Welcome to this Science-to-Strategy SummitWelcome to this Science-to-Strategy Summit
Critical Challenges and LandmarkCritical Challenges and Landmark
Advances inAdvances in Thrombosis ManagementThrombosis Ma...
CME-accredited symposiumCME-accredited symposium jointly sponsored by thejointly sponsored by the
Postgraduate Institute o...
Program Educational ObjectivesProgram Educational Objectives
As a result of this session, physicians will be able to:
► Re...
Program FacultyProgram Faculty
Program Chairman
Ajay Kakkar, MBBS, PhD, FRCS
Head of the Centre for Surgical
Sciences
Bart...
Faculty COI Financial DisclosuresFaculty COI Financial Disclosures
Ajay Kakkar, MBBS, PhD, FRCSAjay Kakkar, MBBS, PhD, FRC...
Introduction and Chairman’s OverviewIntroduction and Chairman’s Overview
Clotting, Cancer, And Controversies:Clotting, Can...
COMORBIDITYCOMORBIDITY
CONNECTIONCONNECTION
CAPCAP
UTIUTI
CancerCancer
Heart FailureHeart Failure
ABE/COPDABE/COPD
Respira...
Epidemiology of First-Time VTEEpidemiology of First-Time VTE
White R. Circulation. 2003;107:I-4 –I-8.)
VariableVariable Fi...
Epidemiology of VTEEpidemiology of VTE
White R. Circulation. 2003;107:I-4 –I-8.)
► One major risk factor for VTE is ethnic...
Comorbidity ConnectionComorbidity Connection
ComorbidityComorbidity
ConnectionConnection
OverviewOverview
Acute Medical Illness and VTEAcute Medical Illness and VTE
Acute MedicalAcute Medical Relative RiskRelative Risk
IllnessIl...
Acute Medical Illness and VTEAcute Medical Illness and VTE
Risk FactorRisk Factor Odds RatioOdds Ratio XX22
(95% CI)(95% C...
Comorbid Condition and DVT RiskComorbid Condition and DVT Risk
► Hospitalization for surgery (24%) and for medical illness...
VTE RecurrenceVTE Recurrence
BaselineBaseline Hazard RatioHazard Ratio
CharacteristicCharacteristic (95% CI)(95% CI)
AgeAg...
Cancer Surgery, Thrombosis, and theCancer Surgery, Thrombosis, and the
Biology of MalignancyBiology of Malignancy
A Scienc...
AuthorAuthor YearYear No. ofNo. of
studiesstudies
Cancer mortalityCancer mortality
UFHUFH LMWHLMWH
GreenGreen 19921992 22 ...
Famous: Trial DesignFamous: Trial Design
Treatment for 1 year or until deathTreatment for 1 year or until death
1º Endpoin...
Kaplan–Meier survival curves for all ITTKaplan–Meier survival curves for all ITT
patients in dalteparin and placebo groups...
Survival Analysis:Survival Analysis:
Good Prognosis PatientsGood Prognosis Patients
Kaplan–MeiersurvivaldistributionKaplan...
LMWH and Survival:LMWH and Survival:
Further Studies (2003)Further Studies (2003)
Solid tumor malignancy
and acute VTE
All...
SCLC Study Survival CurvesSCLC Study Survival Curves
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 15 20 25 30 35 40
Months after randomi...
CLOT Survival CurvesCLOT Survival CurvesProbabilityofsurvival(%)
Dalteparin
OAC
Days after randomization
0
10
20
30
40
50
...
MALT Survival CurvesMALT Survival Curves
ProbabilityofSurvival
1.0
0.8
0.6
0.4
0.2
0.0
0 12 24 36 48 60 72 84 96
Months af...
Mechanistic explanationsMechanistic explanations
VTE Coagulation Protease Direct Heparin OtherVTE Coagulation Protease Dir...
SilverSilver In:In: The Hematologist - modified from Blom et. al.The Hematologist - modified from Blom et. al. JAMAJAMA 20...
Mechanisms of Cancer-InducedMechanisms of Cancer-Induced
Thrombosis: The InterfaceThrombosis: The Interface
1.1. Pathogene...
Fibrinolytic
activities:
t-PA, u-PA, u-PAR,
PAI-1, PAI-2
Procoagulant Activities
FIBRIN
Endothelial cells
IL-1,
TNF-
α, VE...
Pathogenesis of Thrombosis in Cancer –Pathogenesis of Thrombosis in Cancer –
A Modification of Virchow’s TriadA Modificati...
Mechanisms of Cancer-InducedMechanisms of Cancer-Induced
Thrombosis: Clot and Cancer InterfaceThrombosis: Clot and Cancer ...
Activation of Blood Coagulation in CancerActivation of Blood Coagulation in Cancer
Biological Significance?Biological Sign...
TF
VEGF
Angiogenesis
Endothelial cellsEndothelial cells
IL-8IL-8
Blood Coagulation
Activation
FIBRIN
PAR-2
Angiogenesis
FV...
Coagulation Cascade and TumorsCoagulation Cascade and Tumors
TFTF ThrombinThrombin
Clotting-Clotting-
dependentdependent
C...
Regulation of Vascular Endothelial Growth Factor ProductionRegulation of Vascular Endothelial Growth Factor Production
and...
3.3. The cytoplasmic tail of TF, which contains threeThe cytoplasmic tail of TF, which contains three
serine residues, app...
Activation of Blood CoagulationActivation of Blood Coagulation
in Cancer: Malignant Transformationin Cancer: Malignant Tra...
► METMET encodes a tyrosine kinase receptor forencodes a tyrosine kinase receptor for
hepatocyte growth factor/scatter fac...
► Mouse model of Trousseau’s SyndromeMouse model of Trousseau’s Syndrome
Targeted activated human MET to the mouseTargeted...
Blood Coagulation Parameters in MiceBlood Coagulation Parameters in Mice
Transduced with theTransduced with the METMET Onc...
Activation of Blood CoagulationActivation of Blood Coagulation
in Cancer: Malignant Transformationin Cancer: Malignant Tra...
► Glioblastomas characterized histologically byGlioblastomas characterized histologically by
“pseudopalisading necrosis”“p...
Results:Results:
1.1. Hypoxia andHypoxia and PTENPTEN lossloss →↑→↑ TF (mRNA, AgTF (mRNA, Ag
and procoagulant activity); p...
Activation of Blood CoagulationActivation of Blood Coagulation
in Cancer: Malignant Transformationin Cancer: Malignant Tra...
““Oncogenic Events Regulate Tissue Factor Expression InOncogenic Events Regulate Tissue Factor Expression In
Colorectal Ca...
““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells:Exp...
0
2
4
6
8
10
12
14
HCT116 SI-2 SI-3 MG only
Effect of TF si mRNA on new vessel formation in colon cancerEffect of TF si mR...
““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor
Expression In Colorectal Cancer Cells: Im...
Mechanisms of Cancer-InducedMechanisms of Cancer-Induced
Thrombosis: ImplicationsThrombosis: Implications
1.1. Pathogenesi...
A Systematic Overview of VTEA Systematic Overview of VTE
Prophylaxis In TheProphylaxis In The
Setting of CancerSetting of ...
VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology
► Of all cases of VTE:Of all cases of VTE:
About 20% occur in can...
1.1. Ambrus JL et al.Ambrus JL et al. J MedJ Med. 1975;6:61-64. 1975;6:61-64
2.2. Donati MB.Donati MB. HaemostasisHaemosta...
Clinical Features of VTE in CancerClinical Features of VTE in Cancer
► VTE has significant negative impact onVTE has signi...
Risk Factors for Cancer-Associated VTERisk Factors for Cancer-Associated VTE
► CancerCancer
TypeType
• Men: prostate, colo...
Thrombosis and Survival:Thrombosis and Survival:
Likelihood of Death After HospitalizationLikelihood of Death After Hospit...
As Number Of Cancer SurvivorsAs Number Of Cancer Survivors
Increases, VTE Rates IncreaseIncreases, VTE Rates Increase
YEAR...
VTE Risk And Cancer Type:VTE Risk And Cancer Type:
“Solid And Liquid”“Solid And Liquid”
Stein PD, et al. Am J Med 2006; 11...
Thrombosis Risk In Cancer
Primary Prophylaxis
► SurgerySurgery
► ChemotherapyChemotherapy
► RadiotherapyRadiotherapy
► Cen...
Prevention and ManagementPrevention and Management
of VTE in Cancerof VTE in Cancer
► Sparse data specifically related to ...
PharmacologicPharmacologic
(Prophylaxis & Treatment)(Prophylaxis & Treatment)
Low MolecularLow Molecular
Weight HeparinWei...
► Cancer patients haveCancer patients have 2-fold risk of post-2-fold risk of post-
operative DVT/PE and >3-fold risk of f...
Natural History of VTE in CancerNatural History of VTE in Cancer
Surgery:Surgery: The @RISTOS RegistryThe @RISTOS Registry...
Nilsson: Arch Surg, 142;2007:126–132Nilsson: Arch Surg, 142;2007:126–132
Colorectal Cancer Resection
Association Between T...
► Age >40 yearsAge >40 years
► Cancer procoagulantsCancer procoagulants
► ThrombophiliasThrombophilias
► Adjuvant chemothe...
Clinical thromboembolismClinical thromboembolism CancerCancer
0 1.0 2.0 3.0 4.00 1.0 2.0 3.0 4.0
Major hemorrhageMajor hem...
LMWH vs. UFHLMWH vs. UFH
► Abdominal or pelvic surgery for cancer (mostlyAbdominal or pelvic surgery for cancer (mostly
co...
Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients
0%
5%
10%
15%
20%
UFH 5000 U tid
enoxaparin 40 mg
VTE Maj...
0%
5%
10%
15%
20%
UFH 5000 U tid
enoxaparin 40 mg
CanadianCanadian
Colorectal DVTColorectal DVT
Prophylaxis TrialProphylax...
Extended prophylaxisExtended prophylaxis
► Abdominal or pelvic surgery for cancerAbdominal or pelvic surgery for cancer
► ...
0%
5%
10%
15%
placebo
enoxaparin 40 mg
VTE Prox Any MajorVTE Prox Any Major
DVT Bleeding BleedingDVT Bleeding Bleeding
P=0...
► A multicenter, prospective, assessor-blinded, open-A multicenter, prospective, assessor-blinded, open-
label, randomized...
► Paucity of level I/II studies in this populationPaucity of level I/II studies in this population
► Based on small histor...
Cochrane Systematic ReviewCochrane Systematic Review
► Meta-analysis of 8 randomized controlled trialsMeta-analysis of 8 r...
Urological Cancer SurgeryUrological Cancer Surgery
Poorly studied populationPoorly studied population
Risk of VTE varies w...
► Majority of patients undergoingMajority of patients undergoing
neurosurgery for malignancyneurosurgery for malignancy
► ...
Meta-analysis of three (3) RCTs evaluatingMeta-analysis of three (3) RCTs evaluating
LMWH prophylaxisLMWH prophylaxis
► On...
77thth
ACCP Consensus GuidelinesACCP Consensus Guidelines
GradeGrade Recommendations for Cancer PatientsRecommendations fo...
Thrombosis is a potential complication of centralThrombosis is a potential complication of central
venous catheters, inclu...
Placebo-Controlled TrialsPlacebo-Controlled Trials
StudyStudy RegimenRegimen NN CRT (%)CRT (%)
Reichardt*Reichardt*
200220...
Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin
► 95 cancer patients receiving FU-based infusion95 canc...
SummarySummary
► Recent studies demonstrate a lowRecent studies demonstrate a low
incidence of symptomatic catheter-incide...
77thth
ACCP Consensus GuidelinesACCP Consensus Guidelines
GradeGrade Recommendations for Cancer PatientsRecommendations fo...
Primary Prophylaxis in CancerPrimary Prophylaxis in Cancer
Radiotherapy in the Ambulatory PatientRadiotherapy in the Ambul...
Risk Factors for VTE inRisk Factors for VTE in
Medical Oncology PatientsMedical Oncology Patients
► Tumor typeTumor type
O...
Independent Risk Factors for DVT/PEIndependent Risk Factors for DVT/PE
Risk Factor/CharacteristicRisk Factor/Characteristi...
VTE Incidence In Various TumorsVTE Incidence In Various Tumors
47%47%Solid tumors (anti-VEGF + chemo)Solid tumors (anti-VE...
16%16% Zangari, 2002Zangari, 2002
(192 pts)(192 pts)
T+dox atT+dox at
relapserelapse
17.8%17.8%
Baz,Baz,
20042004
(103 pts...
DVTDVT
Len + D(%)Len + D(%) D (%)D (%) Len + D(%)Len + D(%) D (%)D (%)
MM-009MM-009 MM-010MM-010
00
22
44
66
88
1010
1212
...
Knight: N Engl J Med.2006,354:2079Knight: N Engl J Med.2006,354:2079
► rEPO used
more in USA
and Canada
► L+Dex: 23%
VTE w...
Thrombotic Outcomes from rEPO orThrombotic Outcomes from rEPO or
Darbopoietin Use in Cancer PatientsDarbopoietin Use in Ca...
Vitamin K antagonist (INR 2.0 - 3.0)Vitamin K antagonist (INR 2.0 - 3.0)
>> 3 months3 months
LMWH or UFHLMWH or UFH
5 to 7...
Recurrent VTE in Cancer – Subset Analysis ofRecurrent VTE in Cancer – Subset Analysis of
the Home Rx Studies (UH/VKA vs. L...
Recurrent VTE in Cancer – SubsetRecurrent VTE in Cancer – Subset
Analysis of the Home Rx StudiesAnalysis of the Home Rx St...
Oral Anticoagulant TherapyOral Anticoagulant Therapy
in Cancer Patients: Problematicin Cancer Patients: Problematic
► Warf...
CLOT: Landmark Cancer/VTE TrialCLOT: Landmark Cancer/VTE Trial
CANCER PATIENTS WITHCANCER PATIENTS WITH
ACUTE DVT or PEACU...
Landmark CLOT Cancer TrialLandmark CLOT Cancer Trial
Reduction in Recurrent VTEReduction in Recurrent VTE
00
55
1010
1515
...
DalteparinDalteparin
N=338N=338
OACOAC
N=335N=335
P-P-
value*value*
Major bleedMajor bleed 19 ( 5.6%)19 ( 5.6%) 12 ( 3.6%)...
Treatment of Cancer-Associated VTETreatment of Cancer-Associated VTE
StudyStudy DesignDesign LengthLength
ofof
TherapyTher...
Treatment and 2Treatment and 2° Prevention of VTE° Prevention of VTE
in Cancer – Bottom Linein Cancer – Bottom Line
► New ...
CLOT 12-month Mortality
All Patients
0
10
20
30
40
50
60
70
80
90
100
0 30 60 90 120 180 240 300 360
DalteparinDalteparin
...
0
10
20
30
40
50
60
70
80
90
100
Days Post Randomization
0 30 60 90 120 150 180 240 300 360
ProbabilityofSurvival,%
OAC
Da...
