslating Scientific Advances into Clinical Practice

Program ChairmanProgram Chairman Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular Division │ Brigham and Women’s Hospital │ Cardiovascular Division │ Brigham and Women’s Hospital │ Professor of Medicine │ Harvard Medical SchoolProfessor of Medicine │ Harvard Medical School

8:30 PM — 8:45 PM8:30 PM — 8:45 PMInteractive Q&A and Discussion SessionInteractive Q&A and Discussion Session

DisclosuresDisclosures

Research SupportResearch Support

BMS; Boehringer-Ingelheim; Eisai; BMS; Boehringer-Ingelheim; Eisai; Johnson & Johnson, Sanofi-Aventis Johnson & Johnson, Sanofi-Aventis

ConsultantConsultant

Boehringer-Ingelheim; BMS; Eisai; Boehringer-Ingelheim; BMS; Eisai; EKOS: Medscape; Merck; Pfizer; EKOS: Medscape; Merck; Pfizer; Sanofi-AventisSanofi-Aventis

New Frontiers and Evolving New Frontiers and Evolving

Paradigms Paradigms

in Cancer And Thrombosisin Cancer And ThrombosisEpidemiology, Trials, GuidelinesEpidemiology, Trials, Guidelines

A Year 2010 Milestone SummitA Year 2010 Milestone Summit

Program ChairmanProgram ChairmanSamuel Z. Goldhaber, MDSamuel Z. Goldhaber, MD

Cardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s Hospital

Professor of MedicineProfessor of MedicineHarvard Medical SchoolHarvard Medical School

EpidemiologyEpidemiology

New Frontiers New Frontiers andand Evolving Paradigms Evolving Paradigms inin Cancer Cancer andand Thrombosis Thrombosis

As Number of Cancer Survivors As Number of Cancer Survivors Increase, VTE Rates Increase Increase, VTE Rates Increase

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

VTE Risk and Cancer Type: VTE Risk and Cancer Type: “Solid and Liquid”“Solid and Liquid”

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

4.54.5443.53.5332.52.5221.51.5110.50.5

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

Rate of PE Diagnosis Rate of PE Diagnosis is Increasing in the USAis Increasing in the USA

CHEST 2009; 136: 983-990CHEST 2009; 136: 983-990

250,000

200,000

150,000

100,000

50,000

0

1998 1999 2000 2001 2002 2003 2004 20051998 1999 2000 2001 2002 2003 2004 2005

Total cohortTotal cohortSurgical patientsSurgical patientsNon-surgical patientsNon-surgical patients

229,637229,637

163,096163,096

66,54166,541

36,07836,078

90,46890,468

126,546126,546

Hospital Costs are Skyrocketing Hospital Costs are Skyrocketing

CHEST 2009; 136: 983-990CHEST 2009; 136: 983-990

DVT: Ominous SequellaeDVT: Ominous Sequellae

► 30% recur over 10 years (after 30% recur over 10 years (after anticoagulation is discontinued)anticoagulation is discontinued)

► More than ½ of DVTs result in chronic More than ½ of DVTs result in chronic venous insufficiencyvenous insufficiency

► Leads to PE, potentially fatalLeads to PE, potentially fatal

► 1% to 4% of PEs evolve chronic 1% to 4% of PEs evolve chronic thromboembolic pulmonary hypertension thromboembolic pulmonary hypertension (CTEPH)(CTEPH)

Recurrent VTE is Common After A First Recurrent VTE is Common After A First Episode of Symptomatic DVTEpisode of Symptomatic DVT

00 11 22 33 44 55 66 77 8800

55

1010

1515

2020

2525

3030

CumulativeCumulativeIncidence (%)Incidence (%)

YearsYearsPrandoni et al, Prandoni et al, Ann Intern MedAnn Intern Med 1996;125:1-7 1996;125:1-7

355 patients followed for 8 years355 patients followed for 8 years

Stages of Chronic Venous Stages of Chronic Venous InsufficiencyInsufficiency

1.1. Varicose veinsVaricose veins

2.2. Ankle/ leg edemaAnkle/ leg edema

3.3. Stasis dermatitisStasis dermatitis

4.4. LipodermatosclerosisLipodermatosclerosis

5.5. Venous stasis ulcerVenous stasis ulcer

Progression of Progression of Chronic Venous InsufficiencyChronic Venous Insufficiency

From UpToDate 2006

U.S.A.U.S.A.SURGEON SURGEON GENERAL:GENERAL:

CALL TO ACTION CALL TO ACTION TO PREVENT TO PREVENT DVT AND PEDVT AND PE

September 15, September 15, 20082008

100,000-180,000 Deaths/year in USA

http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call-to-action-on-dvt-2008.pdf

Lang, I. M. NEJM 2004;350:2236-2238Lang, I. M. NEJM 2004;350:2236-2238

CTEPHCTEPH

RECURRENT RECURRENT ACUTE PEACUTE PE

DVT FREE RegistryDVT FREE Registry

5,451 patients enrolled prospectively5,451 patients enrolled prospectively● Consecutive acute DVT diagnosed by Consecutive acute DVT diagnosed by

venous ultrasonography venous ultrasonography ● No exclusionsNo exclusions● 183 participating sites in the U.S183 participating sites in the U.S..

Goldhaber SZ, Tapson VF. Am J Cardiol 2004;93:259-262.Goldhaber SZ, Tapson VF. Am J Cardiol 2004;93:259-262.

DVT FREE Registry DVT FREE Registry (N=5,541):(N=5,541):TOP 5 Medical ComorbiditiesTOP 5 Medical Comorbidities

1.1. HypertensionHypertension

2.2. ImmobilityImmobility

3.3. CancerCancer

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

5.5. Cigarette SmokingCigarette Smoking

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

Pivotal VTE Pivotal VTE Primary Prevention TrialsPrimary Prevention Trials


Trials of VTE Prophylaxis in Trials of VTE Prophylaxis in Hospitalized Medical PatientsHospitalized Medical Patients

► MEDENOX (enoxaparin 40 mg)MEDENOX (enoxaparin 40 mg)● Samama MM, et al. N Engl J Med. Samama MM, et al. N Engl J Med.

1999;341:793-800.1999;341:793-800.► PREVENT (dalteparin 5000 IU)PREVENT (dalteparin 5000 IU)

● Leizorovicz A, et al. Circulation. Leizorovicz A, et al. Circulation. 2004;110:874-879.2004;110:874-879.

► ARTEMIS (fondaparinux 2.5 mg)ARTEMIS (fondaparinux 2.5 mg)● Cohen AT, et al. Cohen AT, et al. ● BMJ 2006; 332: 325BMJ 2006; 332: 325..

PREVENT-Dalteparin Trial PREVENT-Dalteparin Trial (N=3,681)(N=3,681)

► A multicenter, randomized, controlled A multicenter, randomized, controlled study in acutely ill medical patients study in acutely ill medical patients

► Compared the incidence in the dalteparin Compared the incidence in the dalteparin and placebo groups ofand placebo groups of::● Any symptomatic VTEAny symptomatic VTE● Asymptomatic proximal DVT Asymptomatic proximal DVT ● Sudden deathSudden death

Circulation 2004; 110: 874-879Circulation 2004; 110: 874-879

Ran

dom

izati

on

•• Dalteparin 5000 Units SC once daily (12-Dalteparin 5000 Units SC once daily (12-14 d)14 d)

•• Placebo SC once daily (12-14 d)Placebo SC once daily (12-14 d)

PREVENT Study Design PREVENT Study Design (N=3,681)(N=3,681)

Follow-up period Treatment period

Day 14 Day 90

Day 21 Primary endpoint/ Bilateral leg U/S

Dalteparin

Placebo

No study drug

No study drug

Primary Efficacy Endpoint: Primary Efficacy Endpoint: VTE (Day 21)VTE (Day 21)

73

4.96%42

2.77%

P = 0.0015

0.38 to 0.80-3.57 to -0.8195% CI

0.55-2.19

RiskRatio

Difference in Incidence

(%)

Dalteparin N=1518 Placebo

N=1473

Circulation 2004; 110: 874-879Circulation 2004; 110: 874-879

Dalteparin Benefit Similar Dalteparin Benefit Similar Across Subgroups Across Subgroups

► AgeAge

► GenderGender

► Cancer Cancer

► ObesityObesity

► Previous DVTPrevious DVT

Quality Improvement Initiative to Quality Improvement Initiative to Improve VTE ProphylaxisImprove VTE Prophylaxis

► Randomized controlled trial to Randomized controlled trial to issue or withhold electronic alerts issue or withhold electronic alerts to MDs whose high-risk patients to MDs whose high-risk patients were not receiving VTE prophylaxiswere not receiving VTE prophylaxis

Kucher N et al. NEJM 2005; 352: 969

Computer ProgramComputer Program

► We developed a computer program We developed a computer program linked to the patient database that linked to the patient database that screened the system daily to identify screened the system daily to identify high-risk patients.high-risk patients.

► We included consecutive high-risk We included consecutive high-risk patients on medical and surgical patients on medical and surgical services who were not receiving DVT services who were not receiving DVT prophylaxis.prophylaxis.

Kucher N et al. NEJM 2005; 352: 969

Definition: “High Risk”Definition: “High Risk”

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 3 3 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

RandomizationRandomization

VTE risk score > 4No prophylaxis

N = 2,506

INTERVENTION:Single alertN = 1,255

CONTROLNo computer alert

N = 1,251

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

Baseline CharacteristicsBaseline Characteristics

► Median age:Median age: 62.5 years 62.5 years► Medical services:Medical services: 83%83%► Surgical services:Surgical services: 17%17%► ComorbiditiesComorbidities

● Cancer:Cancer: 80%80%● Hypertension:Hypertension: 34%34%● Infection:Infection: 30%30%● Prior VTE:Prior VTE: 20% 20%


Primary End PointPrimary End Point

InterventionControl

Number at risk1255 977 900 8531251 976 893 839

InterventionIntervention

Control Control

Time Time ((daysdays))0 30 60 90

%Fr

eedom

fro

m D

VT/

%Fr

eedom

fro

m D

VT/ PEPE

90

92

94

96

98

100


Pivotal VTE Treatment Trial Pivotal VTE Treatment Trial in Patients with Cancerin Patients with Cancer


Cancer and VTECancer and VTE

► 3-fold higher recurrence and bleeding, 3-fold higher recurrence and bleeding, when treating cancer patients when treating cancer patients (Prandoni. (Prandoni. Blood 2002; 100: 3484)Blood 2002; 100: 3484)

► LMWH Monotherapy LMWH Monotherapy halves recurrence, halves recurrence, compared with warfarin. compared with warfarin.

FDA approved May 2007FDA approved May 2007

Lee AYY. NEJM 2003; 349:146Lee AYY. NEJM 2003; 349:146

““CLOT Trial”CLOT Trial”

► Dalteparin monotherapy for 6 months Dalteparin monotherapy for 6 months was more effective (8.8% vs. 17% was more effective (8.8% vs. 17% recurrence) than warfarin in recurrence) than warfarin in 672 cancer 672 cancer patients with DVT.patients with DVT.

► Dalteparin dose: Dalteparin dose: 200 u/kg daily 1200 u/kg daily 1stst month, then 150 u/kg daily.month, then 150 u/kg daily.

Agnes Lee, et al. NEJM 2003; 349:146-153)Agnes Lee, et al. NEJM 2003; 349:146-153)

Dalteparin Reduces VTE Recurrence Dalteparin Reduces VTE Recurrence in Cancer Patients in Cancer Patients (N = 676)(N = 676)

NEJM 2003; 349:146-153NEJM 2003; 349:146-153

CLOT TRIAL

LMWH MonotherapyLMWH Monotherapy

► Cancer patients with DVT/PECancer patients with DVT/PE► Any patient who fails warfarin Any patient who fails warfarin

(has recurrent DVT/PE) despite (has recurrent DVT/PE) despite target INRtarget INR

► Difficulty maintaining target INRDifficulty maintaining target INR► Poor GI absorption of medsPoor GI absorption of meds► Alopecia or rash from CoumadinAlopecia or rash from Coumadin► ““Bridging”Bridging”

ACCP VTE Rx in Cancer: Guidelines ACCP VTE Rx in Cancer: Guidelines 88thth Edition Edition

1.1. At least 3 months of LMWH.At least 3 months of LMWH.

2.2. Then administer LMWH or warfarin Then administer LMWH or warfarin as long as the cancer is active. as long as the cancer is active.

3.3. Indefinite duration anticoagulation Indefinite duration anticoagulation after 2after 2ndnd unprovoked VTE. unprovoked VTE.

CHEST 2008; 133: 454SCHEST 2008; 133: 454S

ConclusionsConclusions

1.1. Cancer and VTE are closely linked.Cancer and VTE are closely linked.

2.2. Cancer increases VTE risk and may Cancer increases VTE risk and may be occult when VTE is diagnosed.be occult when VTE is diagnosed.

3.3. Cancer patients are at high risk for Cancer patients are at high risk for VTE but receive less prophylaxis VTE but receive less prophylaxis than any other at-risk group of than any other at-risk group of hospitalized patients.hospitalized patients.

4.4. Dalteparin 5,000 U/d is effective Dalteparin 5,000 U/d is effective for VTE prophylaxis in cancer for VTE prophylaxis in cancer patients.patients.

Conclusions (Continued)Conclusions (Continued)

5.5. Dalteparin 200 U/kg/day is Dalteparin 200 U/kg/day is effective for treatment of acute effective for treatment of acute VTE as monotherapy without VTE as monotherapy without warfarin. warfarin.

6.6. NCCN, ASCO, and ACCP NCCN, ASCO, and ACCP guidelines endorse VTE guidelines endorse VTE prevention with LMWH and VTE prevention with LMWH and VTE treatment of cancer patients with treatment of cancer patients with LMWH alone (monotherapy LMWH alone (monotherapy without warfarin).without warfarin).

The Role of the Coagulation The Role of the Coagulation Cascade in Malignant Cascade in Malignant

Transformation Transformation

Can Anticoagulation Affect Cancer Can Anticoagulation Affect Cancer Survival?Survival?

The Role of the Coagulation The Role of the Coagulation Cascade in Malignant Cascade in Malignant

Transformation Transformation

Can Anticoagulation Affect Cancer Can Anticoagulation Affect Cancer Survival?Survival?

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




Genmab, Bayer/Ortho‐McNeil/J & J,Genmab, Bayer/Ortho‐McNeil/J & J,

Pharmacyclics, LeoPharmacyclics, Leo

Speaker’s BureauSpeaker’s Bureau

EisaiEisai

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, ASH Education BookASH Education Book, , 20072007

Interface of Coagulation and CancerInterface of Coagulation and Cancer

TF-rich MPsTF-rich MPs

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

1.1. Pathogenesis?Pathogenesis?

2.2. Biological significance?Biological significance?

3.3. Anticoagulation and cancer survival?Anticoagulation and cancer survival?

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

► EpiphenomenonEpiphenomenon? ?

Is this a generic secondary event Is this a generic secondary event where thrombosis is an incidental where thrombosis is an incidental findingfinding

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

► A Primary Event?A Primary Event?

Linked to malignant transformation Linked to malignant transformation

TF

VEGF

Angiogenesis

Endothelial cellsEndothelial cells

IL-8IL-8

Blood CoagulationActivation

FIBRIN

PAR-2

Angiogenesis

FVII/FVIIaFVII/FVIIa

THROMBINTHROMBIN

Tumor Cell

TF

Falanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16; Ruf. J Thromb Haemost 2007;5:1584

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

Coagulation Cascade and Tumor Coagulation Cascade and Tumor BiologyBiology

TFTF ThrombinThrombin

Clotting-Clotting-dependentdependent


Clotting-Clotting-independentindependent


FibrinFibrin

Clotting-Clotting-independentindependent

PARsPARs

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

VIIaVIIa XaXa

Angiogenesis, Tumor Angiogenesis, Tumor Growth and MetastasisGrowth and Metastasis

In Situ In Situ Localization ofLocalization of Tissue Factor in Vascular Endothelium Tissue Factor in Vascular Endothelium of Human Lung Adenocarcinoma – co-localization with vWF of Human Lung Adenocarcinoma – co-localization with vWF

Shoji et al, Amer J Pathol 1998;152:399-411

In Situ In Situ localization of Tissue Factor in Tumor Vascular localization of Tissue Factor in Tumor Vascular Endothelium in Invasive Human Breast Cancer Endothelium in Invasive Human Breast Cancer

Contrino et al. Nature Med 1996;2:209-215

In Situ In Situ Co-Localization of TF and VEGF Co-Localization of TF and VEGF mRNA in Lung Adenocarcinoma mRNA in Lung Adenocarcinoma

Shoji et al. Amer J Pathol 1998;152:399-411

H&EH&E

TFTF

VEGFVEGF

Human melanoma cell lines grown Human melanoma cell lines grown as xenogeneic tumors in SCID miceas xenogeneic tumors in SCID mice

Abe K et al. PNAS 1999;96:8663-8668

©1999 by The National Academy of Sciences

TF high producerTF high producer

TF low producerTF low producer

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

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

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

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

4.4. ThisThisaa and other data on signaling pathways and other data on signaling pathways activated by TF/VIIa engagement of PAR-2activated by TF/VIIa engagement of PAR-2bb and/or thrombin engagement of PAR-1and/or thrombin engagement of PAR-1cc suggest that clotting pathways are directly suggest that clotting pathways are directly involved in regulating tumor growth, involved in regulating tumor growth, angiogenesis and metastasisangiogenesis and metastasis

5.5. Is this a paradigm shift?Is this a paradigm shift?

aa Abe et al Abe et al Proc Nat Acad SciProc Nat Acad Sci 1999;96:8663-68 1999;96:8663-68 bb Ruf et al Ruf et al Nature MedNature Med 2004;10:502-9 2004;10:502-9 cc Karpatkin et al Karpatkin et al Cancer Res Cancer Res 2009;69:3374-812009;69:3374-81

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

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

Epiphenomenon vs. Malignant Transformation?Epiphenomenon vs. Malignant Transformation? Paradigm Shift (2005) Paradigm Shift (2005)

1.1. METMET oncogene induction produces DIC in human oncogene induction produces DIC in human liver carcinomaliver carcinoma (Boccaccio lab) (Boccaccio lab)

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

2.2. PtenPten loss and loss and EGFREGFR amplification produce TF amplification produce TF activation and pseudopalisading necrosis through activation and pseudopalisading necrosis through JunD/Activator Protein-1 in human glioblastoma JunD/Activator Protein-1 in human glioblastoma (Bratt lab)(Bratt lab)

(Rong et al (Rong et al Cancer Res 2005;65:1406-1413; 2005;65:1406-1413; Cancer Res 2009;69:2540-9)2009;69:2540-9)

3.3. K-K-rasras oncogene, oncogene, p53p53 inactivation and TF induction inactivation and TF induction in human colorectal carcinoma; TF and in human colorectal carcinoma; TF and angiogenesis regulation in epithelial tumors by angiogenesis regulation in epithelial tumors by EGFR (ErbB1)EGFR (ErbB1) – relationship to EMTs – relationship to EMTs (Rak lab) (Rak lab)

(Yu et al (Yu et al Blood 2005;105:1734-1741; Milson et al 2005;105:1734-1741; Milson et al Cancer Res 2008;68:10068-76)2008;68:10068-76)

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

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

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


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 = tumor suppressor with lipid and

protein phosphatase activityprotein phosphatase 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 RasRas/MEK/ERK/MEK/ERK signaling signaling cascade cascade

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

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

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

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

► TF expressed by >90% of grade 3 and 4 TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% of malignant astrocytomas (but only 10% of grades 1 and 2)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 TF (mRNA, Ag and procoagulant activity); partially and procoagulant activity); partially reversed with induction of reversed with induction of PTEN PTEN

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

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


Pseudopalisading necrosis

Vascular Endothelium

H&EH&E

TF IHC


Activation of Blood Coagulation Activation of Blood Coagulation in Cancer: Malignant Transformain Cancer: Malignant Transformationtion

3. “Oncogenic Events Regulate Tissue Factor 3. “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”

► 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 phenotype driven phenotype

Yu et al Yu et al Blood 2005;105:1734-412005;105:1734-41

““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 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


Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung Similar amplification of TF with upregulated VEGF induced by mutated EGFR in glioblastoma and lung cancer cells; accompanied by epithelial-to-mesenchymal transition (EMT)cancer cells; accompanied by epithelial-to-mesenchymal transition (EMT) Milsom et al Milsom et al CA Res 2008;68:10068-762008;68:10068-76


MicroparticlesMicroparticles

• Originate directly from membrane surface of activated or Originate directly from membrane surface of activated or apoptotic cellapoptotic cell

• Express surface antigens derived from parent cellExpress surface antigens derived from parent cell• AnucleateAnucleate• <1 µm in diameter<1 µm in diameter• Procoagulant activityProcoagulant activity

mediated by TF and/or PSmediated by TF and/or PS

Burnier L et al. Thromb Haemost 2009;101:439-451

Cumulative incidence of VTE in cancer patients with Cumulative incidence of VTE in cancer patients with (--) /without ( (--) /without ( ) circulating TF-bearing microparticles ) circulating TF-bearing microparticles

Zwicker et al. Clin Cancer Res 2009;15:6830-40

Microparticle TF PCA in Microparticle TF PCA in Cancer Patients ± VTECancer Patients ± VTE

Manly DA, et al. Thromb Res 2010;125:511-512


► QQ: What do these experiments tell us?: What do these experiments tell us?