► 84 patients randomized: CEV +/- LMWH (18 weeks)84 patients randomized: CEV +/- LMWH (18 weeks)
► Patients balanced for a...
VTE Prophylaxis Is UnderusedVTE Prophylaxis Is Underused
in Patients With Cancerin Patients With Cancer
5
89
38
33
42
52
0...
Venous Thromboembolism (VTE)Venous Thromboembolism (VTE)
Prophylaxis in the Cancer PatientProphylaxis in the Cancer Patien...
Outline of PresentationOutline of Presentation
► VTE prophylaxis in cancerVTE prophylaxis in cancer
Surgical, CVC, medical...
Thromboprophylaxis in Cancer vs Non-Thromboprophylaxis in Cancer vs Non-
Cancer Surgical patientsCancer Surgical patients
...
Thromboprophylaxis in Surgical PatientsThromboprophylaxis in Surgical Patients
► ARISTOSARISTOS
Prospective cohort of 2373...
In-hospital Thromboprophylaxis inIn-hospital Thromboprophylaxis in
Cancer SurgeryCancer Surgery
ENOXACANENOXACAN Canadian ...
Extended Thromboprophylaxis inExtended Thromboprophylaxis in
Cancer SurgeryCancer Surgery
ENOXACAN IIENOXACAN II FAMEFAME
...
Systematic Review of DVT Prophylaxis ofSystematic Review of DVT Prophylaxis of
Surgical Cancer PatientsSurgical Cancer Pat...
Thromboprophylaxis for CVCThromboprophylaxis for CVC
► Prior studies with ~ 5% incidence ofPrior studies with ~ 5% inciden...
Thromboprophylaxis in HospitalizedThromboprophylaxis in Hospitalized
Medical Cancer PatientsMedical Cancer Patients
► Ther...
Dentali, F. et. al. Ann Intern Med 2007;146:278-288Dentali, F. et. al. Ann Intern Med 2007;146:278-288
Fatal Pulmonary Emb...
Unfractionated Heparin Prophylaxis:Unfractionated Heparin Prophylaxis:
BID vs TID—What Works, What Doesn’t?BID vs TID—What...
15,231
56,364
0
10,000
20,000
30,000
40,000
50,000
60,000
With HIT Without HIT
Costofadmission($)
Incidence and EconomicIn...
2004 ACCP Recommendations2004 ACCP Recommendations
Cancer patients undergoing surgical procedures receive prophylaxis that...
NCCN Practice Guidelines in VTENCCN Practice Guidelines in VTE
DiseaseDisease
At Risk Population Initial ProphylaxisAt Ris...
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCC...
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCC...
Compliance With ACCP VTECompliance With ACCP VTE
Prophylaxis Guidelines Is PoorProphylaxis Guidelines Is Poor
9.9% 6.7%
35...
In-Hospital Prophylaxis by Medical Condition –In-Hospital Prophylaxis by Medical Condition –
IMPROVE RegistryIMPROVE Regis...
Odds Ratio
Malignancy 0.40
Others 0.58
Infection 0.83
Bleeding Risk 0.91
Gender 0.92
Hospital Size 0.93
Age 1.00
LOS 1.05
...
Independent factors present at admission for in-hospitalIndependent factors present at admission for in-hospital
bleeding ...
Computer Reminder SystemComputer Reminder System
► Computer program linked to patient database to identifyComputer program...
Electronic Alerts to Prevent VTEElectronic Alerts to Prevent VTE
88
90
92
94
96
98
100
0 30 60 90
Freedomfrom
DVTorPE(%)
N...
Cohen A et al Thromb Haemost 2005;94(4):750-9
VTE Risk Assessment forVTE Risk Assessment for
Hospitalized Medical Patients...
Cohen A et al Thromb Haemost 2005;94(4):750-9.
VTE Risk Assessment forVTE Risk Assessment for
Hospitalized Medical Patient...
ConclusionsConclusions
Current practices of VTE prophylaxis in theCurrent practices of VTE prophylaxis in the
cancer patca...
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  • Let’s continue examining the association between DVT/PE and cancer.
    Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE.
    As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer.
    Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer.
  • Several classes of agents have been used for prophylaxis and treatment of VTE
    Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter
    Most commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs)
  • Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study.
    This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data.
    Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included.
    What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE.
    Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of 4.05. In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE.
  • VTE prophylaxis is underused in patients with cancer
    The Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1
    Data from 3891 completed questionnaires were available for analysis1
    The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1
    These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies
    A retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2
    A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3
    A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4
    In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5
  • Retrospective analysis with a nested case-control
    Performed at a University-affiliated tertiary-care center
    Doses were defined as 10,000 -15,000 units/day for UFH and 40-60 mg /day for LMWH (enoxaparin was the only LMWH on formulary)
    Assumed equal efficacy and bleed rates among the agents
    Note: $ values reported on this slide are hospital costs (not charges!)
  • In the 2004 guidelines on venous thromboembolism prophylaxis endorsed by the ACCP, Geerts and coworkers reviewed evidence from 11 studies on the use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) in patients with general medical conditions1
    ACCP Grade 1A treatment options for deep vein thrombosis (DVT) prophylaxis in general medical patients with clinical risk factors for DVT/PE (including active cancer, bed rest, heart failure, severe lung disease, prior DVT/PE, sepsis, acute neurologic disease, or IBD)1
    LMWH
    Low-dose UFH
    The investigators assigned a Grade of 1A to 2 for treatment options, defined as follows:1
    Grade 1: Benefits of a given intervention are certain to outweigh the risks, burdens, and costs of the intervention
    Grade 2: Less certainty that the benefits outweigh the risks, burdens, and costs
    Methodological quality of evidence subcategorized by letters A-C
    A: Randomized clinical trials (RCTs) with consistent results
    B: RCTs with inconsistent results
    C: Observational studies, generalizations from single patient group in an RCT compared to a similar patient group not in the RCT. More compelling evidence in this category is graded C+
  • A study by Yu and colleagues showed that even when risk is recognized, the thromboprophylactic strategy chosen may be inadequate
    The study assessed compliance with the 2001 ACCP guidelines for prophylaxis for DVT and PE. The authors looked at records from more than 120,000 adult hospital admissions between January 2001 and March 20051
    Orthopedic surgery patients (n=2324) had the highest rate of compliance, 52.4%1
    The rate of compliance for patients with at-risk medical conditions (n=62,012) was 15.3%. For general surgery patients (n=35,124), the rate of compliance was 12.7%1
    For urologic (n=1338) and gynecologic (n=9175) surgery patients, the rates of compliance were 9.9% and 6.7%, respectively1
    Overall, only 23.4% of patients received some form of prophylaxis and only 13.3% of patients received guideline-recommended prophylaxis1
    Thus, only about a quarter of patients received prophylaxis at all, and of those only about half received the prophylaxis recommended by ACCP guidelines for patients with their condition1
  • slides

    1. 1. Welcome to this Science-to-Strategy SummitWelcome to this Science-to-Strategy Summit
    2. 2. Critical Challenges and LandmarkCritical Challenges and Landmark Advances inAdvances in Thrombosis ManagementThrombosis Management The Evolving and Foundation Role of LMWHs in Cancer andThe Evolving and Foundation Role of LMWHs in Cancer and VTE Prophylaxis: Applying Science, Expert Analysis, andVTE Prophylaxis: Applying Science, Expert Analysis, and Landmark Trials to the Front Lines of Oncology PracticeLandmark Trials to the Front Lines of Oncology Practice Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies Program ChairmanProgram Chairman Ajay Kakkar, MBBS, PhD, FRCSAjay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical SciencesHead of the Centre for Surgical Sciences Barts and the LondonBarts and the London Queen Mary’s School ofQueen Mary’s School of Medicine and DentistryMedicine and Dentistry The Thrombosis Research InstituteThe Thrombosis Research Institute London, UKLondon, UK
    3. 3. CME-accredited symposiumCME-accredited symposium jointly sponsored by thejointly sponsored by the Postgraduate Institute of Medicine and CMEducation ResourcesPostgraduate Institute of Medicine and CMEducation Resources Commercial Support:Commercial Support: Sponsored by an independent educationalSponsored by an independent educational grant from Eisai, Inc.grant from Eisai, Inc. Mission statement:Mission statement: Improve patient care through evidence-basedImprove patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management Processes:Processes: Strives for fair balance, clinical relevance, on-labelStrives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence andindications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies COI:COI: Full faculty disclosures provided in syllabus and at theFull faculty disclosures provided in syllabus and at the beginning of the programbeginning of the program Welcome and Program OverviewWelcome and Program Overview
    4. 4. Program Educational ObjectivesProgram Educational Objectives As a result of this session, physicians will be able to: ► Review recent trials, research, and expert analysis of issues focused on thrombosis and cancer. ► Specify strategies for risk-directed prophylaxis against DVT in at risk patients with cancer. ► Explain how to assess and manage special needs of cancer patients at risk for DVT, with a focus on protecting against recurrent DVT. ► Describe how to risk stratify patients undergoing cancer surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis. ► Review landmark clinical trials focusing on DVT prophylaxis in patients with cancer. ► Explain how to appropriately use the range of pharmacologic options available for thrombosis management in patients with malignancy.
    5. 5. Program FacultyProgram Faculty Program Chairman Ajay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical Sciences Barts and the London Queen Mary’s School of Medicine and Dentistry Thrombosis Research Institute London, UK Craig M. Kessler, MD Professor of Medicine and Pathology Georgetown University Medical Center Director of the Division of Coagulation Department of Laboratory Medicine Washington, DC Alex C. Spyropoulos, MD, FACP, FCCP Chair, Department of Clinical Thrombosis Lovelace Medical Center Clinical Associate Professor of Medicine University of New Mexico Albuquerque, New Mexico Distinguished Panel Member, Consultant, and Visiting Professor Samuel Z. Goldhaber, MD Professor of Medicine, Cardiovascular Division Harvard Medical School Director, Venous Thromboembolism Research Group Director, Anticoagulation Service Brigham and Women’s Hospital Boston, MA
    6. 6. Faculty COI Financial DisclosuresFaculty COI Financial Disclosures Ajay Kakkar, MBBS, PhD, FRCSAjay Kakkar, MBBS, PhD, FRCS Grants/research support: sanofi-aventis, AstraZeneca, PfizerGrants/research support: sanofi-aventis, AstraZeneca, Pfizer Consultant: Pfizer, sanofi-aventisConsultant: Pfizer, sanofi-aventis Craig M. Kessler, MDCraig M. Kessler, MD Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline,Grants/research support: sanofi-aventis, Eisai, GlaxoSmithKline, OctapharmaOctapharma Consultant: sanofi-aventis, Eisai, NovoNordiskConsultant: sanofi-aventis, Eisai, NovoNordisk Alex C. Spyropoulos, MD, FACP, FCCAlex C. Spyropoulos, MD, FACP, FCC Consultant: sanofi-aventis, Eisai, Bayer, Boehringer-IngelheimConsultant: sanofi-aventis, Eisai, Bayer, Boehringer-Ingelheim Speaker’s Bureau: sanofi-aventis EisaiSpeaker’s Bureau: sanofi-aventis Eisai Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MD Grant/Research Support: sanofi-aventis, GSK, EisaiGrant/Research Support: sanofi-aventis, GSK, Eisai Consultant: sanofi-aventis, BMS, Emisphere, Boehringer-IngelheimConsultant: sanofi-aventis, BMS, Emisphere, Boehringer-Ingelheim
    7. 7. Introduction and Chairman’s OverviewIntroduction and Chairman’s Overview Clotting, Cancer, And Controversies:Clotting, Cancer, And Controversies: What The Cascade Of Evidence AndWhat The Cascade Of Evidence And Current Thinking Tell UsCurrent Thinking Tell Us The Evolving Science, Epidemiology, andThe Evolving Science, Epidemiology, and Foundation Role of Low Molecular Weight HeparinFoundation Role of Low Molecular Weight Heparin in the Setting of Cancerin the Setting of Cancer Program ChairmanProgram Chairman Ajay Kakkar, MBBS, PhD, FRCSAjay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical SciencesHead of the Centre for Surgical Sciences Barts and the LondonBarts and the London Queen Mary’s School of Medicine and DentistryQueen Mary’s School of Medicine and Dentistry The Thrombosis Research InstituteThe Thrombosis Research Institute London, UKLondon, UK
    8. 8. COMORBIDITYCOMORBIDITY CONNECTIONCONNECTION CAPCAP UTIUTI CancerCancer Heart FailureHeart Failure ABE/COPDABE/COPD Respiratory FailureRespiratory Failure Myeloproliferative DisorderMyeloproliferative Disorder ThrombophiliaThrombophilia SurgerySurgery History of DVTHistory of DVT OtherOther SUBSPECIALISTSUBSPECIALIST STAKEHOLDERSSTAKEHOLDERS Infectious diseasesInfectious diseases OncologyOncology CardiologyCardiology Pulmonary medicinePulmonary medicine HematologyHematology Oncology/hematologyOncology/hematology Interventional RadiologyInterventional Radiology HospitalistHospitalist SurgeonsSurgeons EMEM PCPPCP Comorbidity ConnectionComorbidity Connection
    9. 9. Epidemiology of First-Time VTEEpidemiology of First-Time VTE White R. Circulation. 2003;107:I-4 –I-8.) VariableVariable FindingFinding Seasonal VariationSeasonal Variation Possibly more common in winterPossibly more common in winter and less common in summerand less common in summer Risk FactorsRisk Factors 25% to 50% “idiopathic”25% to 50% “idiopathic” 15%–25% associated with cancer15%–25% associated with cancer;; 20% following surgery (3 mo.)20% following surgery (3 mo.) Recurrent VTERecurrent VTE 6-month incidence: 7%;6-month incidence: 7%; higher rate in patients with cancerhigher rate in patients with cancer Recurrent PE more likely after PERecurrent PE more likely after PE than after DVTthan after DVT Death After Treated VTEDeath After Treated VTE 30 day incidence 6% after30 day incidence 6% after incident DVTincident DVT 30 day incidence 12% after PE30 day incidence 12% after PE Death strongly associated withDeath strongly associated with cancercancer, age, and cardiovascular, age, and cardiovascular diseasedisease
    10. 10. Epidemiology of VTEEpidemiology of VTE White R. Circulation. 2003;107:I-4 –I-8.) ► One major risk factor for VTE is ethnicity, with aOne major risk factor for VTE is ethnicity, with a significantly higher incidence amongsignificantly higher incidence among Caucasians and African Americans than amongCaucasians and African Americans than among Hispanic persons and Asian-Pacific Islanders.Hispanic persons and Asian-Pacific Islanders. ► Overall, about 25% to 50% of patient with first-Overall, about 25% to 50% of patient with first- time VTE have an idiopathic condition, withouttime VTE have an idiopathic condition, without a readily identifiable risk factor.a readily identifiable risk factor. ► Early mortality after VTE is strongly associatedEarly mortality after VTE is strongly associated with presentation as PE, advanced age,with presentation as PE, advanced age, cancer,cancer, and underlying cardiovascular disease.and underlying cardiovascular disease.