► AA: They suggest two things:: They suggest two things:● Tumor cell-derived, Tumor cell-derived, TF-rich TF-rich

microparticlesmicroparticles (MPs) may be important (MPs) may be important as a predictive test for VTEas a predictive test for VTE

● All patients with oncogene-driven All patients with oncogene-driven cancer may need prophylactic cancer may need prophylactic anticoagulation anticoagulation

Mechanisms of Cancer-Induced Mechanisms of Cancer-Induced Thrombosis: ImplicationsThrombosis: Implications

1.1. Pathogenesis?Pathogenesis?

2.2. Biological significance?Biological significance?

3.3. Anticoagulation and cancer Anticoagulation and cancer survival ?survival ?

Anticoagulants and SurvivalAnticoagulants and Survival

► Inconclusive evidence to dateInconclusive evidence to date► Experimental data supportive of Experimental data supportive of

antitumor effects but exact mechanisms antitumor effects but exact mechanisms not establishednot established

► Clinical trials provide supportive data for Clinical trials provide supportive data for LMWH but are heterogeneous in design LMWH but are heterogeneous in design and methodology:and methodology:● Tumour typesTumour types● Stage or course of diseaseStage or course of disease● Treatment history or concurrent cancer Treatment history or concurrent cancer

therapiestherapies● LMWH agentsLMWH agents● Doses and regimens of LMWHsDoses and regimens of LMWHs

A Lee ICTHIC, 2010A Lee ICTHIC, 2010

Survival Effect of AnticoagulantsSurvival Effect of Anticoagulants

Kuderer N et al. Cancer 2007;110:1149-60.

► Multicentre, double-blind, placebo-controlled RCTMulticentre, double-blind, placebo-controlled RCT► Advanced lung, breast, GI, pancreas, ovary, H+NAdvanced lung, breast, GI, pancreas, ovary, H+N► Nadroparin vs placebo for duration of chemo (up to Nadroparin vs placebo for duration of chemo (up to

4m)4m)

NadroparinNadroparin PlaceboPlacebo P-valueP-value NNT/HNNT/H

No. PatientsNo. Patients 769769 381381

1° endpoint: VTE + 1° endpoint: VTE + ATEATE 2.0%2.0% 3.9%3.9% 0.02*0.02* 5454

Major bleedingMajor bleeding 0.7%0.7% 00 0.180.18 154154

DeathDeath 4.3%4.3% 4.2%4.2%

1-yr mortality1-yr mortality 43%43% 41%41%

Agnelli et al. Lancet 2009;10:943-949.

PROTECHT StudyPROTECHT Study

*1-sided

Prophylaxis in Pancreatic CancerProphylaxis in Pancreatic Cancer

Riess et al. ASCO May 2009 and ISTH July 2009. Maraveyas et al. Presented at ESMO 2009.

0%

2%

4%

6%

8%

10%

no treatment enoxaparin

VTE bleeding

P<0.01

P=0.6

0%

10%

20%

30%

40%

no treatment dalteparin

VTE fatal PE Gr 3 bleed

P<0.02

P=0.03

NS

CONKO 004 FRAGEM

No survival difference

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

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

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

Key QuestionsKey Questions Key QuestionsKey Questions

Cancer and Thrombosis Cancer and Thrombosis Year 2010 State-of-the-Science UpdateYear 2010 State-of-the-Science Update


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

2. 2. Experimental evidence is 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. 3. Results of recent, randomized clinical trials of Results of recent, randomized clinical trials of LMWHs in cancer patients indicate superiority to LMWHs in cancer patients indicate superiority to oral agents in preventing recurrent VTE; oral agents in preventing recurrent VTE; increasing survival (increasing survival (notnot due to prevention of VTE) due to prevention of VTE) not clearnot clear



Tentative AnswersTentative Answers

Survival StudiesSurvival Studies► INPACT (NSCLC, prostate, pancreatic)INPACT (NSCLC, prostate, pancreatic)

● nadroparin + chemo vs. chemonadroparin + chemo vs. chemo

► ABEL (limited SCLC)ABEL (limited SCLC)● bemiparin + chemo vs. chemobemiparin + chemo vs. chemo

► TILT (nonsmall cell lung cancer)TILT (nonsmall cell lung cancer)● tinzaparin + chemo vs chemotinzaparin + chemo vs chemo

► FRAGMATIC (newly diagnosed lung cancer)FRAGMATIC (newly diagnosed lung cancer)● dalteparin + chemo vs chemodalteparin + chemo vs chemo

LMWH in CancerLMWH in Cancer

A Lee ICTHIC, 2010A Lee ICTHIC, 2010 Stay tuned !Stay tuned !

Optimizing Risk Assessment and Optimizing Risk Assessment and Management of Cancer Patients at Management of Cancer Patients at Risk for Venous Thromboembolism Risk for Venous Thromboembolism

(VTE)(VTE)

Reducing DVT Recurrence and Related Reducing DVT Recurrence and Related ComplicationsComplications


Craig Kessler, MDCraig Kessler, MDProfessor of MedicineProfessor of Medicine

Department of HematologyDepartment of HematologyAnticoagulation ServicesAnticoagulation Services

Georgetown University Medical CenterGeorgetown University Medical CenterWashington, DCWashington, DC

COI Financial DisclosuresCOI Financial Disclosures

Grant/Research Support: Grant/Research Support: GlaxoSmithKline, sanofi-aventis, EisaiGlaxoSmithKline, sanofi-aventis, Eisai

Consultant: Consultant: sanofi-aventis, Eisai sanofi-aventis, Eisai

OutlineOutline

► Guidelines for VTE prevention in Guidelines for VTE prevention in cancer patientscancer patients

► Opportunities for improvementOpportunities for improvement► Guidelines for VTE TreatmentGuidelines for VTE Treatment► LMWHs—What Do the Trials, NCCN LMWHs—What Do the Trials, NCCN

and ASCO Guidelines Teach Us and ASCO Guidelines Teach Us About Duration of Therapy and About Duration of Therapy and Patients at Risk?Patients at Risk?

Recommendations for Venous Thromboembolism Prophylaxis and Treatment

in Patients with Cancer

ASCO Clinical Practice Guideline •www.nccn.org

•NCCN Clinical Practice Guidelines in Oncology™

•Guidelines for supportive care

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

Importance of Guidelines Importance of Guidelines to Clinical Outcomesto Clinical Outcomes

““Clinicians armed with appropriate Clinicians armed with appropriate assessments and the best evidence-based assessments and the best evidence-based practice guidelines can reduce some of the practice guidelines can reduce some of the unpleasant and frequent side-effects that unpleasant and frequent side-effects that often accompany cancer and often accompany cancer and chemotherapy treatment, obtain the best chemotherapy treatment, obtain the best possible clinical outcomes, and avoid possible clinical outcomes, and avoid unnecessary costs.”unnecessary costs.”

Statement from Centers for Medicare and Medicaid Services, Statement from Centers for Medicare and Medicaid Services, August 2005August 2005

Venous Thromboembolism Venous Thromboembolism in Cancer Patientsin Cancer Patients

Of all cases of VTE:Of all cases of VTE: 20% occur in cancer patients20% occur in cancer patients

Of all cancer patients:Of all cancer patients: 0.5% will have symptomatic VTE0.5% will have symptomatic VTE As high as 50% have VTE at autopsyAs high 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

VTE may be the presenting sign of occult VTE may be the presenting sign of occult malignancymalignancy10% with idiopathic VTE develop cancer within 10% with idiopathic VTE develop cancer within

2 years2 years20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE25% have bilateral DVT25% have bilateral DVT

Lee & Levine. Circulation 2003;107:I17 – I21; Bura et. al., J Thromb Haemost 2004;2:445-Bura et. al., J Thromb Haemost 2004;2:445-5151

Cancer and Venous ThromboembolismCancer and Venous ThromboembolismThe Need for Risk StratificationThe Need for Risk Stratification

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

1 2 3 4 5 6

Diagnosis

Chemotherapy

Hospitalization

Remission

End of Life

Metastasis

Average Risk

Time

Rela

tive

Risk

VTE = venous thromboembolism; CA = cancer; OR = odds ratio. Silver In: The Hematologist - modified from Blom JW, et. al. JAMA. 2005;293:715-722.

Effect of Malignancy on Risk of VTEEffect of Malignancy on Risk of VTE

• 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

00

10

20

30

40

50

Hem

atol

ogic

alH

emat

olog

ical

Lung

Lung

Gas

troi

ntes

tinal

Gas

troi

ntes

tinal

Bre

ast

Bre

ast

Dis

tant

Dis

tant

met

asta

ses

met

asta

ses

0 to

3 m

onth

s0

to 3

mon

ths

3 to

12

mon

ths

3 to

12

mon

ths

1 to

3 y

ears

1 to

3 y

ears

5 to

10

year

s5

to 1

0 ye

ars

> 1

5 ye

ars

> 1

5 ye

ars

2828

22.222.220.320.3

4.94.9

19.819.8

53.553.5

14.314.3

2.62.6 1.11.13.63.6

Type of cancer Time since cancer diagnosis

Adju

sted

odd

s ra

tio

MEGA = Multiple Environmentaland Genetic Assessment case-control study

The Importance of DVT Prophylaxis The Importance of DVT Prophylaxis in Patients With Cancer: ASCO Guidelinesin Patients With Cancer: ASCO Guidelines

► VTE is a leading causes of death in CA, occurring in 4% VTE is a leading causes of death in CA, occurring in 4% to 20% patientsto 20% patients

► Hospitalized CA pt and those on chemo tx have greatest Hospitalized CA pt and those on chemo tx have greatest VTE risk VTE risk

● Cancer increased the risk of VTE 4.1-foldCancer increased the risk of VTE 4.1-fold● Chemotherapy increased the risk 6.5-foldChemotherapy increased the risk 6.5-fold

► Major risk factors: older age, comorbid conditions, Major risk factors: older age, comorbid conditions, recent surgery or hospitalization, active chemotherapy recent surgery or hospitalization, active chemotherapy or hormonal therapyor hormonal therapy

► All hospitalized CA patients should be considered for All hospitalized CA patients should be considered for prophylaxisprophylaxis

► Patients with cancer undergoing surgery should be Patients with cancer undergoing surgery should be considered for prophylaxisconsidered for prophylaxis

► LMWH is the preferred drugLMWH is the preferred drugLyman GH, et al. J Clin Oncol. 2007;25:5490-5505.