    11. 11. Comorbidity ConnectionComorbidity Connection ComorbidityComorbidity ConnectionConnection OverviewOverview
    12. 12. Acute Medical Illness and VTEAcute Medical Illness and VTE Acute MedicalAcute Medical Relative RiskRelative Risk IllnessIllness RiskRisk XX22 PP ValueValue Heart failureHeart failure 1.08 (0.72-1.62)1.08 (0.72-1.62) 0.050.05 .82.82 NYHA class IIINYHA class III 0.89 (0.55-1.43)0.89 (0.55-1.43) 0.120.12 .72.72 NYHA class IVNYHA class IV 1.48 (0.84-2.6)1.48 (0.84-2.6) 1.231.23 .27.27 AcuteAcute respiratoryrespiratory diseasedisease 1.26 (0.85-1.87)1.26 (0.85-1.87) 1.031.03 .31.31 AcuteAcute infectiousinfectious diseasedisease 1.50 (1.00-2.26)1.50 (1.00-2.26) 3.543.54 .06.06 AcuteAcute rheumaticrheumatic diseasedisease 1.45 (0.84-2.50)1.45 (0.84-2.50) 1.201.20 .27.27 Among Patients Receiving Placebo orAmong Patients Receiving Placebo or Ineffective Antithrombotic TherapyIneffective Antithrombotic Therapy Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
    13. 13. Acute Medical Illness and VTEAcute Medical Illness and VTE Risk FactorRisk Factor Odds RatioOdds Ratio XX22 (95% CI)(95% CI) Age >75 yAge >75 y 1.03 (1.00-1.06)1.03 (1.00-1.06) 0.00010.0001 CancerCancer 1.62 (0.93-2.75)1.62 (0.93-2.75) 0.080.08 Previous VTEPrevious VTE 2.06 (1.10-3.69)2.06 (1.10-3.69) 0.020.02 AcuteAcute infectiousinfectious diseasedisease 1.74 (1.12-2.75)1.74 (1.12-2.75) 0.020.02 ChronicChronic respiratoryrespiratory diseasedisease 0.60 (0.38-0.92)0.60 (0.38-0.92) 0.020.02 Multivariate Logistic Regression ModelMultivariate Logistic Regression Model for Definite Venous Thromboembolism (VTE)for Definite Venous Thromboembolism (VTE) Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
    14. 14. Comorbid Condition and DVT RiskComorbid Condition and DVT Risk ► Hospitalization for surgery (24%) and for medical illness (22%)Hospitalization for surgery (24%) and for medical illness (22%) accounted for a similar proportion of the cases, while nursingaccounted for a similar proportion of the cases, while nursing home residence accounted for 13%.home residence accounted for 13%. ► The individual attributable risk estimates forThe individual attributable risk estimates for malignantmalignant neoplasmneoplasm, trauma, congestive heart failure, central venous, trauma, congestive heart failure, central venous catheter or pacemaker placement, neurological disease withcatheter or pacemaker placement, neurological disease with extremity paresis, and superficial vein thrombosis wereextremity paresis, and superficial vein thrombosis were 18%,18%, 12%, 10%, 9%, 7%, and 5%, respectively.12%, 10%, 9%, 7%, and 5%, respectively. ► Together, the 8 risk factors accounted for 74% of diseaseTogether, the 8 risk factors accounted for 74% of disease occurrenceoccurrence Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd.Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern MedArch Intern Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based studythrombosis and pulmonary embolism: a population-based study
    15. 15. VTE RecurrenceVTE Recurrence BaselineBaseline Hazard RatioHazard Ratio CharacteristicCharacteristic (95% CI)(95% CI) AgeAge 1.17 (1.11-1.24)1.17 (1.11-1.24) Body Mass IndexBody Mass Index 1.24 (1.04-1.47)1.24 (1.04-1.47) Neurologic disease withNeurologic disease with 1.87 (1.28-2.73)1.87 (1.28-2.73) extremity paresisextremity paresis Malignant neoplasmMalignant neoplasm None 1.00None 1.00 With chemotherapyWith chemotherapy 4.24 (2.58-6.95)4.24 (2.58-6.95) Without chemotherapyWithout chemotherapy 2.21 (1.60-3.06)2.21 (1.60-3.06) Predictors of First Overall VTE RecurrencePredictors of First Overall VTE Recurrence Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
    16. 16. Cancer Surgery, Thrombosis, and theCancer Surgery, Thrombosis, and the Biology of MalignancyBiology of Malignancy A Science-to-Strategy Perspective—TheA Science-to-Strategy Perspective—The Foundation Role of LWMH at the Interface ofFoundation Role of LWMH at the Interface of Thrombosis and CancerThrombosis and Cancer Program ChairmanProgram Chairman Ajay Kakkar, MBBS, PhD, FRCSAjay Kakkar, MBBS, PhD, FRCS Head of the Centre for Surgical SciencesHead of the Centre for Surgical Sciences Barts and the LondonBarts and the London Queen Mary’s School ofQueen Mary’s School of Medicine and DentistryMedicine and Dentistry The Thrombosis Research InstituteThe Thrombosis Research Institute London, UKLondon, UK Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies
    17. 17. AuthorAuthor YearYear No. ofNo. of studiesstudies Cancer mortalityCancer mortality UFHUFH LMWHLMWH GreenGreen 19921992 22 21/67 (31%)21/67 (31%) 7/62 (11%)7/62 (11%) SiragusaSiragusa 19951995 1313 23/81 (28%)23/81 (28%) 10/74 (14%)10/74 (14%) Meta-analysis ofMeta-analysis of DVT Treatment StudiesDVT Treatment Studies
    18. 18. Famous: Trial DesignFamous: Trial Design Treatment for 1 year or until deathTreatment for 1 year or until death 1º Endpoint: 1 year mortality (50%1º Endpoint: 1 year mortality (50% ⇒⇒ 35%)35%) 2º Endpoints: VTE and bleeding2º Endpoints: VTE and bleeding RRAdvanced solidAdvanced solid tumour malignancytumour malignancy N/Saline placeboN/Saline placebo DalteparinDalteparin 5000 IU od5000 IU od Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
    19. 19. Kaplan–Meier survival curves for all ITTKaplan–Meier survival curves for all ITT patients in dalteparin and placebo groupspatients in dalteparin and placebo groups Kaplan–MeiersurvivaldistributionKaplan–Meiersurvivaldistribution functionestimatefunctionestimate 0 12 24 36 48 60 72 84 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time from randomisation (months)Time from randomisation (months) No. at risk:No. at risk: DalteparinDalteparin PlaceboPlacebo 190190 8585 3030 2222 1212 55 44 DalteparinDalteparin 184184 7272 1515 99 88 55 22 PlaceboPlacebo Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
    20. 20. Survival Analysis:Survival Analysis: Good Prognosis PatientsGood Prognosis Patients Kaplan–MeiersurvivaldistributionKaplan–Meiersurvivaldistribution estimateestimate 17 23 29 35 41 47 53 5917 23 29 35 41 47 53 59 6565 71 77 8371 77 83 1.01.0 0.90.9 0.80.8 0.70.7 0.60.6 0.50.5 0.40.4 0.30.3 0.20.2 0.00.0 4747 17 10 9 917 10 9 9 8 8 5 3 28 8 5 3 2 00 PlaceboPlacebo 55 31 26 22 20 13 8 5 5 555 31 26 22 20 13 8 5 5 5 3 Dalteparin3 Dalteparin Time from randomisation (months)Time from randomisation (months) No. at risk:No. at risk: DalteparinDalteparin PlaceboPlacebo Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.Kakkar AK, et al. J Clin Oncol. 2004;22:1944-1948.
    21. 21. LMWH and Survival:LMWH and Survival: Further Studies (2003)Further Studies (2003) Solid tumor malignancy and acute VTE All patients received dalteparin 200 IU/kg od 5–7 days R Dalteparin 1 month 200 IU/kg od 5 months ≅160 IU/kg od Oral anticoagulant 6 months Small cell lung cancer (SCLC) Patients with responsive limited disease received thoracic radiotherapy Chemotherapy plus dalteparin 5000 IU od 18 weeks Chemotherapy (cyclophosphamide, epirubicin, vincristine) 18 weeks Solid tumor malignancy Nadroparin 2 weeks therapeutic dose 4 weeks 1/2 therapeutic dose Placebo 6 weeks CLOT SCLC study MALT R R Klerk CPW, et al.Klerk CPW, et al. J Clin OncolJ Clin Oncol. 2005;23:2130-2135.. 2005;23:2130-2135. Altinbas M, et al.Altinbas M, et al. J Thromb HaemostJ Thromb Haemost. 2004;2:1-6.. 2004;2:1-6. Lee, et.al.Lee, et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    22. 22. SCLC Study Survival CurvesSCLC Study Survival Curves 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 Months after randomization Probabilityofsurvival Good prognosis population limited disease1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 Months after randomization Probabilityofsurvival Overall population p=0.01 p=0.007 DalteparinDalteparin Placebo Placebo Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.Altinbas M, et al. J Thromb Haemost. 2004;2:1-6.
    23. 23. CLOT Survival CurvesCLOT Survival CurvesProbabilityofsurvival(%) Dalteparin OAC Days after randomization 0 10 20 30 40 50 60 70 80 90 100 0 30 60 90 120 150 180 210 240 270 300 330 360 390 OAC Dalteparin Probabilityofsurvival(%) 0 10 20 30 40 50 60 70 80 90 100 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Overall population Good prognosis population without metastases p=0.62 p=0.03 Days after randomization Lee, et.al.Lee, et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    24. 24. MALT Survival CurvesMALT Survival Curves ProbabilityofSurvival 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 Months after randomization Placebo Nadroparin p=0.010 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 Months after randomization ProbabilityofSurvival Placebo Nadroparin p=0.021 Overall population Good prognosis population >6 months survival Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.Klerk CPW, et al. J Clin Oncol. 2005;23:2130-2135.
    25. 25. Mechanistic explanationsMechanistic explanations VTE Coagulation Protease Direct Heparin OtherVTE Coagulation Protease Direct Heparin Other LMWH and Prolonged Cancer SurvivalLMWH and Prolonged Cancer Survival
    26. 26. SilverSilver In:In: The Hematologist - modified from Blom et. al.The Hematologist - modified from Blom et. al. JAMAJAMA 2005;293:7152005;293:715 • Population-based case-control (MEGA) study • N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects • CA patients = 7x OR for VTE vs. non-CA patients Effect of Malignancy on Risk ofEffect of Malignancy on Risk of Venous Thromboembolism (VTE)Venous Thromboembolism (VTE) 0 10 20 30 40 50 Hematological Lung Gastrointestinal Breast Distant metastases 0to3months 3to12months 1to3years 5to10years >15years Adjustedoddsratio Type of cancer Time since cancer diagnosis 2828 22.222.2 20.320.3 4.94.9 19.819.8 53.553.5 14.314.3 2.62.6 1.11.13.63.6
    27. 27. Mechanisms of Cancer-InducedMechanisms of Cancer-Induced Thrombosis: The InterfaceThrombosis: The Interface 1.1. Pathogenesis?Pathogenesis? 2.2. Biological significance?Biological significance? 33. Potential importance for cancer therapy?. Potential importance for cancer therapy?
    28. 28. Fibrinolytic activities: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities FIBRIN Endothelial cells IL-1, TNF- α, VEG F 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 Interface of Biology and CancerInterface of Biology and Cancer
    29. 29. Pathogenesis of Thrombosis in Cancer –Pathogenesis of Thrombosis in Cancer – A Modification of Virchow’s TriadA Modification of Virchow’s Triad 1.1. StasisStasis Prolonged bed restProlonged bed rest Extrinsic compression of blood vessels by tumorExtrinsic compression of blood vessels by tumor 2.2. Vascular InjuryVascular Injury Direct invasion by tumorDirect invasion by tumor Prolonged use of central venous cathetersProlonged use of central venous catheters Endothelial damage by chemotherapy drugsEndothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endotheliumEffect of tumor cytokines on vascular endothelium 3.3. HypercoagulabilityHypercoagulability Tumor-associated procoagulants and cytokines (tissueTumor-associated procoagulants and cytokines (tissue factor, CP, TNFfactor, CP, TNFαα, IL-1, IL-1ββ, VEGF, etc.), VEGF, etc.) Impaired endothelial cell defense mechanisms (APCImpaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S)resistance; deficiencies of AT, Protein C and S) Enhanced selectin/integrin-mediated, adhesive interactionsEnhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets andbetween tumor cells,vascular endothelial cells, platelets and host macrophageshost macrophages
    30. 30. Mechanisms of Cancer-InducedMechanisms of Cancer-Induced Thrombosis: Clot and Cancer InterfaceThrombosis: Clot and Cancer Interface ► Pathogenesis?Pathogenesis? ► Biological signBiological significanificance?ce? ► Potential importance for cancer therapy?Potential importance for cancer therapy?
    31. 31. Activation of Blood Coagulation in CancerActivation of Blood Coagulation in Cancer Biological Significance?Biological Significance? ► EpiphenomenonEpiphenomenon?? Is this a generic secondary event (as inIs this a generic secondary event (as in inflammation, where clot formation is aninflammation, where clot formation is an incidental finding)incidental finding) Or, is clotting . . .Or, is clotting . . . ► A Primary Event?A Primary Event? Linked to malignant transformationLinked to malignant transformation
    32. 32. TF VEGF Angiogenesis Endothelial cellsEndothelial cells IL-8IL-8 Blood Coagulation Activation FIBRIN PAR-2 Angiogenesis FVII/FVIIaFVII/FVIIa THROMBINTHROMBIN Tumor Cell TF Falanga and Rickles, New Oncology:Thrombosis, 2005 Interface of Biology and CancerInterface of Biology and Cancer
    33. 33. Coagulation Cascade and TumorsCoagulation Cascade and Tumors TFTF ThrombinThrombin Clotting-Clotting- dependentdependent Clotting-Clotting- dependentdependent Clotting-Clotting- independentindependent Clotting-Clotting- dependentdependent ANGIOGENESISANGIOGENESIS FibrinFibrin Clotting-Clotting- independentindependent PARsPARs Tumor Growth And MetastasisTumor Growth And Metastasis Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31
    34. 34. Regulation of Vascular Endothelial Growth Factor ProductionRegulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factorand Angiogenesis by the Cytoplasmic Tail of Tissue Factor 1.1. TF regulates VEGF expression in humanTF regulates VEGF expression in human melanoma cell linesmelanoma cell lines 2.2. Human cancer cells with increased TF are moreHuman cancer cells with increased TF are more angiogenic (and, therefore, more “metastatic’)angiogenic (and, therefore, more “metastatic’) in vivoin vivo due to high VEGF productiondue to high VEGF production Abe et.al.Abe et.al. Proc Nat Acad SciProc Nat Acad Sci 1999;96:8663-86681999;96:8663-8668
    35. 35. 3.3. The cytoplasmic tail of TF, which contains threeThe cytoplasmic tail of TF, which contains three serine residues, appears to play a role inserine residues, appears to play a role in regulating VEGF expression in human cancerregulating VEGF expression in human cancer cells, perhaps by mediating signal transductioncells, perhaps by mediating signal transduction 4.4. Data consistent with new mechanism(s) byData consistent with new mechanism(s) by which TF signals VEGF synthesis in humanwhich TF signals VEGF synthesis in human cancer cells; may provide insight into thecancer cells; may provide insight into the relationship between clotting and cancerrelationship between clotting and cancer Abe et.al.Abe et.al. Proc Nat Acad SciProc Nat Acad Sci 1999;96:8663-86681999;96:8663-8668 Regulation of Vascular Endothelial Growth Factor ProductionRegulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factorand Angiogenesis by the Cytoplasmic Tail of Tissue Factor
    36. 36. Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation ► Epiphenomenon?Epiphenomenon? ► Linked to malignant transformation?Linked to malignant transformation? 1.1. METMET oncogene induction produces DIC inoncogene induction produces DIC in human liver carcinomahuman liver carcinoma (Boccaccio et. al.(Boccaccio et. al. NatureNature 2005;434:396-400)2005;434:396-400) 2.2. PtenPten loss produces TF activation andloss produces TF activation and pseudopalisading necrosis in humanpseudopalisading necrosis in human glioblastomaglioblastoma (Rong et.al.(Rong et.al. Ca ResCa Res 2005;65:1406-1413)2005;65:1406-1413) 3.3. K-K-rasras oncogene, p53 inactivation and TFoncogene, p53 inactivation and TF induction in human colorectal carcinomainduction in human colorectal carcinoma (Yu et.al.(Yu et.al. BloodBlood 2005;105:1734-1741)2005;105:1734-1741)
    37. 37. ► METMET encodes a tyrosine kinase receptor forencodes a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF)hepatocyte growth factor/scatter factor (HGF/SF) →→ Drives physiologicalDrives physiological cellular program ofcellular program of “invasive growth” (tissue morphogenesis,“invasive growth” (tissue morphogenesis, angiogenesis and repair)angiogenesis and repair) Aberrant execution (e.g. hypoxia-inducedAberrant execution (e.g. hypoxia-induced transcription) is associated with neoplastictranscription) is associated with neoplastic transformation, invasion, and metastasistransformation, invasion, and metastasis Boccaccio et alBoccaccio et al NatureNature 2005;434:396-4002005;434:396-400 ““1.1. METMET Oncogene Drives a Genetic ProgrammeOncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Linking Cancer to Haemostasis” Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignantin Cancer: Malignant TransformationTransformation
    38. 38. ► Mouse model of Trousseau’s SyndromeMouse model of Trousseau’s Syndrome Targeted activated human MET to the mouseTargeted activated human MET to the mouse liver with lentiviral vector and liver-specificliver with lentiviral vector and liver-specific promoterpromoter →→ slowly, progressiveslowly, progressive hepatocarcinogenesishepatocarcinogenesis Preceded and accompanied by aPreceded and accompanied by a thrombohemorrhagic syndromethrombohemorrhagic syndrome Venous thrombosis in tail vein occurred earlyVenous thrombosis in tail vein occurred early and was followed by fatal internal hemorrhageand was followed by fatal internal hemorrhage Syndrome characterized bySyndrome characterized by ↑↑ d-dimer and PTd-dimer and PT andand ↓↓ platelet count (DIC)platelet count (DIC) ““METMET Oncogene Drives a Genetic ProgrammeOncogene Drives a Genetic Programme Linking Cancer to Haemostasis”Linking Cancer to Haemostasis”
    39. 39. Blood Coagulation Parameters in MiceBlood Coagulation Parameters in Mice Transduced with theTransduced with the METMET OncogeneOncogene TransgeneTransgene ParameterParameter Time after Transduction (days)Time after Transduction (days) 0 30 900 30 90 GFPGFP __________________ METMET Platelets (x10Platelets (x1033 )) D-dimer (D-dimer (µg/ml)µg/ml) PT (s)PT (s) ________________________________ Platelets (x10Platelets (x1033 )) D-dimer (µg/ml)D-dimer (µg/ml) PT (s)PT (s) 968 656 800968 656 800 <0.05 <0.05 <0.05<0.05 <0.05 <0.05 12.4 11.6 11.412.4 11.6 11.4 ______________________________________________________________ 974 350 150974 350 150 <0.05 0.11 0.22<0.05 0.11 0.22 12.9 11.8 25.112.9 11.8 25.1
    40. 40. Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation 2. “2. “PtenPten and Hypoxia Regulate Tissue Factorand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation ByExpression and Plasma Coagulation By Glioblastoma”Glioblastoma” ► PtenPten = tumor suppressor with lipid and protein= tumor suppressor with lipid and protein phosphatase activityphosphatase activity ► Loss or inactivation ofLoss or inactivation of PtenPten (70-80% of(70-80% of glioblastomas) leads to Akt activation andglioblastomas) leads to Akt activation and upregulation ofupregulation of Ras/MEK/ERKRas/MEK/ERK signaling cascadesignaling cascade Rong, Brat et.al. Ca Res 2005;65:1406-1413
    41. 41. ► Glioblastomas characterized histologically byGlioblastomas characterized histologically by “pseudopalisading necrosis”“pseudopalisading necrosis” ► Thought to be wave of tumor cells migratingThought to be wave of tumor cells migrating away from a central hypoxic zone, perhapsaway from a central hypoxic zone, perhaps created by thrombosiscreated by thrombosis ► Pseudopalisading cells produce VEGF and IL-8Pseudopalisading cells produce VEGF and IL-8 and drive angiogenesis and rapid tumor growthand drive angiogenesis and rapid tumor growth ► TF expressed by >90% of grade 3 and 4TF expressed by >90% of grade 3 and 4 malignant astrocytomas (but only 10% ofmalignant astrocytomas (but only 10% of grades 1 and 2)grades 1 and 2) ““PtenPten and Hypoxia Regulate Tissue Factor Expressionand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”and Plasma Coagulation By Glioblastoma”
    42. 42. Results:Results: 1.1. Hypoxia andHypoxia and PTENPTEN lossloss →↑→↑ TF (mRNA, AgTF (mRNA, Ag and procoagulant activity); partially reversedand procoagulant activity); partially reversed with induction ofwith induction of PTENPTEN 2.2. PTENPTEN effect independent of lipid phosphataseeffect independent of lipid phosphatase activity; dependent on protein phosphataseactivity; dependent on protein phosphatase 3.3. BothBoth AktAkt andand RasRas pathways modulated TF inpathways modulated TF in sequentially transformed astrocytes.sequentially transformed astrocytes. 4.4. Ex vivoEx vivo data:data: ↑↑ TF by immunohistochemicalTF by immunohistochemical staining in pseudopalisades of 7 humanstaining in pseudopalisades of 7 human glioblastoma specimensglioblastoma specimens ““PtenPten and Hypoxia Regulate Tissue Factor Expressionand Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation By Glioblastoma”and Plasma Coagulation By Glioblastoma”
    43. 43. Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation 3. “Oncogenic Events Regulate Tissue Factor3. “Oncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: ImplicationsExpression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”For Tumor Progression And Angiogenesis” ► Activation of K-Activation of K-rasras oncogene and inactivation ofoncogene and inactivation of p53p53 tumortumor suppressorsuppressor ↑↑ TF expression inTF expression in humanhuman 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 geneticCell-associated and MP-associated TF activity linked to genetic status of cancer cellsstatus of cancer cells ► TF siRNA reduced cell surface TF expression, tumor growthTF siRNA reduced cell surface TF expression, tumor growth and angiogenesisand angiogenesis ► TF may be required for K-TF may be required for K-ras-ras-driven phenotypedriven phenotype Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41
    44. 44. ““Oncogenic Events Regulate Tissue Factor Expression InOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: Implications For TumorColorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”Progression And Angiogenesis” TF expression in cancer cells parallels genetic tumor progression with an impact of K-ras and p53 status Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41 0 50 100 150 200 250 300 350 400 450 HKh-2 HCT116 379.2 0 20 40 60 80 100 120 140 160 HKh-2 HCT116 379.2 MeanChannelTFFlourescenceMeanChannelTFFlourescence TFActivity(U/10TFActivity(U/1066 cells)cells) del/+del/+ mut/+mut/+ mut/+mut/+ +/++/+ +/++/+ del/deldel/del
    45. 45. ““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells:Expression In Colorectal Cancer Cells: Implications For Tumor Progression AndImplications For Tumor Progression And Angiogenesis”Angiogenesis” Effect of TF si mRNA on tumor growth in vitro and in vivo Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41 Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation
    46. 46. 0 2 4 6 8 10 12 14 HCT116 SI-2 SI-3 MG only Effect of TF si mRNA on new vessel formation in colon cancerEffect of TF si mRNA on new vessel formation in colon cancer ““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells”Expression In Colorectal Cancer Cells” Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41 %VWF-PositiveArea%VWF-PositiveArea
    47. 47. ““Oncogenic Events Regulate Tissue FactorOncogenic Events Regulate Tissue Factor Expression In Colorectal Cancer Cells: ImplicationsExpression In Colorectal Cancer Cells: Implications For Tumor Progression And Angiogenesis”For Tumor Progression And Angiogenesis” Matrigel Assay: (D) HCT 116; (E) SI-3 cells – vWF immunohistology Activation of Blood CoagulationActivation of Blood Coagulation in Cancer: Malignant Transformationin Cancer: Malignant Transformation Yu, Mackman, Rak et.al.Yu, Mackman, Rak et.al. BloodBlood 2005;105:1734-412005;105:1734-41
    48. 48. Mechanisms of Cancer-InducedMechanisms of Cancer-Induced Thrombosis: ImplicationsThrombosis: Implications 1.1. Pathogenesis?Pathogenesis? 2.2. Biological significance?Biological significance? 3.3. Potential importance forPotential importance for cancer therapy?cancer therapy?
    49. 49. A Systematic Overview of VTEA Systematic Overview of VTE Prophylaxis In TheProphylaxis In The Setting of CancerSetting of Cancer Linking Science to Clinical PracticeLinking Science to Clinical Practice Craig M. Kessler, MDCraig M. Kessler, MD Professor of Medicine and PathologyProfessor of Medicine and Pathology Georgetown University Medical CenterGeorgetown University Medical Center Director of the Division of CoagulationDirector of the Division of Coagulation Department of Laboratory MedicineDepartment of Laboratory Medicine Lombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer Center Washington, DCWashington, DC Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies
    50. 50. VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology ► Of all cases of VTE:Of all cases of VTE: About 20% occur in cancer patientsAbout 20% occur in cancer patients Annual incidence of VTE in cancerAnnual incidence of VTE in cancer patients ≈ 1/250patients ≈ 1/250 ► Of all cancer patients:Of all cancer patients: 15% will have symptomatic VTE15% will have symptomatic VTE As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy ► Compared to patients without cancer:Compared to patients without cancer: Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants Higher risk of dyingHigher risk of dying Lee AY, Levine MN.Lee AY, Levine MN. CirculationCirculation. 2003;107:23 Suppl 1:I17-I21. 2003;107:23 Suppl 1:I17-I21
    51. 51. 1.1. Ambrus JL et al.Ambrus JL et al. J MedJ Med. 1975;6:61-64. 1975;6:61-64 2.2. Donati MB.Donati MB. HaemostasisHaemostasis. 1994;24:128-131. 1994;24:128-131 3.3. Johnson MJ et al.Johnson MJ et al. Clin Lab HaemClin Lab Haem. 1999;21:51-54. 1999;21:51-54 4.4. Prandoni P et al.Prandoni P et al. Ann Intern MedAnn Intern Med. 1996;125:1-7. 1996;125:1-7 DVT and PE in CancerDVT and PE in Cancer Facts, Findings, and Natural HistoryFacts, Findings, and Natural History ► VTE is the second leading cause of deathVTE is the second leading cause of death inin hospitalized cancer patientshospitalized cancer patients1,21,2 ► The risk of VTE in cancer patients undergoingThe risk of VTE in cancer patients undergoing surgery issurgery is 3- to 5-fold higher3- to 5-fold higher than those withoutthan those without cancercancer22 ► Up toUp to 50% of cancer patients50% of cancer patients may havemay have evidence ofevidence of asymptomatic DVT/PEasymptomatic DVT/PE33 ► Cancer patients with symptomatic DVT exhibit aCancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists forhigh risk for recurrent DVT/PE that persists for many yearsmany years44
    52. 52. Clinical Features of VTE in CancerClinical Features of VTE in Cancer ► VTE has significant negative impact onVTE has significant negative impact on quality of lifequality of life ► VTE may be the presenting sign of occultVTE may be the presenting sign of occult malignancymalignancy • 10% with idiopathic VTE develop10% with idiopathic VTE develop cancer within 2 yearscancer within 2 years • 20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE • 25% have bilateral DVT25% have bilateral DVT BuraBura et. al.,et. al., J Thromb HaemostJ Thromb Haemost 2004;2:445-512004;2:445-51
    53. 53. Risk Factors for Cancer-Associated VTERisk Factors for Cancer-Associated VTE ► CancerCancer TypeType • Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung • Women: breast, ovary, lungWomen: breast, ovary, lung StageStage ► TreatmentsTreatments SurgerySurgery • 10-20% proximal DVT10-20% proximal DVT • 4-10% clinically evident PE4-10% clinically evident PE • 0.2-5% fatal PE0.2-5% fatal PE SystemicSystemic Central venous cathetersCentral venous catheters (~4% generate(~4% generate clinically relevant VTE)clinically relevant VTE)
    54. 54. Thrombosis and Survival:Thrombosis and Survival: Likelihood of Death After HospitalizationLikelihood of Death After Hospitalization 0 20 40 60 80 100 120140 160 180 0.00 0.20 0.40 1.00 0.80 0.60 DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease Malignant DiseaseMalignant Disease DVT/PE OnlyDVT/PE Only Nonmalignant DiseaseNonmalignant Disease Number of Days Probabilityof Death Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285
    55. 55. As Number Of Cancer SurvivorsAs Number Of Cancer Survivors Increases, VTE Rates IncreaseIncreases, VTE Rates Increase YEARYEAR 0 0.5 1 1.5 2 2.5 3 3.5 4 79 81 83 85 87 89 91 93 95 97 99 VTEinHospitalizedCancerVTEinHospitalizedCancer AndNoncancerPatients(%)AndNoncancerPatients(%) Cancer PatientsCancer Patients Noncancer PatientsNoncancer Patients
    56. 56. 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 RelativeRiskofVTEinRelativeRiskofVTEin CancerPatientsCancerPatients PancreasPancreas BrainBrain MyeloprolMyeloprol StomachStomach LymphomaLymphoma UterusUterus LungLung EsophagusEsophagus ProstateProstate RectalRectal KidneyKidney ColonColon OvaryOvary LiverLiver LeukemiaLeukemia BreastBreast CervixCervix BladderBladder 4.54.5 44 3.53.5 33 2.52.5 22 1.51.5 11 0.50.5 Relative Risk of VTE Ranged From 1.02 to 4.34Relative Risk of VTE Ranged From 1.02 to 4.34
    57. 57. Thrombosis Risk In Cancer Primary Prophylaxis ► SurgerySurgery ► ChemotherapyChemotherapy ► RadiotherapyRadiotherapy ► Central Venous CathetersCentral Venous Catheters ► Acute Illness (immobilization)Acute Illness (immobilization)
    58. 58. Prevention and ManagementPrevention and Management of VTE in Cancerof VTE in Cancer ► Sparse data specifically related to cancerSparse data specifically related to cancer patients was available until recentlypatients was available until recently ► Cancer patients are a small subset (< 20%) inCancer patients are a small subset (< 20%) in most of the largest trials of antithromboticmost of the largest trials of antithrombotic therapytherapy ► Therefore, until the last two or three years, weTherefore, until the last two or three years, we needed to extrapolate from non-cancerneeded to extrapolate from non-cancer patients, bearing in mind that cancer patientspatients, bearing in mind that cancer patients are in the highest risk groupsare in the highest risk groups
    59. 59. PharmacologicPharmacologic (Prophylaxis & Treatment)(Prophylaxis & Treatment) Low MolecularLow Molecular Weight HeparinWeight Heparin (LMWH)(LMWH) NonpharmacologicNonpharmacologic (Prophylaxis)(Prophylaxis) UnfractionatedUnfractionated Heparin (UH)Heparin (UH) OralOral AnticoagulantsAnticoagulants ElasticElastic StockingsStockings InferiorInferior Vena CavaVena Cava FilterFilter IntermittentIntermittent PneumaticPneumatic CompressionCompression Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices New Agents: e.g.New Agents: e.g. Fondaparinux,Fondaparinux, Direct anti-Xa inhibitors,Direct anti-Xa inhibitors, Direct anti-IIa, etc.?Direct anti-IIa, etc.?