Updated ASCO Guidelines Updated ASCO Guidelines Hospitalized Patients with CancerHospitalized Patients with Cancer

Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence

Patients with cancer should be Patients with cancer should be considered candidates for VTE considered candidates for VTE prophylaxis with anticoagulants prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in (UFH, LMWH, or fondaparinux) in the absence of bleeding or other the absence of bleeding or other contraindications to anticoagulationcontraindications to anticoagulation

Multiple RCTs of hospitalized Multiple RCTs of hospitalized medical patients with subgroups of medical patients with subgroups of patients with cancer. The 8th ACCP patients with cancer. The 8th ACCP guidelines strongly recommend guidelines strongly recommend (1A) prophylaxis with either low-(1A) prophylaxis with either low-dose heparin or LMWH for dose heparin or LMWH for bedridden patients with active bedridden patients with active cancer.cancer.

VOLUME 25 NUMBER 34 DECEMBER 1 2007

Prophylaxis in Cancer PatientsProphylaxis in Cancer Patients

Cancer patients undergoing surgical procedures: routine Cancer patients undergoing surgical procedures: routine thromboprophylaxis that is appropriate for the type of thromboprophylaxis that is appropriate for the type of surgery (Grade 1A)surgery (Grade 1A)

Cancer patients who are bedridden with an acute medical Cancer patients who are bedridden with an acute medical illness: routine thromboprophylaxis as for other high-risk illness: routine thromboprophylaxis as for other high-risk medical patients (Grade 1A)medical patients (Grade 1A)

Cancer patients receiving chemotherapy or hormonal Cancer patients receiving chemotherapy or hormonal therapy: recommend against the routine use of therapy: recommend against the routine use of thromboprophylaxis for the primary prevention of VTE thromboprophylaxis for the primary prevention of VTE (Grade 1C)(Grade 1C)

Cancer patients overall: recommend against the routine Cancer patients overall: recommend against the routine use use of primary thromboprophylaxis to try to improve survival of primary thromboprophylaxis to try to improve survival (Grade 1B) (Grade 1B)

Geerts WH, et al. Chest. 2008;133(6 suppl):381S-453S.

2008 ACCP Prevention of Venous Thromboembolism Practice 2008 ACCP Prevention of Venous Thromboembolism Practice GuidelinesGuidelines

Therapeutic Anticoagulation Treatment for Therapeutic Anticoagulation Treatment for VenousThromboembolismVenousThromboembolism

► The NCCN panel recommends VTE The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such cancer who do not have contraindications to such therapytherapy

► Panel also emphasized that an increased level of Panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for clinical suspicion of VTE should be maintained for cancer patients. cancer patients.

► Following hospital discharge, it is recommended that Following hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation.to 4 weeks post-operation.

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

CaveatsCaveats

► No randomized controlled trials (RCTs) No randomized controlled trials (RCTs) designed ad hoc for hospitalized medical designed ad hoc for hospitalized medical cancer patients are availablecancer patients are available

► Recommendations are based on RCTs of Recommendations are based on RCTs of acutely ill medical patients, involving a acutely ill medical patients, involving a small proportion of patients with cancersmall proportion of patients with cancer

► No bleeding data are reported specifically No bleeding data are reported specifically in the subgroup of patients with cancer in the subgroup of patients with cancer

MEDENOX1

StudyStudy RRRRRR Thromboprophylaxis Thromboprophylaxis Patients with VTE (%)Patients with VTE (%)

14.9

5.5

5.0

2.8

10.5

5.6

1Samama MM, et al. N Engl J Med. 1999;341:793-800.2 Leizorovicz A, et al. Circulation. 2004;110:874-9.3Cohen AT, et al. BMJ 2006; 332: 325-329.

P < 0.001

P = 0.0015

RRR

63%

45%

47%

Placebo

Placebo

Placebo

Enoxaparin 40 mg

Dalteparin 5,000 units

Fondaparinux 2.5 mg

ARTEMIS3

PREVENT2

Anticoagulant Prophylaxis to Prevent Anticoagulant Prophylaxis to Prevent Screen-Detected VTEScreen-Detected VTE

High Risk Hospitalized Medical PatientsHigh Risk Hospitalized Medical Patients

(Hull RD et al. Ann Intern Med 2010; 153:8)

EXCLAIM: Extended-duration Enoxaparin EXCLAIM: Extended-duration Enoxaparin Prophylaxis in High-risk Medical Patients Prophylaxis in High-risk Medical Patients

End pointsEnd points

Outcome, Outcome, extended extended

prophylaxis, prophylaxis, n=2052 (%)n=2052 (%)

Outcome, Outcome, placebo, placebo,

n=2062(%)n=2062(%)

RR RR reduction reduction

(%)(%)pp

Major bleedingMajor bleeding 0.8%0.8% 0.3%0.3%

VTE eventsVTE events 2.52.5 4.04.0 38%38% 0.0010.001

SymptomaticSymptomatic 0.30.3 1.11.1 73%73% 0.0040.004

No SxsNo Sxs 2.52.5 3.73.7 34%34% 0.0320.032

(Most benefit seen in Level 1 Disability Patients (Most benefit seen in Level 1 Disability Patients with bedrest or sedentary without BRP-some with with bedrest or sedentary without BRP-some with

CA) CA)

PRODIGE: Dalteparin for Primary VTE Prophylaxis PRODIGE: Dalteparin for Primary VTE Prophylaxis in Newly Diagnosed Malignant Gliomain Newly Diagnosed Malignant Glioma

► Reduced VTE for Reduced VTE for dalteparin 5,000 anti-Xa dalteparin 5,000 anti-Xa units qd for 6 mos: 11% units qd for 6 mos: 11% vs 17% for placebo vs 17% for placebo

► Increased ICH: 5.1% vs Increased ICH: 5.1% vs 1.2% for placebo 1.2% for placebo

► Both NS significantBoth NS significant

Perry JR et al. JTH 2010;8;1959Perry JR et al. JTH 2010;8;1959

2009 NCCN Guidelines: 2009 NCCN Guidelines: DVT ProphylaxisDVT Prophylaxis

AdultCancer

InpatientContraindication to Anticoagulation Treatment

NoNo

Yes

Pharmacologic ProphylaxisPharmacologic ProphylaxisUFH UFH LMWHLMWHPentasaccharidePentasaccharide

Mechanical ProphylaxisSequential Compression DevicesCompression Stockings

NCCN, National Comprehensive Cancer Network.NCCN. Venous Thromboembolic Disease: Version 1.2006. Available at: http://www.nccn.org/professionals/ physician_gls/PDF/vte.pdf.

Mechanical thromboprophylaxis in critically ill Mechanical thromboprophylaxis in critically ill patients: a systematic review and meta-analysispatients: a systematic review and meta-analysis

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

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

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

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

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

The beneficial role for mechanical thromboprophylaxis in cancer pts is empiric and derived from benefits seen in surgical studies; No controlled studies in cancer patients

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

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;8:381-388.2. Stratton MA et al. Arch Intern Med. 2000;160:334-340. 3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912.

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

Rate

of

Appro

pri

ate

Pro

phyla

xis

, %

Rate

of

Appro

pri

ate

Pro

phyla

xis

, %

Major Major SurgerySurgery22

Major Major Abdominothoracic Abdominothoracic Surgery (Elderly)Surgery (Elderly)33

Medical Medical InpatientsInpatients44

Confirmed DVT Confirmed DVT (Inpatients)(Inpatients)55

Cancer:Cancer: SurgicalSurgical

Cancer: Cancer: MedicalMedical

4. Rahim SA et al. Thromb Res. 2003;111:215-219.5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262.

52

5

Despite Evidence, Medical Patients Despite Evidence, Medical Patients at Risk Remain Unprotectedat Risk Remain Unprotected

Medical Surgical

No. of patients

37,356 30,827

At risk for VTE

42% 64%

Receiving ACCP Tx

40% 59%

ENDORSE1

1. Cohen AT, et al. Presented at: 2007 Congress of the International Society on Thrombosis and Haemostasis; July 6-12, 2007; Geneva, Switzerland.

2. Tapson VF, et al. Chest. 2007;132(3):936-945.

IMPROVE2

United States

Other Countries

No. of patients

3,410 11,746

VTE prophylaxis

1852 (54%) 5788 (49%)

LMWH 476 (14%) 4657 (40%)

UFH 717 (21%) 1014 (9%)

Electronic Alerts to Prevent VTE in Electronic Alerts to Prevent VTE in Hospitalized PatientsHospitalized Patients

P<.001 by the log-rank test for the comparison of the outcome between groups at 90 days.

Reprinted with permission from Kucher N, et al. N Engl J Med. 2005;352:969-977.

0

92

94

98

100

300

Free

dom

Fro

m D

VT

or P

E (%

) 96

600 900Days

90

Intervention group

Control group

P<.001

No. at RiskIntervention group 1255 977 900 853Control group 1251 976 893 839

Ambulatory Patients with Cancer Without Ambulatory Patients with Cancer Without VTE Receiving Systemic ChemotherapyVTE Receiving Systemic Chemotherapy


Routine prophylaxis with an Routine prophylaxis with an antithrombotic agents is not antithrombotic agents is not recommended recommended except as noted belowexcept as noted below

Routine prophylaxis in ambulatory Routine prophylaxis in ambulatory patients receiving chemotherapy is not patients receiving chemotherapy is not recommended due to conflicting trials, recommended due to conflicting trials, potential bleeding, the need for potential bleeding, the need for laboratory monitoring and dose laboratory monitoring and dose adjustment, and the relatively low adjustment, and the relatively low incidence of VTE.incidence of VTE.

LMWH or adjusted dose warfarin (INR LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma ~ 1.5) is recommended in myeloma patients on thalidomide or patients on thalidomide or lenalidomide plus chemotherapy or lenalidomide plus chemotherapy or dexamethasonedexamethasone

This recommendation is based on This recommendation is based on nonrandomized trial data and nonrandomized trial data and extrapolation from studies of extrapolation from studies of postoperative prophylaxis in postoperative prophylaxis in orthopedic surgery and a trial of orthopedic surgery and a trial of adjusted-dose warfarin in breast adjusted-dose warfarin in breast cancercancer

Updated ASCO GuidelinesUpdated ASCO Guidelines

Prospective Study of Adult Cancer Patients Prospective Study of Adult Cancer Patients Receiving Systemic ChemotherapyReceiving Systemic Chemotherapy

Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008).

► Prospective observational study Prospective observational study conducted at 117 randomly conducted at 117 randomly selected US practice sites.selected US practice sites.