    60. 60. ► Cancer patients haveCancer patients have 2-fold risk of post-2-fold risk of post- operative DVT/PE and >3-fold risk of fataloperative DVT/PE and >3-fold risk of fatal PE despite prophylaxisPE despite prophylaxis:: Kakkar AK, et al.Kakkar AK, et al. Thromb HaemostThromb Haemost 2001; 86 (suppl 1): OC17322001; 86 (suppl 1): OC1732 Incidence of VTE in Surgical PatientsIncidence of VTE in Surgical Patients No CancerNo Cancer N=16,954N=16,954 CancerCancer N=6124N=6124 P-valueP-value Post-op VTEPost-op VTE 0.61%0.61% 1.26%1.26% <0.0001<0.0001 Non-fatal PENon-fatal PE 0.27%0.27% 0.54%0.54% <0.0003<0.0003 Autopsy PEAutopsy PE 0.11%0.11% 0.41%0.41% <0.0001<0.0001 DeathDeath 0.71%0.71% 3.14%3.14% <0.0001<0.0001
    61. 61. Natural History of VTE in CancerNatural History of VTE in Cancer Surgery:Surgery: The @RISTOS RegistryThe @RISTOS Registry ► Web-Based Registry of Cancer SurgeryWeb-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patientsTracked 30-day incidence of VTE in 2373 patients Type of surgeryType of surgery •• 52% General52% General •• 29% Urological29% Urological •• 19% Gynecologic19% Gynecologic 82% received in-hospital thromboprophylaxis82% received in-hospital thromboprophylaxis 31% received post-discharge thromboprophylaxis31% received post-discharge thromboprophylaxis FindingsFindings ► 2.1% incidence of clinically overt VTE (0.8% fatal)2.1% incidence of clinically overt VTE (0.8% fatal) ► Most events occur after hospital dischargeMost events occur after hospital discharge ► Most common cause of 30-day post-op deathMost common cause of 30-day post-op death Agnelli, abstract OC191, ISTH 2003Agnelli, abstract OC191, ISTH 2003
    62. 62. Nilsson: Arch Surg, 142;2007:126–132Nilsson: Arch Surg, 142;2007:126–132 Colorectal Cancer Resection Association Between Transfusion and Venous Thromboembolism Stratified by SexAssociation Between Transfusion and Venous Thromboembolism Stratified by Sex in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000in 14,104 Patients Undergoing Colorectal Cancer Resection in Maryland, 1994-2000 VariableVariable Incidence of VTE, %Incidence of VTE, % P ValueP Value Stratified ORStratified OR AdjustedAdjusted (95% CI)*(95% CI)* P ValueP Value Male SexMale Sex No Transfusion (n = 5683)No Transfusion (n = 5683) 0.70.7 ReferentReferent Transfusion (n = 1156)Transfusion (n = 1156) 0.80.8 .84.84 0.9 (0.5-1.9)0.9 (0.5-1.9) .85.85 Female SexFemale Sex No Transfusion (n = 5565)No Transfusion (n = 5565) 0.90.9 ReferentReferent Transfusion (n = 1610)Transfusion (n = 1610) 2.12.1 <.<.001001 1.8 (1.2-2.6)1.8 (1.2-2.6) .004.004 Overall, 1% incidence of VTE with 3.8 fold mortality Transfused women 1.8-fold more likely to develop VTE than non-transfused women
    63. 63. ► Age >40 yearsAge >40 years ► Cancer procoagulantsCancer procoagulants ► ThrombophiliasThrombophilias ► Adjuvant chemotherapy or hormonalAdjuvant chemotherapy or hormonal treatmenttreatment ► Complicated, lengthy surgery (tissueComplicated, lengthy surgery (tissue trauma, immobilization)trauma, immobilization) ► Debilitation and slower recoveryDebilitation and slower recovery ► Indwelling venous accessIndwelling venous access VTE Risk Factors in SurgicalVTE Risk Factors in Surgical Oncology PatientsOncology Patients
    64. 64. Clinical thromboembolismClinical thromboembolism CancerCancer 0 1.0 2.0 3.0 4.00 1.0 2.0 3.0 4.0 Major hemorrhageMajor hemorrhage Asymptomatic DVTAsymptomatic DVT Clinical PEClinical PE DeathDeath Total hemorrhageTotal hemorrhage Wound hematomaWound hematoma TransfusionTransfusion Non-cancerNon-cancer Mismetti P et al. Br J Surg 2001;88:913–30Mismetti P et al. Br J Surg 2001;88:913–30 Surgical ProphylaxisSurgical Prophylaxis LMWH betterLMWH better UFH betterUFH better
    65. 65. LMWH vs. UFHLMWH vs. UFH ► Abdominal or pelvic surgery for cancer (mostlyAbdominal or pelvic surgery for cancer (mostly colorectal)colorectal) ► LMWH once daily vs. UFH tid for 7–10 days post-opLMWH once daily vs. UFH tid for 7–10 days post-op ► DVT on venography at day 7–10 and symptomatic VTEDVT on venography at day 7–10 and symptomatic VTE 1. ENOXACAN Study Group.1. ENOXACAN Study Group. Br J SurgBr J Surg 1997;84:1099–1031997;84:1099–103 2. McLeod R, et al.2. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-4442001;233:438-444 Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients StudyStudy NN DesignDesign RegimensRegimens ENOXACANENOXACAN 11 631631 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH Canadian ColorectalCanadian Colorectal DVT ProphylaxisDVT Prophylaxis 22 475475 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH
    66. 66. Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients 0% 5% 10% 15% 20% UFH 5000 U tid enoxaparin 40 mg VTE Major Bleeding IncidenceofOutcomeEvent ENOXACANENOXACAN14.7%14.7% 2.9% 4.1%2.9% 4.1% 18.2% N=319N=319 N=312N=312 ENOXACAN Study Group. Br J Surg 1997;84:1099–103 P>0.05P>0.05
    67. 67. 0% 5% 10% 15% 20% UFH 5000 U tid enoxaparin 40 mg CanadianCanadian Colorectal DVTColorectal DVT Prophylaxis TrialProphylaxis Trial 13.9%13.9% 1.5% 2.7%1.5% 2.7% 16.9%16.9% N=234N=234 N=241N=241 McLeod R, et al.McLeod R, et al. Ann SurgAnn Surg 2001;233:438-4442001;233:438-444 P=0.052P=0.052 IncidenceofOutcomeEvent VTEVTE Major BleedingMajor Bleeding (Cancer) (All)(Cancer) (All) Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients
    68. 68. Extended prophylaxisExtended prophylaxis ► Abdominal or pelvic surgery for cancerAbdominal or pelvic surgery for cancer ► LMWH for ~ 7 days vs. 28 days post-opLMWH for ~ 7 days vs. 28 days post-op ► Routine bilateral venography at ~day 28Routine bilateral venography at ~day 28 1. Bergqvist D, et al. (for the ENOXACAN II investigators)1. Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-9802002;346:975-980 2. Rasmussen M, et al (FAME)2. Rasmussen M, et al (FAME) BloodBlood 2003;102:56a2003;102:56a Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients StudyStudy NN DesignDesign RegimensRegimens ENOXACAN IIENOXACAN II 332332 Double-blindDouble-blind Enoxaparin vs. placeboEnoxaparin vs. placebo FAMEFAME (subgroup)(subgroup) 198198 Open-labelOpen-label Dalteparin vs. noDalteparin vs. no prophylaxisprophylaxis
    69. 69. 0% 5% 10% 15% placebo enoxaparin 40 mg VTE Prox Any MajorVTE Prox Any Major DVT Bleeding BleedingDVT Bleeding Bleeding P=0.02P=0.02 5.1%5.1% 1.8%1.8% Bergqvist D, et al. (for the ENOXACAN II investigators)Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-9802002;346:975-980 ENOXACAN IIENOXACAN II IncidenceofOutcomeEventIncidenceofOutcomeEvent N=167N=167 N=165N=165 0% 0.4%0% 0.4% 12.0%12.0% 4.8%4.8% NNT = 14NNT = 140.6%0.6% 3.6%3.6% Extended Prophylaxis inExtended Prophylaxis in Surgical PatientsSurgical Patients
    70. 70. ► A multicenter, prospective, assessor-blinded, open-A multicenter, prospective, assessor-blinded, open- label, randomized trial:label, randomized trial: Dalteparin administered forDalteparin administered for 28 days after major abdominal surgery28 days after major abdominal surgery compared to 7compared to 7 days of treatmentdays of treatment ► RESULTS:RESULTS: CumulativeCumulative incidence of VTE was reducedincidence of VTE was reduced from 16.3% with short-term thromboprophylaxisfrom 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3%(29/178 patients) to 7.3% after prolongedafter prolonged thromboprophylaxis (12/165) (thromboprophylaxis (12/165) (relative risk reductionrelative risk reduction 55%;55%; 95% confidence interval 15-76; P=0.012).95% confidence interval 15-76; P=0.012). ► CONCLUSIONS:CONCLUSIONS: 4-week administration of dalteparin,4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTEsignificantly reduces the rate of VTE, without, without increasing the risk of bleeding, compared with 1increasing the risk of bleeding, compared with 1 week of thromboprophylaxis.week of thromboprophylaxis. Major Abdominal Surgery: FAMEMajor Abdominal Surgery: FAME Investigators—Dalteparin ExtendedInvestigators—Dalteparin Extended Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
    71. 71. ► Paucity of level I/II studies in this populationPaucity of level I/II studies in this population ► Based on small historical studies:Based on small historical studies: Postoperative risk of DVT/PE varies 12%Postoperative risk of DVT/PE varies 12%––35%35% LDUH (5000 u bid) ineffectiveLDUH (5000 u bid) ineffective LDUH 5000 u tid reduces risk by 50%LDUH 5000 u tid reduces risk by 50%––60%60% Once-daily LMWH comparable to LDUH for efficacyOnce-daily LMWH comparable to LDUH for efficacy and safetyand safety Gynecological Cancer SurgeryGynecological Cancer Surgery
    72. 72. Cochrane Systematic ReviewCochrane Systematic Review ► Meta-analysis of 8 randomized controlled trialsMeta-analysis of 8 randomized controlled trials ► Heparin reduces risk of DVT by 70% (95% CIHeparin reduces risk of DVT by 70% (95% CI 0.10–0.89)0.10–0.89) ► No evidence that anticoagulation reduces riskNo evidence that anticoagulation reduces risk of PEof PE ► No statistical difference between LDUH andNo statistical difference between LDUH and LMWH in efficacy and bleedingLMWH in efficacy and bleeding Gynecological SurgeryGynecological Surgery Oates-Whitehead et al.Oates-Whitehead et al. Cochrane Database Syst RevCochrane Database Syst Rev 2003;4:CD0036792003;4:CD003679
    73. 73. Urological Cancer SurgeryUrological Cancer Surgery Poorly studied populationPoorly studied population Risk of VTE varies with type of surgery and diagnosisRisk of VTE varies with type of surgery and diagnosis ► Small studies have suggested prophylaxis with either LDUH orSmall studies have suggested prophylaxis with either LDUH or LMWH is effective and safeLMWH is effective and safe ► Possible increased risk of pelvic hematoma and lymphocelePossible increased risk of pelvic hematoma and lymphocele formationformation Kibel, Loughlin.Kibel, Loughlin. J UrolJ Urol. 1995;153:1763-1774. 1995;153:1763-1774 DVTDVT PEPE Fatal PEFatal PE Radical retropubicRadical retropubic prostatectomyprostatectomy 11––3%3% 11––3%3% 0.6%0.6% CystectomyCystectomy 8%8% 22––4%4% 2%2% Radiological studiesRadiological studies 51%51% 22%22%
    74. 74. ► Majority of patients undergoingMajority of patients undergoing neurosurgery for malignancyneurosurgery for malignancy ► Risk of venographic VTE ~30%-40%Risk of venographic VTE ~30%-40% ► High risk of intracranial or intraspinalHigh risk of intracranial or intraspinal hemorrhagehemorrhage ► Mechanical prophylaxis preferred methodMechanical prophylaxis preferred method ► Use of anticoagulant prophylaxis remainsUse of anticoagulant prophylaxis remains controversial in this settingcontroversial in this setting Neurosurgery and VTENeurosurgery and VTE OBSERVATIONSOBSERVATIONS
    75. 75. Meta-analysis of three (3) RCTs evaluatingMeta-analysis of three (3) RCTs evaluating LMWH prophylaxisLMWH prophylaxis ► One major bleeding event observed for every 7 proximalOne major bleeding event observed for every 7 proximal DVTs prevented with LMWHDVTs prevented with LMWH ESES LMWHLMWH RRRR NNT/NNHNNT/NNH PP VTEVTE 28.3%28.3% 17.5%17.5% 0.60.6 99 0.0010.001 Proximal DVTProximal DVT 12.5%12.5% 6.2%6.2% 0.50.5 1616 <0.01<0.01 Total bleedingTotal bleeding 3.0%3.0% 6.1%6.1% 2.02.0 3333 0.020.02 Major bleedingMajor bleeding 1.3%1.3% 2.2%2.2% 1.71.7 115115 0.300.30 Iorio A, AgnellIorio A, Agnelli Gi G.. Arch Intern Med.Arch Intern Med. 2000;160:23272000;160:2327--23322332 Neurosurgery and VTE ProphylaxisNeurosurgery and VTE Prophylaxis
    76. 76. 77thth ACCP Consensus GuidelinesACCP Consensus Guidelines GradeGrade Recommendations for Cancer PatientsRecommendations for Cancer Patients 1A1A PatientsPatients undergoing surgeryundergoing surgery should receive LDUH 5000should receive LDUH 5000 U tid or LMWH > 3400 U dailyU tid or LMWH > 3400 U daily 2A2A Patients undergoing surgeryPatients undergoing surgery may receive post-hospitalmay receive post-hospital discharge prophylaxis with LMWHdischarge prophylaxis with LMWH 2A2A No routine prophylaxis to prevent thrombosis secondaryNo routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) andto central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)fixed-dose warfarin (1B) 1A1A Patients hospitalized with an acute medical illnessPatients hospitalized with an acute medical illness should receive LDUH or LMWHshould receive LDUH or LMWH Geerts W, et al.Geerts W, et al. ChestChest 2004; 126: 338S-400S2004; 126: 338S-400S