► Data obtained on 4,458 Data obtained on 4,458 consecutive adult patients consecutive adult patients initiating a new chemotherapy initiating a new chemotherapy regimen between March 2003 regimen between March 2003 and February 2006. and February 2006.

► There were no exclusions for There were no exclusions for age, prior history or comorbid- age, prior history or comorbidities with nearly 40% of ities with nearly 40% of patients age 65 and older.patients age 65 and older.

Time (Days)

1501401301201101009080706050403020100

Pro

po

rtio

n w

ith

VT

E

.04

.03

.02

.01

0.00

Reported Cause of Early Mortality Reported Cause of Early Mortality Cancer Patients Starting New ChemotherapyCancer Patients Starting New Chemotherapy

Kuderer NM et al; J Clin Oncol 2008 (ASCO 2008)

Cause of Death

No VTE

N=4,365

VTE N=9

3

All N=4,4

58

PD 2.1 2.2 2.1

Infection 0.3 0 0.3

PE 0 5.4 0.1

Pulmonary 0.2 0 0.2

Bleeding 0.1 0 0.1

Other vascular

0.2 0 0.2

Unknown 0.3 0 0.3

All 3.2 7.6 3.3Time (Days)

1501401301201101009080706050403020100

Cu

mla

tive

Su

rviv

al

1.00

.99

.98

.97

.96

.95

.94

.93

.92

.91

.90

[HR=5.48, 95%CI: 2.21-13.61; P<.0001]

VTE

No VTE

RCTs of Thromboprophylaxis in RCTs of Thromboprophylaxis in Ambulatory Cancer Patients: WarfarinAmbulatory Cancer Patients: Warfarin

Double-blind, placebo-controlled RCT demonstrated the Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (INR 1.3-1.9) in patients efficacy of low-intensity warfarin (INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancerreceiving chemotherapy for metastatic breast cancer

311 women with metastatic breast cancer on 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy1st- or 2nd-line chemotherapy

Randomized to 1 mg warfarin for 6 weeks, then warfarin Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebotitrated to INR 1.3-1.9 or placebo

1 VTE in warfarin group vs 7 in placebo arm 1 VTE in warfarin group vs 7 in placebo arm

85% risk reduction, 85% risk reduction, P P = .03, with no increased bleeding= .03, with no increased bleeding

Levine M, et al. Lancet. 1994;343:886-889.

INR=international normalized ratio

Trial N Treatment Chemo

Duration VTE MajorBleedin

g

FAMOUSSolid tumors(Stage III/IV)

385 DalteparinPlacebo

64% 12 months 2.4%3.3%

0.5%0

TOPIC-IBreast(Stage IV)

353 CertoparinPlacebo

100% 6 months 4%4%

1.7%0

TOPIC-2NSCLC(Stage IV)

547 CertoparinPlacebo

100% 6 months 4.5%†

8.3%3.7%2.2%

PRODIGEGlioma

186 DalteparinPlacebo

- 6-12 months

11%17%

5.1%1.2%

SIDERASSolid Tumors(Stage IV)

141 DalteparinPlacebo/Control

54% Indefinitely 5.9%7.1%

2.9%7.1%

PROTECHTSolid Tumors(Stage III/IV)

1166

Nadroparin 2:1 Placebo

100% < 4 monthswith chemo

1.4%2.9%

0.7%0

1. Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948. 2. Haas SK, et al. J Thromb Haemost. 2005(suppl 1):abstract OR059. 3. Perry JR et al. Proc ASCO 2007. 2011 4. Sideras K et al. Mayo Clin Proc 2006; 81:758-767. 5. Agnelli G et al. Am Soc Hemat Sunday December 7, 2008

Low Molecular Weight Heparin in RCTs of Low Molecular Weight Heparin in RCTs of Thromboprophylaxis in Ambulatory Cancer PatientsThromboprophylaxis in Ambulatory Cancer Patients

The PROTECHT StudyThe PROTECHT StudyRCT of Thromboprophylaxis in Cancer Patients Receiving RCT of Thromboprophylaxis in Cancer Patients Receiving

ChemotherapyChemotherapy

DESIGNDESIGN Placebo-controlled, double blind, multicenter RCTPlacebo-controlled, double blind, multicenter RCT Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1Nadroparin 3,800 anti Xa IU daily vs placebo: 2:1 1150 patients receiving chemotherapy for locally 1150 patients receiving chemotherapy for locally

advanced or metastatic cancer. advanced or metastatic cancer. Start with new CTX; continue for maximum of 4 mosStart with new CTX; continue for maximum of 4 mos Mean treatment duration: 90 daysMean treatment duration: 90 days Primary outcome: clinically detected thrombotic events, Primary outcome: clinically detected thrombotic events,

i.e., composite of venous and arterial TE*i.e., composite of venous and arterial TE* Main safety outcome: Major bleedingMain safety outcome: Major bleeding

* deep vein thrombosis of the lower and upper limbs, visceral and * deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic originunexplained death of possible thromboembolic origin

Agnelli G et al: Lancet 2009;10, 930

The PROTECHT StudyThe PROTECHT StudyRCT of Thromboprophylaxis in Cancer Patients Receiving RCT of Thromboprophylaxis in Cancer Patients Receiving

ChemotherapyChemotherapy

► Primary Efficacy Outcome: Any TE Event*Primary Efficacy Outcome: Any TE Event*● Nadroparin: 16 of 769 (2.1%) Nadroparin: 16 of 769 (2.1%) ● Placebo: 15 of 381 (3.9%) Placebo: 15 of 381 (3.9%) ● Relative risk reduction: 47.2%, (interim-adjusted p=0.033)Relative risk reduction: 47.2%, (interim-adjusted p=0.033)● Absolute risk decrease: 1.8%; NNT = 53.8Absolute risk decrease: 1.8%; NNT = 53.8

► Venous thromboembolism (VTE): Venous thromboembolism (VTE): ● Nadroparin: 11 of 769 (1.4%)Nadroparin: 11 of 769 (1.4%)● Placebo: 11 of 381 (2.9%) NSPlacebo: 11 of 381 (2.9%) NS

► Major Bleeding: Major Bleeding: ● Nadroparin: 5 (0.7%)Nadroparin: 5 (0.7%)● Placebo: 0 (p= 0.177)Placebo: 0 (p= 0.177)● Absolute risk increase: 0.7%; NNH = 153.8 Absolute risk increase: 0.7%; NNH = 153.8

Agnelli G et al: Lancet 2009;10:930

RESULTS

33 patients in the nadroparin group and 16 in the placebo group had died; 48 of these deaths were due to disease progression.

LMWH “halves” VTE in ambulatory patients with LMWH “halves” VTE in ambulatory patients with metastatic or locally advanced cancer who are metastatic or locally advanced cancer who are

receiving chemotherapy receiving chemotherapy

PROTECHTPROTECHT All cause All cause

thromboembolic thromboembolic events: 2% events: 2% LMWH vs 3.9% in LMWH vs 3.9% in placeboplacebo

Major bleeding: Major bleeding: 0.7% LMWH vs 0.7% LMWH vs none in placebo none in placebo ((PP=0.18) =0.18)

By the end of By the end of study treatment, study treatment, 33 LMWH deaths 33 LMWH deaths vs 16 in placebo vs 16 in placebo group; 48 of group; 48 of these deaths due these deaths due to CA progression to CA progression

Benefits most Benefits most apparent in apparent in those with those with lung or GI CA lung or GI CA (not (not pancreatic)pancreatic)

1% DVT and 0.4% PE with LMWH (N=769 pts)

1% DVT and 0.4% PE with LMWH (N=769 pts)

2.1% DVT and 0.8% PE with placebo

(N=381 pts)

2.1% DVT and 0.8% PE with placebo

(N=381 pts)

Agnelli G et al. www.thelancet.com/Oncology Oct 2009 Agnelli G et al. www.thelancet.com/Oncology Oct 2009

p=0.02

NNT=53.8

http://www.thelancet.com/Oncology

http://www.thelancet.com/Oncology

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 treatment 0.2%

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

Breast cancer (Stage IV) w/ chemo 8%

Non-Hodgkin’s lymphomas w/ chemo 3%

Hodgkin’s disease w/ chemo 6%

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

High-grade glioma 26%

Multiple myeloma (thalidomide + chemo) 28%

Renal cell carcinoma 43%

Solid tumors (anti-VEGF + chemo) 47%

Wilms tumor (cavoatrial extension) 4%

Arterial Thrombotic Complications Arterial Thrombotic Complications of Myelomaof Myeloma

VAD (n 6, 5.9%)TAD (n 2, 4.5%)PAD (n 3, 6.4%)

N=195 ATE=11

5.6%

Libourel et al. Blood 2010;116:2

4 developed thrombosis while on VKAs;2 on LMWH

Palumbo A et al. Leukemia 2008;22:414

LMWH Warfarin ASA

9 3 9 14 18

15-24 31 (LDW)

3-14

These VTE prophylaxis regimens have not been assessed in any prospective, randomized trial and are recommended based on anecdotal experience

Palumbo A et al. Leukemia 2008;22:414

Naluri SR et al. JAMA. 2008;300:2277

VTE Risk with Bevacizumab in Colorectal Cancer VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in MyelomaApproaches Risk of Antiangiogenesis in Myeloma

Pritchard , J Clin Onc, 1996

02468

10121416

Tamoxifen Tamoxifen + CT

Rate of thrombosis (%)p=0.0001

(n=352) (n=353)

1.4%

9.6%

Tamoxifen and ChemotherapyTamoxifen and Chemotherapy

► 705 postmenopeusal women with breast cancer705 postmenopeusal women with breast cancer► CMF regimenCMF regimen► Total thromboembolic eventsTotal thromboembolic events► 39 of 54 events occurred during chemotherapy39 of 54 events occurred during chemotherapy

Treatment of Patients with Treatment of Patients with Established VTE to Prevent Established VTE to Prevent

Recurrence Recurrence (continued)(continued)


Anticoagulation for an indefinite period Anticoagulation for an indefinite period should be considered for patients with should be considered for patients with active cancer (metastatic disease, active cancer (metastatic disease, continuing chemotherapy)continuing chemotherapy)

In the absence of clinical trials, In the absence of clinical trials, benefits and risks of benefits and risks of continuing LMWH continuing LMWH beyond 6 months is a clinical beyond 6 months is a clinical judgment in the individual patient.judgment in the individual patient. Caution is urged in elderly patients Caution is urged in elderly patients and those with intracranial and those with intracranial malignancy.malignancy.