    77. 77. Thrombosis is a potential complication of centralThrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events: –Fibrin sheath formationFibrin sheath formation –Superficial phlebitisSuperficial phlebitis –Ball-valve clotBall-valve clot –Deep vein thrombosis (DVT)Deep vein thrombosis (DVT) •• Incidence up to 60% from historical dataIncidence up to 60% from historical data •• ACCP guidelines recommended routine prophylaxisACCP guidelines recommended routine prophylaxis with low dose warfarin or LMWHwith low dose warfarin or LMWH Central Venous CathetersCentral Venous Catheters Geerts W, et al.Geerts W, et al. ChestChest 2001;119:132S-175S2001;119:132S-175S
    78. 78. Placebo-Controlled TrialsPlacebo-Controlled Trials StudyStudy RegimenRegimen NN CRT (%)CRT (%) Reichardt*Reichardt* 20022002 Dalteparin 5000 U odDalteparin 5000 U od placeboplacebo 285285 140140 11 (3.7)11 (3.7) 5 (3.4)5 (3.4) Couban*Couban* 20022002 Warfarin 1mg odWarfarin 1mg od placeboplacebo 130130 125125 6 (4.6)6 (4.6) 5 (4.0)5 (4.0) ETHICSETHICS†† 20042004 Enoxaparin 40 mg odEnoxaparin 40 mg od placeboplacebo 155155 155155 22 (14.2)22 (14.2) 28 (18.1)28 (18.1) ** symptomatic outcomessymptomatic outcomes;; †† routine venography at 6 weeksroutine venography at 6 weeks Prophylaxis for Venous CathetersProphylaxis for Venous Catheters Reichardt P, et al.Reichardt P, et al. Proc ASCOProc ASCO 2002;21:369a; Couban S, et al,2002;21:369a; Couban S, et al, BloodBlood 2002;100:703a; Agnelli2002;100:703a; Agnelli G, et al.G, et al. Proc ASCOProc ASCO 2004;23:7302004;23:730
    79. 79. Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin ► 95 cancer patients receiving FU-based infusion95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailychemotherapy and 1 mg warfarin daily ► INR measured at baseline and four time pointsINR measured at baseline and four time points ► 10% of all recorded INRs >1.510% of all recorded INRs >1.5 ► Patients with elevated INRPatients with elevated INR 2.0–2.92.0–2.9 6%6% 3.0–4.93.0–4.9 19%19% >5.0>5.0 7%7% Central Venous Catheters: WarfarinCentral Venous Catheters: Warfarin Masci et al. J Clin Oncol. 2003;21:736-739
    80. 80. SummarySummary ► Recent studies demonstrate a lowRecent studies demonstrate a low incidence of symptomatic catheter-incidence of symptomatic catheter- related thrombosis (~4%)related thrombosis (~4%) ► Routine prophylaxis isRoutine prophylaxis is not warrantednot warranted toto prevent catheter-related thrombosis,prevent catheter-related thrombosis, but catheter patency rates/infectionsbut catheter patency rates/infections have not been studiedhave not been studied ► Low-dose LMWH and fixed-doseLow-dose LMWH and fixed-dose warfarin have not been shown to bewarfarin have not been shown to be effective for preventing symptomaticeffective for preventing symptomatic and asymptomatic thrombosisand asymptomatic thrombosis Prophylaxis for CentralProphylaxis for Central Venous Access DevicesVenous Access Devices
    81. 81. 77thth ACCP Consensus GuidelinesACCP Consensus Guidelines GradeGrade Recommendations for Cancer PatientsRecommendations for Cancer Patients 1A1A Patients undergoing surgery should receive LDUH 5000 U tidPatients undergoing surgery should receive LDUH 5000 U tid or LMWH > 3400 U dailyor LMWH > 3400 U daily 2A2A Patients undergoing surgery may receive post-hospitalPatients undergoing surgery may receive post-hospital discharge prophylaxis with LMWHdischarge prophylaxis with LMWH 2A2A No routine prophylaxis to prevent thrombosis secondary toNo routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-central venous catheters, including LMWH (2B) and fixed- dose warfarin (1B)dose warfarin (1B) 1A1A Patients hospitalized with an acute medical illness shouldPatients hospitalized with an acute medical illness should receive LDUH or LMWHreceive LDUH or LMWH Geerts W, et al.Geerts W, et al. ChestChest 2004; 126: 338S-400S2004; 126: 338S-400S
    82. 82. Primary Prophylaxis in CancerPrimary Prophylaxis in Cancer Radiotherapy in the Ambulatory PatientRadiotherapy in the Ambulatory Patient ► No recommendations from ACCPNo recommendations from ACCP ► No data from randomized trials (RCTs)No data from randomized trials (RCTs) ► Weak data from observational studiesWeak data from observational studies in high risk tumors (e.g. brain tumors;in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas-mucin-secreting adenocarcinomas- colorectal, pancreatic, lung, renal cell,colorectal, pancreatic, lung, renal cell, ovarian)ovarian) ► Recommendations extrapolated fromRecommendations extrapolated from other groups of patients if additionalother groups of patients if additional risk factors present (e.g. hemiparesisrisk factors present (e.g. hemiparesis in brain tumors, etc.)in brain tumors, etc.)
    83. 83. Risk Factors for VTE inRisk Factors for VTE in Medical Oncology PatientsMedical Oncology Patients ► Tumor typeTumor type Ovary, brain, pancreas, lung, colonOvary, brain, pancreas, lung, colon ► Stage, grade, and extent of cancerStage, grade, and extent of cancer Metastatic disease, venous stasis dueMetastatic disease, venous stasis due to bulky diseaseto bulky disease ► Type of antineoplastic treatmentType of antineoplastic treatment Multiagent regimens, hormones,Multiagent regimens, hormones, anti-VEGF, radiationanti-VEGF, radiation ► Miscellaneous VTE risk factorsMiscellaneous VTE risk factors Previous VTE,Previous VTE, hospitalization,hospitalization, immobility, infection, thrombophiliaimmobility, infection, thrombophilia
    84. 84. Independent Risk Factors for DVT/PEIndependent Risk Factors for DVT/PE Risk Factor/CharacteristicRisk Factor/Characteristic O.R.O.R. Recent surgery w/ institutionalizationRecent surgery w/ institutionalization 21.7221.72 TraumaTrauma 12.6912.69 Institutionalization without recent surgeryInstitutionalization without recent surgery 7.987.98 Malignancy with chemotherapyMalignancy with chemotherapy 6.536.53 Prior CVAD or pacemakerPrior CVAD or pacemaker 5.555.55 Prior superficial vein thrombosisPrior superficial vein thrombosis 4.324.32 Malignancy without chemotherapyMalignancy without chemotherapy 4.054.05 Neurologic disease w/ extremity paresisNeurologic disease w/ extremity paresis 3.043.04 Serious liver diseaseSerious liver disease 0.100.10 Heit JA et al.Heit JA et al. Thromb HaemostThromb Haemost. 2001;86:452-463. 2001;86:452-463
    85. 85. VTE Incidence In Various TumorsVTE Incidence In Various Tumors 47%47%Solid tumors (anti-VEGF + chemo)Solid tumors (anti-VEGF + chemo) 43%43%Renal cell carcinomaRenal cell carcinoma 28%28%Multiple myeloma (thalidomide + chemo)Multiple myeloma (thalidomide + chemo) 9%9%Advanced cancer (1-year survival=12%)Advanced cancer (1-year survival=12%) 6%6%Hodgkin’s disease w/ chemoHodgkin’s disease w/ chemo 3%3%Non-Hodgkin’s lymphomas w/ chemoNon-Hodgkin’s lymphomas w/ chemo 8%8%Breast cancer (Stage IV) w/ chemoBreast cancer (Stage IV) w/ chemo 26%26%High-grade gliomaHigh-grade glioma 2%2%Breast cancer (Stage I & II) w/ chemoBreast cancer (Stage I & II) w/ chemo 0.2%0.2%Breast cancer (Stage I & II) w/o further treatmentBreast cancer (Stage I & II) w/o further treatment VTEVTE IncidenceIncidenceOncology SettingOncology Setting Wilms tumor (cavoatrial extension) 4% 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
    86. 86. 16%16% Zangari, 2002Zangari, 2002 (192 pts)(192 pts) T+dox atT+dox at relapserelapse 17.8%17.8% Baz,Baz, 20042004 (103 pts)(103 pts) 14.7%14.7% Zangari, 2004Zangari, 2004 (68pts)(68pts) 7%7% Minnema,Minnema, 20042004 (412 pts)(412 pts) 31.4% Z31.4% Zangari,angari, 20042004 (35 pts)(35 pts) 34.5%34.5% Zangari, 2004Zangari, 2004 (87 pts)(87 pts) T+ dox inT+ dox in newlynewly diagnoseddiagnosed patientspatients 7%7% Weber,Weber, 20022002 (46 pts)(46 pts) 25%25% Weber, 2002Weber, 2002 (24 pts)(24 pts) 13%13% Cavo, 2004Cavo, 2004 (52 pts)(52 pts) 26%26% Cavo, 2002Cavo, 2002 (19 pts)(19 pts) 18%18% Rajkumar, 2004Rajkumar, 2004 (102 pts)(102 pts) T+ D in newlyT+ D in newly diagnoseddiagnosed patientspatients AspirinAspirin (81(81 mg/d)mg/d) LMWHLMWHWarfarinWarfarin (INR 2 – 3)(INR 2 – 3) WarfarinWarfarin 1mg/daily1mg/daily No prophylaxisNo prophylaxisTherapyTherapy Strategies for Thromboprophylaxis inStrategies for Thromboprophylaxis in Thalidomide Treated MM PatientsThalidomide Treated MM Patients
    87. 87. DVTDVT Len + D(%)Len + D(%) D (%)D (%) Len + D(%)Len + D(%) D (%)D (%) MM-009MM-009 MM-010MM-010 00 22 44 66 88 1010 1212 1414 1616 PEPE Weber D. ASCO 2005 Annual MeetingWeber D. ASCO 2005 Annual Meeting MM-009/010: Thromboembolic EventsMM-009/010: Thromboembolic Events
    88. 88. Knight: N Engl J Med.2006,354:2079Knight: N Engl J Med.2006,354:2079 ► rEPO used more in USA and Canada ► L+Dex: 23% VTE with EPO vs 5% w/o EPO ► Placebo + Dex: 7% VTE with EPO vs 1% without EPO Incidence of VTE: USA and CanadaIncidence of VTE: USA and Canada >Israel, Australia, and Europe>Israel, Australia, and Europe Multivariate Analysis of the Risk of Thrombosis AssociatedMultivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone andwith Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of MultipleConcomitant Erythropoietin for the Treatment of Multiple MyelomaMyeloma TreatmentTreatment Odds RatioOdds Ratio P ValueP Value (95% CI)(95% CI) Lenalidomide plusLenalidomide plus 3.51 (1.77-6.97)3.51 (1.77-6.97) <0.001<0.001 High-dose dexamethasoneHigh-dose dexamethasone Concomitant erythropoietinConcomitant erythropoietin 3.21 (1.72-6.01)3.21 (1.72-6.01) <0.001<0.001
    89. 89. Thrombotic Outcomes from rEPO orThrombotic Outcomes from rEPO or Darbopoietin Use in Cancer PatientsDarbopoietin Use in Cancer Patients Bohlius: The Cochrane Library, Volume (4).2006 Among 6,769Among 6,769 pts with cancer,pts with cancer, RR for DVT withRR for DVT with rEPO/DarbeporEPO/Darbepo was increasedwas increased by 67%by 67% (RR=1.67; 95%(RR=1.67; 95% CI 1.35 to 2.06)CI 1.35 to 2.06)
    90. 90. Vitamin K antagonist (INR 2.0 - 3.0)Vitamin K antagonist (INR 2.0 - 3.0) >> 3 months3 months LMWH or UFHLMWH or UFH 5 to 7 days5 to 7 daysInitial treatment Long-term therapy Standard Treatment of VTEStandard Treatment of VTE Can We Do Better Than This?Can We Do Better Than This?
    91. 91. Recurrent VTE in Cancer – Subset Analysis ofRecurrent VTE in Cancer – Subset Analysis of the Home Rx Studies (UH/VKA vs. LMWH/VKA)the Home Rx Studies (UH/VKA vs. LMWH/VKA) Recurrent VTERecurrent VTE Events per 100 patient yearsEvents per 100 patient years P valueP value MalignantMalignant Non- MalignantNon- Malignant 27.127.1 9.09.0 0.0030.003 Hutten et.al.Hutten et.al. J Clin OncolJ Clin Oncol 2000;18:30782000;18:3078
    92. 92. Recurrent VTE in Cancer – SubsetRecurrent VTE in Cancer – Subset Analysis of the Home Rx StudiesAnalysis of the Home Rx Studies Major BleedingMajor Bleeding Events per 100 patient yearsEvents per 100 patient years P-valueP-value MalignantMalignant Non-Non- malignantmalignant 13.313.3 2.12.1 0.0020.002 Hutten et.al.Hutten et.al. J Clin OncolJ Clin Oncol 2000;18:30782000;18:3078
    93. 93. Oral Anticoagulant TherapyOral Anticoagulant Therapy in Cancer Patients: Problematicin Cancer Patients: Problematic ► Warfarin (Coumadin®) therapy isWarfarin (Coumadin®) therapy is complicated by:complicated by: Difficulty maintaining tight therapeutic control,Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions,due to anorexia, vomiting, drug interactions, etc.etc. Frequent interruptions for thrombocytopeniaFrequent interruptions for thrombocytopenia and proceduresand procedures Difficulty in venous access for monitoringDifficulty in venous access for monitoring Increased risk of both recurrence and bleedingIncreased risk of both recurrence and bleeding ► Is it reasonable to substitute long-termIs it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?LMWH for warfarin ? When? How? Why?