Inferior vena cava filters are reserved Inferior vena cava filters are reserved for those with contraindications to for those with contraindications to anticoagulation or PE despite anticoagulation or PE despite adequate long-term LMWH.adequate long-term LMWH.

Consensus recommendations due to Consensus recommendations due to lack of date in cancer-specific lack of date in cancer-specific populationspopulations

Treatment of Patients with Established Treatment of Patients with Established VTE to Prevent RecurrenceVTE to Prevent Recurrence


LMWH is the preferred approach for the initial LMWH is the preferred approach for the initial 5-10 days in cancer patient with established 5-10 days in cancer patient with established VTE.VTE.

LMWH for 3-6 months is LMWH for 3-6 months is more effective than vitamin K more effective than vitamin K antagonists given for a antagonists given for a similar duration for similar duration for preventing recurrent VTE.preventing recurrent VTE.

LMWH for at least 6 months is preferred for LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are antagonists with a targeted INR of 2-3 are acceptable when LMWH is not available. The acceptable when LMWH is not available. The CLOT study demonstrated a relative risk CLOT study demonstrated a relative risk reduction of 49% with LMWH vs. a vitamin K reduction of 49% with LMWH vs. a vitamin K antagonist. Dalteparin sodium approved by the antagonist. Dalteparin sodium approved by the FDA for extended treatment of symptomatic FDA for extended treatment of symptomatic VTE to reduce the risk of recurrence of VTE in VTE to reduce the risk of recurrence of VTE in patients with cancerpatients with cancer (FDA 2007) (FDA 2007)

5 to 7 days

Dalteparin 200 IU/kg OD

Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo

Control Group

Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo

Experimental Group

Ran

dom

izati

on

1 month 6 months

The CLOT TrialThe CLOT TrialStudy SchemaStudy Schema

Lee AY, et al. N Engl J Med. 2003;349:146-153.

0

5

10

15

20

25

Days Post RandomizationDays Post Randomization

0 30 60 90 120 150 180 210

Pro

babili

ty o

f R

ecu

rren

t V

TE,

%Pro

babili

ty o

f R

ecu

rren

t V

TE,

%

dalteparin, 9%

VKA, 17%

risk reduction = 52%HR 0.48 (95% CI 0.30, 0.77)log-rank p = 0.002

CLOT Trial:CLOT Trial:Results: Symptomatic Recurrent VTEResults: Symptomatic Recurrent VTE


ResultsDaltepariDaltepari

nnN=338N=338

VKAVKAN=335N=335

p-p-valuevalue

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

Associated with death 1 0

Critical site* 4 3

Transfusion of > 2 units of RBC

or drop in Hb > 20 g/L14 9

Any bleed 46 (13.6%) 62 (18.5%) 0.09

*intracranial, intraspinal, pericardial, retroperitoneal, intra-ocular, intra-articular

CLOT Trial:CLOT Trial:Results: BleedingResults: Bleeding


Overall, these meta-analyses and clinical trials do not Overall, these meta-analyses and clinical trials do not conclusively establish the need for prophylaxis of conclusively establish the need for prophylaxis of

CVC-related thrombosis in cancer patients CVC-related thrombosis in cancer patients

Chaukiyal P et al. Thromb Haemost 2008;99:38

Influence of Thrombophilia on Thrombotic Influence of Thrombophilia on Thrombotic Complications of CVADs in CancerComplications of CVADs in Cancer

In 10 studies involving more than 1250 cancer patients In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls:with CVADs vs CA controls:

CA + FVL OR=5.18 (95% confidence interval: 3.0-CA + FVL OR=5.18 (95% confidence interval: 3.0-8.8) 8.8)

CA + G20210A OR=3.95 (95% confidence interval: 1.5-CA + G20210A OR=3.95 (95% confidence interval: 1.5-10.6)10.6)

The attributable risk of catheter associated thrombosis The attributable risk of catheter associated thrombosis conferred by:conferred by:

FVL 13.5%FVL 13.5%

G20210A 3.6%G20210A 3.6%

In 10 studies involving more than 1250 cancer patients In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls:with CVADs vs CA controls:

CA + FVL OR=5.18 (95% confidence interval: 3.0-CA + FVL OR=5.18 (95% confidence interval: 3.0-8.8) 8.8)

CA + G20210A OR=3.95 (95% confidence interval: 1.5-CA + G20210A OR=3.95 (95% confidence interval: 1.5-10.6)10.6)

The attributable risk of catheter associated thrombosis The attributable risk of catheter associated thrombosis conferred by:conferred by:

FVL 13.5%FVL 13.5%

G20210A 3.6%G20210A 3.6%CAVD = central venous access devicesDentali F, et al. JTH. 2007;5(Suppl 2):P-S-564.

Patient GroupPatient Group RecommendedRecommended Not Not RecommendedRecommended

Hospitalized patients with cancer

VTE prophylaxis with anticoagulantsIf bleeding or contraindication to anticoagulation

Ambulatory patients with cancer receiving chemotherapy

Myeloma patients receiving thalidomide or lenalidomide + chemotherapy/ dexamethasone. LMWH or adjusted dose warfarin.

Otherwise, no routine prophylaxis

Patients with cancer undergoing surgery

Prophylaxis with low-dose UFH or LMWH

Prophylaxis with mechanical methods for patients with contraindications to pharmacologic methods

Consider mechanical methods when contraindications to anticoagulation.

Patients with cancer with established VTE

Pharmacologic treatment for at least 6 months. Consider continued anticoagulation beyond 6 months in those with active cancer.

-

To improve survival - Not recommended

ASCO Recommendations for VTE ASCO Recommendations for VTE Prophylaxis in Patients with CancerProphylaxis in Patients with Cancer

Lyman GH et al: J Clin Oncol 2007; 25:5490-5505

SummarySummary

What the ASCO/NCCN Guidelines What the ASCO/NCCN Guidelines Do Not Tell UsDo Not Tell Us

► What is the role for emerging novel anticoagulant What is the role for emerging novel anticoagulant medications? No comparisons with LMWHmedications? No comparisons with LMWH

► Is there equivalent safety and efficacy between m-Is there equivalent safety and efficacy between m-enoxaparin and Lovenox?enoxaparin and Lovenox?

► Is there a survival advantage to the use of LMWH in Is there a survival advantage to the use of LMWH in cancer patients?cancer patients?

► Is there a role for adjunctive statins with Is there a role for adjunctive statins with anticoagulation in cancer patients?anticoagulation in cancer patients?

► Is there a role for monitoring hypercoagulability Is there a role for monitoring hypercoagulability markers in cancer patients? markers in cancer patients?

► How does palliative care influence the survival and How does palliative care influence the survival and VTE incidence data in cancer patients?VTE incidence data in cancer patients?

► How should incidental VTE be anticoagulated?How should incidental VTE be anticoagulated?► What is the role for retrievable IVC filters in CA What is the role for retrievable IVC filters in CA

patientspatients

Risk Stratification Tools to Identify Risk Stratification Tools to Identify Patients for Primary and Secondary Patients for Primary and Secondary Prevention of VTE in the Setting of Prevention of VTE in the Setting of

MalignancyMalignancy

Screening and VTE Risk Assessment Across the Screening and VTE Risk Assessment Across the Complex Spectrum of Malignant Disorders—Complex Spectrum of Malignant Disorders—

What Works? What Doesn’t?What Works? What Doesn’t?

Alok A. Khorana, MD, FACPAlok A. Khorana, MD, FACPVice-Chief, Division of Hematology/OncologyVice-Chief, Division of Hematology/Oncology

Associate Professor of Medicine and OncologyAssociate Professor of Medicine and OncologyJames P. Wilmot Cancer CenterJames P. Wilmot Cancer Center

University of RochesterUniversity of RochesterRochester, New YorkRochester, New York




sanofi‐aventis, Eisai, Leo Pharmasanofi‐aventis, Eisai, Leo Pharma

Speaker’s BureauSpeaker’s Bureau

sanofi‐aventis, Leo Pharmasanofi‐aventis, Leo Pharma

Grant/Research SupportGrant/Research Support

sanofi‐aventissanofi‐aventis

Risk assessment for VTE in Risk assessment for VTE in cancer patientscancer patients Clinical risk factorsClinical risk factors BiomarkersBiomarkers

Risk assessment toolsRisk assessment tools

Implications for Implications for thromboprophylaxis studiesthromboprophylaxis studies

Secondary prophylaxisSecondary prophylaxis

VTE in Cancer PatientsVTE in Cancer Patients

Risk Factors for VTERisk Factors for VTE

Patient-related factorsPatient-related factors Older age Older age Race, genderRace, gender ComorbiditiesComorbidities

Treatment-related Treatment-related factorsfactors

Hospitalization Hospitalization Chemotherapy Chemotherapy Anti-angiogenicsAnti-angiogenics Major surgeryMajor surgery Erythropoiesis-Erythropoiesis-

stimulating agents stimulating agents TransfusionsTransfusions

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

diagnosis diagnosis

Rao et al., in Rao et al., in Cancer-Associated Thrombosis. Cancer-Associated Thrombosis. (Khorana and Francis, Eds)(Khorana and Francis, Eds) 20072007

Type of Type of cancercancer

Adjusted OR Adjusted OR (95% CI)(95% CI)

Hematologic 28 (4-199.7)28 (4-199.7)

Lung 22.2 (3.6-136.1)22.2 (3.6-136.1)

GI 20.3 (4.9-83)20.3 (4.9-83)

Breast 4.9 (2.3-10.5)4.9 (2.3-10.5)

Prostate 2.2 (0.9-5.4)2.2 (0.9-5.4)

Blom JW et al. Blom JW et al. JAMA JAMA 20052005

VTE and Site of CancerVTE and Site of Cancer

VTE With BevacizumabVTE With Bevacizumab

Bevacizumab(n=1,196)

Control (n=1,083)

Nalluri SR, et al. Nalluri SR, et al. JAMA.JAMA. 2008;300:2277-2285. 2008;300:2277-2285.