    94. 94. CLOT: Landmark Cancer/VTE TrialCLOT: Landmark Cancer/VTE Trial CANCER PATIENTS WITHCANCER PATIENTS WITH ACUTE DVT or PEACUTE DVT or PE RandomizationRandomization DalteparinDalteparin DalteparinDalteparin Oral AnticoagulantOral Anticoagulant DalteparinDalteparin [N = 677][N = 677] ► Primary Endpoints:Primary Endpoints: Recurrent VTE and BleedingRecurrent VTE and Bleeding ► Secondary Endpoint:Secondary Endpoint: SurvivalSurvival Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    95. 95. Landmark CLOT Cancer TrialLandmark CLOT Cancer Trial Reduction in Recurrent VTEReduction in Recurrent VTE 00 55 1010 1515 2020 2525 Days Post RandomizationDays Post Randomization 00 3030 6060 9090 120120 150150 180180 210210 ProbabilityofRecurrentVTE,%ProbabilityofRecurrentVTE,% Risk reduction =Risk reduction = 52%52% pp-value = 0.0017-value = 0.0017 DalteparinDalteparin OACOAC Recurrent VTERecurrent VTE Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    96. 96. DalteparinDalteparin N=338N=338 OACOAC N=335N=335 P-P- value*value* Major bleedMajor bleed 19 ( 5.6%)19 ( 5.6%) 12 ( 3.6%)12 ( 3.6%) 0.270.27 Any bleedAny bleed 46 (13.6%)46 (13.6%) 62 (18.5%)62 (18.5%) 0.0930.093 * Fisher’s exact test* Fisher’s exact test Bleeding Events in CLOTBleeding Events in CLOT Lee, Levine, Kakkar, Rickles et.al.Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,N Engl J Med, 2003;349:1462003;349:146
    97. 97. Treatment of Cancer-Associated VTETreatment of Cancer-Associated VTE StudyStudy DesignDesign LengthLength ofof TherapyTherapy (Months)(Months) NN RecurrentRecurrent VTEVTE (%)(%) MajorMajor BleedingBleeding (%)(%) DeathDeath (%)(%) CLOT TrialCLOT Trial (Lee 2003)(Lee 2003) DalteparinDalteparin OACOAC 66 336336 336336 99 1717 66 44 3939 4141 CANTHENOXCANTHENOX (Meyer 2002)(Meyer 2002) EnoxaparinEnoxaparin OACOAC 33 6767 7171 1111 2121 77 1616 1111 2323 LITELITE (Hull ISTH 2003)(Hull ISTH 2003) TinzaparinTinzaparin OACOAC 33 8080 8787 66 1111 66 88 2323 2222 ONCENOXONCENOX (Deitcher ISTH(Deitcher ISTH 2003)2003) Enox (Low)Enox (Low) Enox (High)Enox (High) OACOAC 66 3232 3636 3434 3.43.4 3.13.1 6.76.7 NS NS0.03 NS NS0.002 NS NS NR 0.09 0.030.09
    98. 98. Treatment and 2Treatment and 2° Prevention of VTE° Prevention of VTE in Cancer – Bottom Linein Cancer – Bottom Line ► New standard of care is LMWH atNew standard of care is LMWH at therapeutic doses for atherapeutic doses for a minimum of 3-6minimum of 3-6 monthsmonths (Grade 1A recommendation—ACCP)(Grade 1A recommendation—ACCP) ► Oral anticoagulant therapy to follow for asOral anticoagulant therapy to follow for as long as cancer is active (Grade 1Clong as cancer is active (Grade 1C recommendation—ACCP)recommendation—ACCP) Buller et.al. Chest Suppl 2004;126:401S-428SBuller et.al. Chest Suppl 2004;126:401S-428S New DevelopmentNew Development
    99. 99. CLOT 12-month Mortality All Patients 0 10 20 30 40 50 60 70 80 90 100 0 30 60 90 120 180 240 300 360 DalteparinDalteparin OACOAC HR 0.94 P-value = 0.40 Days Post Randomization ProbabilityofSurvival,% Lee A, et al. ASCO. 2003
    100. 100. 0 10 20 30 40 50 60 70 80 90 100 Days Post Randomization 0 30 60 90 120 150 180 240 300 360 ProbabilityofSurvival,% OAC Dalteparin HR = 0.50 P-value = 0.03 Anti-Tumor Effects of LMWH CLOT 12-month Mortality Lee A, et al. ASCO. 2003 Patients Without Metastases (N=150)
    101. 101. ► 84 patients randomized: CEV +/- LMWH (18 weeks)84 patients randomized: CEV +/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smokingPatients balanced for age, gender, stage, smoking history, ECOG performance statushistory, ECOG performance status LMWH for Small Cell Lung CancerLMWH for Small Cell Lung Cancer Turkish StudyTurkish Study Altinbas et al. J Thromb Haemost 2004;2:1266.Altinbas et al. J Thromb Haemost 2004;2:1266. Chemo +Chemo + DalteparinDalteparin Chemo aloneChemo alone P-valueP-value 1-y overall survival, %1-y overall survival, % 51.351.3 29.529.5 0.010.01 2-y overall survival, %2-y overall survival, % 17.217.2 0.00.0 0.010.01 Median survival, mMedian survival, m 13.013.0 8.08.0 0.010.01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily
    102. 102. VTE Prophylaxis Is UnderusedVTE Prophylaxis Is Underused in Patients With Cancerin Patients With Cancer 5 89 38 33 42 52 0 10 20 30 40 50 60 70 80 90 100 FRONTLINE Surgical 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: FRONTLINE Survey1 — 3891 Clinician Respondents RateofAppropriateProphylaxis,% Major Surgery2 Major Abdominothoracic Surgery (Elderly)3 Medical Inpatients4 Confirmed DVT (Inpatients)5 Cancer: Surgical Cancer: Medical 4. Rahim SA et al. Thromb Res. 2003;111:215-219 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
    103. 103. Venous Thromboembolism (VTE)Venous Thromboembolism (VTE) Prophylaxis in the Cancer PatientProphylaxis in the Cancer Patient Guidelines and Implications forGuidelines and Implications for Clinical PracticeClinical Practice Alex C Spyropoulos, MD, FACP, FCCPAlex C Spyropoulos, MD, FACP, FCCP Chair, Department of Clinical ThrombosisChair, Department of Clinical Thrombosis Lovelace Medical CenterLovelace Medical Center Clinical Associate Professor of MedicineClinical Associate Professor of Medicine Associate Professor of PharmacyAssociate Professor of Pharmacy University of New Mexico Health Sciences CenterUniversity of New Mexico Health Sciences Center Albuquerque, NM, USAAlbuquerque, NM, USA Clotting, Cancer, and ControversiesClotting, Cancer, and Controversies
    104. 104. Outline of PresentationOutline of Presentation ► VTE prophylaxis in cancerVTE prophylaxis in cancer Surgical, CVC, medicalSurgical, CVC, medical ► Guidelines for VTE prophylaxisGuidelines for VTE prophylaxis in the cancer patientin the cancer patient ACCP, NCCNACCP, NCCN ► Performance to datePerformance to date ► Opportunities for improvementOpportunities for improvement
    105. 105. Thromboprophylaxis in Cancer vs Non-Thromboprophylaxis in Cancer vs Non- Cancer Surgical patientsCancer Surgical patients Non-Cancer (%) N=16,954 Cancer (%) N=6124 P Post-op VTEPost-op VTE 0.610.61 1.261.26 <0.0001<0.0001 Non-fatal PENon-fatal PE 0.270.27 0.540.54 <0.0003<0.0003 Autopsy PEAutopsy PE 0.110.11 0.410.41 0.00010.0001 DeathDeath 0.710.71 3.143.14 0.00010.0001 Cancer patients have a 2-fold increased riskCancer patients have a 2-fold increased risk Of VTE and 3-fold increased risk of fatal PEOf VTE and 3-fold increased risk of fatal PE despite prophylaxisdespite prophylaxis Haas S et al Thromb Haemost 2005;94:814-819Haas S et al Thromb Haemost 2005;94:814-819 Kakkar AJ et al Thromb Haemost 2005;94:867-71Kakkar AJ et al Thromb Haemost 2005;94:867-71
    106. 106. Thromboprophylaxis in Surgical PatientsThromboprophylaxis in Surgical Patients ► ARISTOSARISTOS Prospective cohort of 2373 patientsProspective cohort of 2373 patients ► Overall symptomatic VTE 2.1% andOverall symptomatic VTE 2.1% and death 1.7%death 1.7% ► Advanced tumorAdvanced tumor OR 4.4 (95% CI 1.4 – 5.2)OR 4.4 (95% CI 1.4 – 5.2) Agnelli G Ann Surg 2006; 243:85-89Agnelli G Ann Surg 2006; 243:85-89
    107. 107. In-hospital Thromboprophylaxis inIn-hospital Thromboprophylaxis in Cancer SurgeryCancer Surgery ENOXACANENOXACAN Canadian Colorectal StudyCanadian Colorectal Study P=NSP=NS NNT=29NNT=29 P=0.05P=0.05 NNT=33NNT=33 ENOXACAN Study Group Br J Surg 1997;84:1099-1103ENOXACAN Study Group Br J Surg 1997;84:1099-1103 Mcleod R et al Ann Surg 2001;233:436-44Mcleod R et al Ann Surg 2001;233:436-44 0 2 4 6 8 10 12 14 VTE Major Bleed VTE Major Bleed UFH 5000 Enox 40 mg
    108. 108. Extended Thromboprophylaxis inExtended Thromboprophylaxis in Cancer SurgeryCancer Surgery ENOXACAN IIENOXACAN II FAMEFAME P= 0.02P= 0.02 NNT=14NNT=14 P<0.03P<0.03 NNT= 9NNT= 9 Berquvist D et al NEJM 2002;346:975-80Berquvist D et al NEJM 2002;346:975-80 Rasmusan M et al Blood 2003;102;52aRasmusan M et al Blood 2003;102;52a 0 5 10 15 20 25 30 35 40 VTE Prox DVT VTE Prox DVT Placebo Enox 40 mg Placebo 2 Dalteparin
    109. 109. Systematic Review of DVT Prophylaxis ofSystematic Review of DVT Prophylaxis of Surgical Cancer PatientsSurgical Cancer Patients ► 26 RCTs of 7,639 patients26 RCTs of 7,639 patients Overall DVT of pharmacological PxOverall DVT of pharmacological Px vs controls - 12.7% vs 35.2%vs controls - 12.7% vs 35.2% High dose vs Low dose LMWH forHigh dose vs Low dose LMWH for DVT 7.9% vs 14.5% (p<0.01)DVT 7.9% vs 14.5% (p<0.01) No differences in LMWH vs UFH inNo differences in LMWH vs UFH in efficacy, DVT location, or bleedingefficacy, DVT location, or bleeding Overall bleeding complications 3%Overall bleeding complications 3% Leonardi MJ et al Ann Surg Oncol 2007;14(2):929-36
    110. 110. Thromboprophylaxis for CVCThromboprophylaxis for CVC ► Prior studies with ~ 5% incidence ofPrior studies with ~ 5% incidence of symptomatic catheter-related thrombosissymptomatic catheter-related thrombosis RegimenRegimen NN CathCath Thrombosis (%)Thrombosis (%) KathausKathaus 20062006 dalteparin 5000U qddalteparin 5000U qd placeboplacebo 285285 140140 11 (3.7)11 (3.7) 5 (3.4)5 (3.4) CoubanCouban 20052005 warfarin 1mg QDwarfarin 1mg QD PlaceboPlacebo 130130 125125 6 (4.6)6 (4.6) 5 (4.0)5 (4.0) Verso 2005Verso 2005 enoxaparin 40mg qdenoxaparin 40mg qd placeboplacebo 155155 155155 22 (14.2)22 (14.2) 28 (18.1)28 (18.1) Karthaus et al Oncol 2006;17:286-296Karthaus et al Oncol 2006;17:286-296 Couban et al JCO 2006: 23:4063-8Couban et al JCO 2006: 23:4063-8 Verso et al JCO 2006;23:4057-62Verso et al JCO 2006;23:4057-62
    111. 111. Thromboprophylaxis in HospitalizedThromboprophylaxis in Hospitalized Medical Cancer PatientsMedical Cancer Patients ► There are no randomized trials in hospitalzed medicalThere are no randomized trials in hospitalzed medical oncology patientsoncology patients ► Randomized, placebo controlled trials in acutely illRandomized, placebo controlled trials in acutely ill hospitalized medical patients (of which cancer patientshospitalized medical patients (of which cancer patients area percentagearea percentage)) 0 2 4 6 8 10 12 14 16 ME DE NOX PRE VE NT ARTE MIS E noxaparin 40mg Plac ebo Dalteparin 5000IU Plac ebo2 F onda 2.5mg QD Plac ebo3 Pt noPt no 866866 29912991 644644 Cancer (%)Cancer (%) 1414 55 55
    112. 112. Dentali, F. et. al. Ann Intern Med 2007;146:278-288Dentali, F. et. al. Ann Intern Med 2007;146:278-288 Fatal Pulmonary Embolism DuringFatal Pulmonary Embolism During Anticoagulant ProphylaxisAnticoagulant Prophylaxis 0.001 0.01 0.1 1.0 10 100 1000 Favors Treatment Favors Placebo Study, Year (Reference) Prophylaxis n/n Placebo n/n RR Fixed (95% CI) RR Fixed (95% CI) Dahan et al, 1986 (41) 1/132 3/131 0.33 (0.03 to 3.14) Garlund at al, 1996 (35) 3/5776 12/5917 0.26 (0.07 to 0.91) Leizorovic et al, 2004 (23) 0/1829 2/1807 0.20 (0.01 to 4.11) Mahe et al, 2005 (22) 10/1230 17/1244 0.59 (0.27 to 1.29) Cohen at, 2006 (42) 0/321 5/323 0.09 (0.01 to 1.65) Total (95% CI) 0.38 (0.21 to 0.69) Total events 14 39
    113. 113. Unfractionated Heparin Prophylaxis:Unfractionated Heparin Prophylaxis: BID vs TID—What Works, What Doesn’t?BID vs TID—What Works, What Doesn’t? Meta-analysis: 12Meta-analysis: 12 RCTsRCTs ► DVT, PE, all VTE events, BleedingDVT, PE, all VTE events, Bleeding ► Proximal DVT plus PEProximal DVT plus PE BID VTE event rate:BID VTE event rate: 2.34 events per 1,0002.34 events per 1,000 patient dayspatient days TID event rate:TID event rate: 0.86 events per 1,0000.86 events per 1,000 patient dayspatient days P=0.05P=0.05 ► NNTNNT 676 hospital prophylaxis days676 hospital prophylaxis days with UFH TID to preventwith UFH TID to prevent 1 major bleed with 1,6491 major bleed with 1,649 hospital prophylaxis days ofhospital prophylaxis days of TID dosingTID dosing King CS et al. CHEST 2007;131:507-516King CS et al. CHEST 2007;131:507-516
    114. 114. 15,231 56,364 0 10,000 20,000 30,000 40,000 50,000 60,000 With HIT Without HIT Costofadmission($) Incidence and EconomicIncidence and Economic Implications of HITImplications of HIT 0.084 0.51 0 0.1 0.2 0.3 0.4 0.5 0.6 UFH LWMH IncidenceofHIT(%) Creekmore FM, et al.Creekmore FM, et al. Pharmacotherapy.Pharmacotherapy. 2006;26:1438-14452006;26:1438-1445.. N = 10,121N = 10,121 PP = 0.037= 0.037 PP < 0.001< 0.001