Chu D. and Wu S. Chu D. and Wu S. JAMAJAMA 2009; In reply 2009; In reply

RR=1.29 (95% CI, 1.03-RR=1.29 (95% CI, 1.03-1.63)1.63)

Rate

of

VTE (

%)

Rate

of

VTE (

%)

13%13%

9.9%

Bevacizumab (n=3,795)

Control (n=3,167)

6.2%6.2%

4.2%

RR=1.38 (95% CI, 1.12-RR=1.38 (95% CI, 1.12-1.70)1.70)

All-Grade VTEAll-Grade VTE((6 studies)6 studies)

High-Grade VTEHigh-Grade VTE((13 studies)13 studies)

However, when corrected for exposure time, RR =1.1 (95% CI, 0.89-1.36)

Biomarkers for Biomarkers for Cancer-Associated VTECancer-Associated VTE

►Blood countsBlood counts Platelet countPlatelet count Leukocyte countLeukocyte count HemoglobinHemoglobin

►D-dimerD-dimer

►Soluble P-selectinSoluble P-selectin

►Tissue factorTissue factor

►C-reactive proteinC-reactive protein

►Factor VIIIFactor VIII

Incidence of VTE By Quartiles Of Incidence of VTE By Quartiles Of Pre-Chemotherapy Platelet CountPre-Chemotherapy Platelet Count

Khorana AA et al. Khorana AA et al. Cancer Cancer 20052005

0%

1%

2%

3%

4%

5%

6%

<250 250-300 300-350 >350

Pre-chemotherapy Platelet Counts (x1000)Pre-chemotherapy Platelet Counts (x1000)

Inci

dence

Of

VTE O

ver

2.5

Month

s(%

)

Inci

dence

Of

VTE O

ver

2.5

Month

s(%

)

•P =0.005

Incidence of VTE by Pre-Chemotherapy Incidence of VTE by Pre-Chemotherapy Leukocyte CountLeukocyte Count

Khorana AA et al. Khorana AA et al. Blood Blood 20082008

0%0%

1%1%

2%2%

3%3%

4%4%

5%5%

6%6%

<4.5 (n=342)<4.5 (n=342) 4.5-11 (n=3202)4.5-11 (n=3202) >11 (n=513)>11 (n=513)

Pre-chemotherapy WBC Counts (x1000/mmPre-chemotherapy WBC Counts (x1000/mm33))

Inci

dence

Of

VTE O

ver

2.4

In

cidence

Of

VTE O

ver

2.4

Month

sM

onth

s (%

) (

%)

•P =0.0008

Incidence of VTE by Type of LeukocyteIncidence of VTE by Type of Leukocyte

Absolute Neutrophil Absolute Neutrophil Count Count

Absolute Monocyte Absolute Monocyte Count Count

P=0.0001

P<0.0001

Connolly et al ISTH 2009 Abs 1573Connolly et al ISTH 2009 Abs 1573

Pro

port

ion w

ith V

TE

Pro

port

ion w

ith V

TE

Effect Effect of Leukocyte and Platelet Counts of Leukocyte and Platelet Counts on VTE Riskon VTE Risk

In the Vienna CATS registry, platelet count In the Vienna CATS registry, platelet count >>443,000 was associated with VTE 443,000 was associated with VTE (HR3.5)(HR3.5)

Simanek et alSimanek et al, J Thromb Hemost , J Thromb Hemost 20092009

In the REAL-2 study of advanced In the REAL-2 study of advanced GEJ/gastric cancers, leukocytosis was GEJ/gastric cancers, leukocytosis was associated with VTE during associated with VTE during chemotherapy (HR 2.0)chemotherapy (HR 2.0)

Starling et al, Starling et al, J Clin Oncol J Clin Oncol 20092009

Mortality by Pre-chemotherapy Mortality by Pre-chemotherapy Leukocyte CountLeukocyte Count

14.0% (8.9%-21.6%) 14.0% (8.9%-21.6%)

4.4% (3.2%-6.1%) 4.4% (3.2%-6.1%)

P <0.0001P <0.0001

MVA for early mortality: HR 2.0, p = 0.001MVA for early mortality: HR 2.0, p = 0.001

Kuderer et al ASH 2008Kuderer et al ASH 2008Connolly et al ISTH 2009, Connolly et al ISTH 2009, Throm Res Throm Res 20102010

WBC>11x10WBC>11x1099/L/L

WBCWBC<<11x1011x1099/L/L

Time (Days)Time (Days)

Pro

port

ion D

ied

Pro

port

ion D

ied

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 1500 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

0.200.20

0.180.18

0.160.16

0.140.14

0.120.12

0.100.10

0.080.08

0.060.06

0.040.04

0.020.02

0.000.00

Tissue Factor in Cancer: Tissue Factor in Cancer: Lack of Standardized AssaysLack of Standardized Assays

► Immunohistochemistry of tumor Immunohistochemistry of tumor specimensspecimens

► TF ELISATF ELISA

► TF MP procoagulant activity assayTF MP procoagulant activity assay

► Impedance-based flow cytometryImpedance-based flow cytometry

Tissue Factor Expression and VTETissue Factor Expression and VTE

Khorana AA, et al. Clin Cancer Res. 2007;13:2870-2875.

Rate

of

VTE (

%)

Rate

of

VTE (

%)

P = 0.04

Cumulative Incidence of VTE for Cancer Cumulative Incidence of VTE for Cancer Patients According to TF–bearing Patients According to TF–bearing

MicroparticlesMicroparticles

Zwicker J I et al. Clin Cancer Res 2009;15:6830-6840Zwicker J I et al. Clin Cancer Res 2009;15:6830-6840

Log Rank P=0.002Log Rank P=0.002

MonthsMonths

Cum

ula

tive In

cidence

of

VTE

Cum

ula

tive In

cidence

of

VTE

0 5 10 15 20 250 5 10 15 20 25

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

FRAGEM and TF Biomarker DataFRAGEM and TF Biomarker Data

Maraveyas, et al. Blood Coagul Fibrinolysis 2010Maraveyas, et al. Blood Coagul Fibrinolysis 2010

250250

200200

150150

100100

5050

00

-50-50

ControlControl DalteparinDalteparin

Boxplot of the percentage change of tissue factor antigen in the Boxplot of the percentage change of tissue factor antigen in the sera of pancreatic cancer patients in both the control and dalteparin sera of pancreatic cancer patients in both the control and dalteparin

groupsgroups

TF and Survival In Pancreatic CancerTF and Survival In Pancreatic Cancer

Bharthuar et al Bharthuar et al ASCO GI ASCO GI 20102010

Median Survival in pts with TF MP-PCA >2.5 and Median Survival in pts with TF MP-PCA >2.5 and </=2.5pg/ml. </=2.5pg/ml.

Median survival Median survival was was 98.5 days 98.5 days for for TF >2.5 pg/mL vs.TF >2.5 pg/mL vs.231 days 231 days for TF for TF </= 2.5 pg/mL</= 2.5 pg/mLp=< 0.0001p=< 0.0001

N=117 patients N=117 patients with with pancreaticobiliary pancreaticobiliary cancerscancers

Pro

port

ion s

urv

ivin

gPro

port

ion s

urv

ivin

g

Days on studyDays on study

TF (pg/mL) <2.5 >=2.5TF (pg/mL) <2.5 >=2.5

0 100 200 300 400 500 600 700 800 900 10000 100 200 300 400 500 600 700 800 900 1000

10100.90.90.80.80.70.70.60.60.50.50.40.40.30.30.20.20.10.1

00

Ay, C. et al. J Clin Oncol; 27:4124-4129 2009

D-dimer, F1/2 and VTE in CancerD-dimer, F1/2 and VTE in Cancer

Elevated D-d + F1/2Elevated D-d + F1/2

Elevated F1/2Elevated F1/2

Elevated D-dimerElevated D-dimer

NonelevaNonelevated D-dimer and F1/2

Observation Time (Days)Observation Time (Days)

Cum

ula

tive R

isk

(pro

bab

ility

)C

um

ula

tive R

isk

(pro

bab

ility

)

0 100 200 300 400 500 600 7000 100 200 300 400 500 600 700

0.250.25

0.200.20

0.150.15

0.100.10

0.050.05

VTE in Cancer OutpatientsVTE in Cancer Outpatients

► The overwhelming majority of cancer The overwhelming majority of cancer patients are treated in the patients are treated in the outpatient/ambulatory settingoutpatient/ambulatory setting

► Which patients are most at risk?Which patients are most at risk?

► Which patients will benefit most from Which patients will benefit most from prophylaxis?prophylaxis?

How do you define “high” risk?► Level of risk for which prophylaxis is

considered acceptable by both patients and oncologists

Risk ModelRisk Model

Patient CharacteristicPatient Characteristic ScoreScore

Site of CancerVery high risk (stomach, pancreas)High risk (lung, lymphoma, gynecologic, GU excluding prostate)

22

11

Platelet count > 350,000/mm3 11

Hb < 10g/dL or use of ESA 11

Leukocyte count > 11,000/mm3 11

BMI > 35 kg/m2 11


Risk Model ValidationRisk Model Validation

Risk Low (0) Intermediate(1-2) High(Risk 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%

Rate

of

VTE o

ver

2.5

mos

(%)

Rate

of

VTE o

ver

2.5

mos

(%)

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


► Full data available in 839 patientsFull data available in 839 patients► Median observation time/follow-up: 643 days Median observation time/follow-up: 643 days

Score 0

Score 1

Score 2

Score ≥3

6 months

1.5%

3.8%

9.4%

17.7%

Number ofPatients Events

n n (%)

Score ≥3 96

16 (17%)

Score 2 23125

(11%)

Score 1 233 14 (6%)

Score 0 279 7 (3%)

Vienna CATS ValidationVienna CATS Validation

Ay et al ISTH 2009 Abs Ay et al ISTH 2009 Abs

Expanded Risk Score withExpanded Risk Score withD-Dimer and sP-selectinD-Dimer and sP-selectin

Score Score ≥≥55

Score 4Score 4

Score 3Score 3

Score 2Score 2Score 1Score 1Score 0Score 0

30.3%

1.0%

6 months

Number ofNumber ofPatients Patients EventsEvents

n n n (%)n (%)

Score Score ≥≥55 3131 9 (29%)9 (29%)

Score 4Score 4 525210 10

(19%)(19%)

Score 3Score 3 13713715 15

(11%)(11%)

Score 2Score 2 226226 11 (5%) 11 (5%)

Score 1Score 1 192192 13 (7%)13 (7%)

Score 0Score 0 201201 4 (2%)4 (2%)

Ay et al ISTH 2009 Abs Ay et al ISTH 2009 Abs

Risk Score and Short-Term MortalityRisk Score and Short-Term Mortality by VTE Risk Score Categoriesby VTE Risk Score Categories

Time (Days)

1201101009080706050403020100

Ove

rall

Su

rviv

al

1.00

.95

.90

.85

.80

.75

Low

Intermediate

High

P < 0.0001

Kuderer NM et al. Kuderer NM et al. ASH ASH 20082008

International Myeloma Working Group International Myeloma Working Group Thromboprophylaxis RecommendationsThromboprophylaxis Recommendations

Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated thrombosis in myeloma. Leukemia. 2008 Feb;22(2): 414-23.

Individual risk factors: Individual risk factors: obesity (BMI ≥ 30), prior VTE, central venous obesity (BMI ≥ 30), prior VTE, central venous cathetercatheter

Comorbid risk factors: Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, cardiac disease, chronic renal disease, diabetes, acute infection, immobilizationacute infection, immobilization

Surgery risk factorsSurgery risk factors: trauma, general surgery or any anesthesia: trauma, general surgery or any anesthesia

Medications: Medications: erythropoietinerythropoietin

Myeloma-related risk factors: Myeloma-related risk factors: diagnosis, hyperviscositydiagnosis, hyperviscosity

Myeloma therapy risk factors: Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-multiagent chemotherapy, doxorubicin, high-dose steroidsdose steroidsPatients with ≤ 1 VTE risk factor: Aspirin (81-325 mg daily)Patients with ≤ 1 VTE risk factor: Aspirin (81-325 mg daily)Patients with ≥ 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose Patients with ≥ 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose warfarin, although less existing supporting data for the latterwarfarin, although less existing supporting data for the latterPatients receiving thalidomide/lenalidomide concurrently with high-dose Patients receiving thalidomide/lenalidomide concurrently with high-dose dexamethasone or doxorubicin should receive LMWH thromboprophylaxis dexamethasone or doxorubicin should receive LMWH thromboprophylaxis Anticoagulant treatment can continue for 4 to 6 months or longer if Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are presentadditional risk factors are present

Rates of VTE in Recent Rates of VTE in Recent Prophylaxis StudiesProphylaxis Studies

N=930 N=312 N=123N=1165

Agnelli et al Agnelli et al Lancet Onc Lancet Onc 20092009Palumbo et al Palumbo et al ASH ASH 20092009Riess et al IRiess et al ISTHSTH 2009 2009Maraveyas et al Maraveyas et al ESMOESMO 2009 2009

VTE in Lung Cancer: VTE in Lung Cancer: PROTECHT and TOPIC studiesPROTECHT and TOPIC studies

sVTE LMWH

sVTE Placebo

All VTE LMWH

All VTE Placebo

PROTECHT 3.5% 5% 4% 6.2%

TOPIC-2 3% 5.7% 4.5% 8.3%

All 3.2% 5.5% 4.3% 7.8%

Verso et al. JTH 2010 onlineVerso et al. JTH 2010 online

Major Major Bleeding Bleeding LMWHLMWH

Major Major Bleeding Bleeding PlaceboPlacebo

PROTECHT 1%1% 0%0%

TOPIC-2 3.7%3.7% 2.2%2.2%

All 2.5%2.5% 1.7%1.7%

NNT=50 (sVTE)NNT=28 (allVTE)RRR=46%NNH=125

Ongoing Clinical TrialsOngoing Clinical Trials

Study (Agent)Study (Agent) Criteria for Criteria for inclusion*inclusion* NN EndpointsEndpoints

PHACS (dalteparin x 12 wks)

-Risk score >=3-Risk score >=3 404404

Asymptomatic Asymptomatic and and symptomatic symptomatic VTEVTE

SAVE-ONCO (semuloparin up to 4 mos)

-Lung, bladder, GI, -Lung, bladder, GI, ovaryovary-Metastatic or locally -Metastatic or locally advancedadvanced

32003200 DVT, PE, VTE-DVT, PE, VTE-related deathrelated death

MicroTEC (enoxaparin x 6 mos)

-Lung, colon, -Lung, colon, pancreas pancreas -Metastatic or -Metastatic or unresectableunresectable-Elevated TF MPs-Elevated TF MPs

227227 VTEVTE

* All studies enroll patients initiating a new chemotherapy regimen

Predictors of Recurrent VTE: Findings Predictors of Recurrent VTE: Findings from the RIETE Registryfrom the RIETE Registry

► Recurrent PERecurrent PE● Age < 65 (OR 3.0)Age < 65 (OR 3.0)● PE at entry (OR 1.9)PE at entry (OR 1.9)● < 3 months from diagnosis of cancer (OR < 3 months from diagnosis of cancer (OR

2.0)2.0)

► Recurrent DVTRecurrent DVT● Age < 65 (OR 1.6)Age < 65 (OR 1.6)● < 3 months from diagnosis of cancer (OR < 3 months from diagnosis of cancer (OR

2.4)2.4)

► Patients with leukocytosis had increased Patients with leukocytosis had increased risk of recurrent VTE and death (OR 2.7)risk of recurrent VTE and death (OR 2.7)

Trujillo-Santos et al Thromb Haem 2008

CLOT Study:CLOT Study:Reduction in Recurrent VTEReduction in Recurrent VTE

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

00

55

1010

1515

2020

2525

Days Post RandomizationDays Post Randomization

00 3030 6060 9090 120120 150150 180180 210210

Pro

babi

lity

of R

ecur

rent

VT

E,

%P

roba

bilit

y of

Rec

urre

nt V

TE

, %

Risk reduction = 52%Risk reduction = 52%pp-value = 0.0017-value = 0.0017

DalteparinDalteparin

OACOAC

Recurrent VTERecurrent VTE

Treatment of Treatment of Cancer-Associated VTECancer-Associated VTE

StudyStudy DesignDesign

Length Length of of

TherapTherapyy

(Months)(Months)

NNRecurrenRecurren

t VTEt VTE (%)(%)

Major Major BleedinBleedin

gg

(%)(%)

DeathDeath

(%)(%)

CLOT Trial

(Lee 2003)

Dalteparin

OAC

6 336

336

9

17

6

4

39

41

CANTHENOX

(Meyer 2002)

Enoxaparin

OAC

3 67

71

11

21

7

16

11

23

LITE

(Hull ISTH 2003)

Tinzaparin

OAC

3 80

87

6

11

6

8

23

22

ONCENOX

(Deitcher ISTH 2003)

Enox (Low)

Enox (High)

OAC

6 32

36

34

3.4

3.1

6.7

NS

NS0.03

NS

NS0.002

NS

NS

NR

0.09

0.030.09


►LMWH-based prophylaxis is safe and LMWH-based prophylaxis is safe and effective in certain high-risk settingseffective in certain high-risk settings● Hospitalized and surgical patientsHospitalized and surgical patients● Highly selected cancer outpatients (myeloma, ?Highly selected cancer outpatients (myeloma, ?

pancreas, ?? lung)pancreas, ?? lung)

►Ongoing studies are adopting novel Ongoing studies are adopting novel approaches to selecting patients for approaches to selecting patients for prophylaxisprophylaxis

►Clinicians need to conduct baseline and Clinicians need to conduct baseline and ongoing risk assessment for VTE in cancer ongoing risk assessment for VTE in cancer patients receiving chemotherapypatients receiving chemotherapy

VISION STATEMENTVISION STATEMENT

VTE in the Setting of MalignancyVTE in the Setting of Malignancy

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School



Research Support:Research Support:

BMS; Boehringer-Ingelheim; Eisai; BMS; Boehringer-Ingelheim; Eisai; Johnson & Johnson, Sanofi-Aventis Johnson & Johnson, Sanofi-Aventis

Consultant:Consultant:

Boehringer-Ingelheim; BMS; Eisai; Boehringer-Ingelheim; BMS; Eisai; EKOS: Medscape; Merck; Pfizer; EKOS: Medscape; Merck; Pfizer; Sanofi-AventisSanofi-Aventis

Toward Eradication of Toward Eradication of In-Hospital VTE: In-Hospital VTE: The Promise of The Promise of

ProphylaxisProphylaxis

“VITAE” Studies“VITAE” Studies


VTE Prophylaxis in 19,958 Medical VTE Prophylaxis in 19,958 Medical Patients/9 Studies (Meta-analysis)Patients/9 Studies (Meta-analysis)

► 62% reduction in fatal PE62% reduction in fatal PE

► 57% reduction in fatal or nonfatal PE57% reduction in fatal or nonfatal PE

► 53% reduction in DVT53% reduction in DVT

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

VITAE IVITAE I

► VITAE I uses a Federal database to VITAE I uses a Federal database to model Hospitalized Medical Patients model Hospitalized Medical Patients with VTE. with VTE.

► 2 of every 100 hospitalized Medical 2 of every 100 hospitalized Medical Service patients suffer VTE. Service patients suffer VTE.

With universal in-hospital prophylaxis, the With universal in-hospital prophylaxis, the VTE rate would be cut by 58%.VTE rate would be cut by 58%.Thromb Haemost 2009; 102: 505-510

58% Reduction in VTE with Universal 58% Reduction in VTE with Universal Prophylaxis in Hospitalized Medical Prophylaxis in Hospitalized Medical

PatientsPatients

Thromb Haemostas 2009; 102: 505-510

VITAE IIVITAE II

► VITAE II models the 5-year aftermath of VITAE II models the 5-year aftermath of initial VTE among these same initial VTE among these same Hospitalized Medical Patients who were Hospitalized Medical Patients who were initially stricken. initially stricken.

► If universal prophylaxis had been utilized If universal prophylaxis had been utilized initially, the 5-year VTE complication initially, the 5-year VTE complication rates of death, recurrence, PTS, and rates of death, recurrence, PTS, and CTEPH would have been reduced by CTEPH would have been reduced by 60%. 60%. Thromb Haemost 2009; 102: 688-693Thromb Haemost 2009; 102: 688-693

VITAE IIVITAE II

Thromb Haemost 2009; 102: 688-693Thromb Haemost 2009; 102: 688-693

Status Quo

100% VTE Prophylaxis


1.1. Electronic alerts can identify Electronic alerts can identify hospitalized cancer patients at risk hospitalized cancer patients at risk for VTE.for VTE.

2.2. Optimal prophylaxis for hospitalized Optimal prophylaxis for hospitalized cancer patients is LMWH.cancer patients is LMWH.

3.3. When VTE is diagnosed in cancer When VTE is diagnosed in cancer patients, the only FDA-approved patients, the only FDA-approved LMWH for Rx as monotherapy LMWH for Rx as monotherapy without warfarin is dalteparin. without warfarin is dalteparin.

Conclusions (Continued)Conclusions (Continued)

4.4. ACCP guidelines state that “every ACCP guidelines state that “every hospital should develop a formal hospital should develop a formal strategy to prevent VTE.”strategy to prevent VTE.”

5.5. As cancer therapies improve, quality As cancer therapies improve, quality life-years will be extended.life-years will be extended.

6.6. DVT and PE will be mostly prevented DVT and PE will be mostly prevented in cancer patients, and when in cancer patients, and when necessary to treat, will be managed necessary to treat, will be managed will LMWH monotherapy.will LMWH monotherapy.

new frontiers and evolving paradigms in cancer and thrombosis optimizing prevention, risk...

Documents

thrombosis slide

dc slide

usa slide

milestone summit slide

venous stasis ulcer

discussion session slide

ctephrecurrent acute

vte risk