    115. 115. 2004 ACCP Recommendations2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that isCancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A)appropriate for their current risk state (Grade 1A) General, Gynecologic, Urologic SurgeryGeneral, Gynecologic, Urologic Surgery • Low Dose Unfractionated Heparin 5,000 units TIDLow Dose Unfractionated Heparin 5,000 units TID • LMWH > 3,400 units DailyLMWH > 3,400 units Daily – Dalteparin 5,000 unitsDalteparin 5,000 units – Enoxaparin 40 mgEnoxaparin 40 mg – Tinzaparin 4,500 unitsTinzaparin 4,500 units • GCS and/or IPCGCS and/or IPC Surgical patients may receive post-discharge prophylaxis with LMWH (Grade 2A)Surgical patients may receive post-discharge prophylaxis with LMWH (Grade 2A) No routine prophylaxis for central venous catheters, including LMWH (Grade 2B)No routine prophylaxis for central venous catheters, including LMWH (Grade 2B) and fixed-dose warfarin (Grade 1B)and fixed-dose warfarin (Grade 1B) Cancer patients with an acute medical illness receive prophylaxisCancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A)that is appropriate for their current risk state (Grade 1A) • Low Dose Unfractionated HeparinLow Dose Unfractionated Heparin • LMWHLMWH Contraindication to anticoagulant prophylaxis (Grade 1C+)Contraindication to anticoagulant prophylaxis (Grade 1C+) • GCS or IPCGCS or IPC Geerts WH et al. Chest. 2004;126(suppl):338S-400S
    116. 116. NCCN Practice Guidelines in VTENCCN Practice Guidelines in VTE DiseaseDisease At Risk Population Initial ProphylaxisAt Risk Population Initial Prophylaxis http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf ► Adult patientAdult patient ► Diagnosis orDiagnosis or clinicalclinical suspicion ofsuspicion of cancercancer ► InpatientInpatient Relative contra-Relative contra- indication toindication to anticoagulationanticoagulation treatmenttreatment Prophylactic anticoagulationProphylactic anticoagulation therapy (category 1)therapy (category 1) ++ sequentialsequential compression device (SCD)compression device (SCD) Mechanical prophylaxis (options)Mechanical prophylaxis (options) - SCD- SCD - Graduated compression stockings- Graduated compression stockings NONO YES YES RISK FACTOR ASSESSMENTRISK FACTOR ASSESSMENT ► AgeAge ► Prior VTEPrior VTE ► Familial thrombophiliaFamilial thrombophilia ► Active cancerActive cancer ► TraumaTrauma ► Major surgical proceduresMajor surgical procedures ► Acute or chronic medical illness requiringAcute or chronic medical illness requiring hospitalization or prolonged bed resthospitalization or prolonged bed rest ► Central venous catheter/IV catheterCentral venous catheter/IV catheter ► Congestive heart failureCongestive heart failure ► PregnancyPregnancy ► Regional bulky lymphadenopathy withRegional bulky lymphadenopathy with extrinsic vascular compressionextrinsic vascular compression AGENTS ASSOCIATEDAGENTS ASSOCIATED WITH INCREASED RISKWITH INCREASED RISK ► ChemotherapyChemotherapy ► Exogenous estrogenExogenous estrogen compoundscompounds - HRT- HRT - Oral contraceptives- Oral contraceptives - Tamoxifen/Raloxifene- Tamoxifen/Raloxifene - Diethystilbestrol- Diethystilbestrol ► Thalidomide/lenalidomideThalidomide/lenalidomide Modifiable risk factors: Lifestyle,Modifiable risk factors: Lifestyle, smoking, tobacco, obesity,smoking, tobacco, obesity, activity level/exerciseactivity level/exercise
    117. 117. http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesNCCN Practice Guidelines in VTE Diseasein VTE Disease Inpatient Prophylactic Anticoagulation TherapyInpatient Prophylactic Anticoagulation Therapy ► LMWHLMWH - Dalteparin 5,000 units subcutaneous daily- Dalteparin 5,000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily- Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily or 75- Tinzaparin 4,500 units (fixed dose) subcutaneous daily or 75 units/kg cubcutaneous dailyunits/kg cubcutaneous daily ► PentasaccharidePentasaccharide - Fondaparinux 2.5 mg subcutaneous daily- Fondaparinux 2.5 mg subcutaneous daily ► Unfractioned heparin 5,000 units subcutaneous 3 times dailyUnfractioned heparin 5,000 units subcutaneous 3 times daily
    118. 118. http://www.nccn.org/professionals/physician_gls/PDF/vte.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice GuidelinesNCCN Practice Guidelines in VTE Diseasein VTE Disease Relative Contraindications to Prophylactic orRelative Contraindications to Prophylactic or Therapeutic AnticoagulationTherapeutic Anticoagulation ► Recent CNS bleed, intracranial or spinal lesion at high risk forRecent CNS bleed, intracranial or spinal lesion at high risk for bleedingbleeding ► Active bleeding (major): more than 2 units transfused in 24 hoursActive bleeding (major): more than 2 units transfused in 24 hours ► Chronic, clinically significant measurable bleeding > 48 hoursChronic, clinically significant measurable bleeding > 48 hours ► Thrombocytopenia (platelets < 50,000/mcL)Thrombocytopenia (platelets < 50,000/mcL) ► Severe platelet dysfunction (uremia, medications, dysplasticSevere platelet dysfunction (uremia, medications, dysplastic hematopoiesis)hematopoiesis) ► Recent major operation at high risk for bleedingRecent major operation at high risk for bleeding ► Underlying coagulopathyUnderlying coagulopathy ► Clotting factor abnormalitiesClotting factor abnormalities - Elevated PT or aPTT (excluding lupus inhibitors)- Elevated PT or aPTT (excluding lupus inhibitors) - Spinal anesthesia/lumbar puncture- Spinal anesthesia/lumbar puncture ► High risk for fallsHigh risk for falls
    119. 119. Compliance With ACCP VTECompliance With ACCP VTE Prophylaxis Guidelines Is PoorProphylaxis Guidelines Is Poor 9.9% 6.7% 35,124 62,012 0 5,000 10,000 70,000 Numberofpatients At risk for DVT/PE Received compliant care 15.3% 12.7% 52.4% 2324 9175 1388 Orthopedic Surgery At-risk Medical Conditions General Surgery Urologic Surgery Gynecologic Surgery Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient GroupCompliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group
    120. 120. In-Hospital Prophylaxis by Medical Condition –In-Hospital Prophylaxis by Medical Condition – IMPROVE RegistryIMPROVE Registry 57% 45% 49% 63% 60% 55% 59% 55% 49% 64% 0% 20% 40% 60% 80% 100% Malignancy Other disease Renal failure Diabetes Severe Infection Hypertension Ischemic heart disease COPD or Resp. failure Stroke Heart failure (CHF) Tapson V et al Chest 2007 (in press)Tapson V et al Chest 2007 (in press)
    121. 121. Odds Ratio Malignancy 0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender 0.92 Hospital Size 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC 1.46 Duration of Immobility 1.60 VTE Risk Factors 1.78 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Effect Odds Ratio (95% CI) Predictors of the Use ofPredictors of the Use of ThromboprophylaxisThromboprophylaxis Kahn SR et Al. Thromb Res 2007; 119:145-155Kahn SR et Al. Thromb Res 2007; 119:145-155
    122. 122. Independent factors present at admission for in-hospitalIndependent factors present at admission for in-hospital bleeding – multivariate analysis (IMPROVE Registry)bleeding – multivariate analysis (IMPROVE Registry) Adjusted Odds RatioAdjusted Odds Ratio (95% CI)(95% CI) Bleeding disorderBleeding disorder 5.115.11 (2.38, 10.98)(2.38, 10.98) Active G-duodenal ulcerActive G-duodenal ulcer 4.934.93 (2.86, 8.50)(2.86, 8.50) Adm platelets<50 x 10Adm platelets<50 x 1099 3.003.00 (1.67, 5.41)(1.67, 5.41) Hepatic failureHepatic failure 2.792.79 (1.57, 4.95)(1.57, 4.95) ICU/CCU stayICU/CCU stay 2.412.41 (1.60, 3.63)(1.60, 3.63) Current cancerCurrent cancer 1.991.99 (1.39, 2.85)(1.39, 2.85) Central venous catheterCentral venous catheter 1.981.98 (1.33, 2.95)(1.33, 2.95) AgeAge ≥≥85 years85 years 1.911.91 (1.29, 2.85)(1.29, 2.85) S. creatinineS. creatinine ≥2.5 mg/dL≥2.5 mg/dL 1.881.88 (1.26, 2.79)(1.26, 2.79) Decousus H et al Blood 2005
    123. 123. Computer Reminder SystemComputer Reminder System ► Computer program linked to patient database to identifyComputer program linked to patient database to identify consecutive hospitalized patients at risk for VTEconsecutive hospitalized patients at risk for VTE ► Patients randomized to intervention group or control groupPatients randomized to intervention group or control group ► In the intervention group the physicians were alerted to theIn the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxisVTE risk and offered the option to order VTE prophylaxis ► Point scale for VTE riskPoint scale for VTE risk Major riskMajor risk:: CancerCancer, prior VTE, hypercoagulability, prior VTE, hypercoagulability (3 points)(3 points) Intermediate riskIntermediate risk: Major surgery (2 points): Major surgery (2 points) Minor riskMinor risk: Advanced age, obesity, bedrest, HRT,: Advanced age, obesity, bedrest, HRT, use of oral contraceptives (1 point)use of oral contraceptives (1 point) ► VTE prophylaxis (VTE prophylaxis (graduated elastic stockingsgraduated elastic stockings, IPC, UFH,, IPC, UFH, LMWH, warfarin)LMWH, warfarin) Kucher N, et al. N Engl J Med. 2005;352:969-77Kucher N, et al. N Engl J Med. 2005;352:969-77
    124. 124. Electronic Alerts to Prevent VTEElectronic Alerts to Prevent VTE 88 90 92 94 96 98 100 0 30 60 90 Freedomfrom DVTorPE(%) Number at risk Intervention group 1,255 977 900 853 Control group 1,251 876 893 839 Control group Intervention group P<0.001 Time (days) Kucher N, et al. N Engl J Med. 2005;352:969-77
    125. 125. Cohen A et al Thromb Haemost 2005;94(4):750-9 VTE Risk Assessment forVTE Risk Assessment for Hospitalized Medical PatientsHospitalized Medical Patients All medical patientsAll medical patients should be routinelyshould be routinely assessedassessed and considered forand considered for thromboprophylaxisthromboprophylaxis Is the patient > 40 yearsIs the patient > 40 years old with acute medicalold with acute medical illness and reducedillness and reduced mobility?mobility? Does the patient have one of the followingDoes the patient have one of the following acute medical illnesses/conditions?acute medical illnesses/conditions? Evidence-based: ■ Acute MIAcute MI ■ Acute heart failure—NYHA III/IVAcute heart failure—NYHA III/IV ■ Active cancer requiring therapyActive cancer requiring therapy ■ Severe infection/sepsisSevere infection/sepsis ■ Respiratory disease (respiratory failureRespiratory disease (respiratory failure with/without mechanical ventilation,with/without mechanical ventilation, exacerbations of chronic respiratoryexacerbations of chronic respiratory disease)disease) ■ Rheumatic disease (including acuteRheumatic disease (including acute arthritis of lower extremities and vertebralarthritis of lower extremities and vertebral compression)compression) ■ Ischemic strokeIschemic stroke ■ ParaplegiaParaplegia Consensus view only: ■ Inflammatory disorder with immobilityInflammatory disorder with immobility ■ Inflammatory bowel diseaseInflammatory bowel disease YESYES Does the patient have one of the followingDoes the patient have one of the following risk factors?risk factors? Evidence-based in acutely ill medical patients: ■ History of VTEHistory of VTE ■ History of malignancyHistory of malignancy ■ Concurrent acute infectious diseaseConcurrent acute infectious disease ■ Age > 75 yearsAge > 75 years Consensus view only: ■ Prolonged immobilityProlonged immobility ■ Age > 60 yearsAge > 60 years ■ Varicose veinsVaricose veins ■ ObesityObesity ■ Hormone therapyHormone therapy ■ Pregnancy/postpartumPregnancy/postpartum ■ Nephrotic syndromeNephrotic syndrome ■ DehydrationDehydration ■ ThrombopiliaThrombopilia ■ ThrombocytosisThrombocytosis
    126. 126. Cohen A et al Thromb Haemost 2005;94(4):750-9. VTE Risk Assessment forVTE Risk Assessment for Hospitalized Medical PatientsHospitalized Medical Patients Is pharmacologicalIs pharmacological thromboprophylaxisthromboprophylaxis contraindicated?contraindicated? YESYES MechanicalMechanical thromboprophylaxis withthromboprophylaxis with graduated compressiongraduated compression stockings or intermittentstockings or intermittent pneumatic compression ispneumatic compression is recommendedrecommended YESYES LMWH (enoxaparin 40 mg o.d. orLMWH (enoxaparin 40 mg o.d. or dalteparin 5000 IU o.d.) ordalteparin 5000 IU o.d.) or UFH (5000 IU t.i.d.)UFH (5000 IU t.i.d.) (LMWH preferred due to(LMWH preferred due to better safety profile)better safety profile) NONO No evidence for the benefits ofNo evidence for the benefits of thromboprophylaxis. However,thromboprophylaxis. However, patients should be considered forpatients should be considered for thromboprophylaxis on a case-by-thromboprophylaxis on a case-by- case basiscase basis NONO
    127. 127. ConclusionsConclusions Current practices of VTE prophylaxis in theCurrent practices of VTE prophylaxis in the cancer patcancer patientient ► Cancer surgical patients have an increased risk ofCancer surgical patients have an increased risk of VTE and fatal PE despite prophylaxisVTE and fatal PE despite prophylaxis ► Prophylaxis with LMWH or UFH reducesProphylaxis with LMWH or UFH reduces venographic VTE but not CVC-related thrombosisvenographic VTE but not CVC-related thrombosis ► Out-of-hospital prophylaxis with LMWH isOut-of-hospital prophylaxis with LMWH is warranted in specific surgical cancer populationswarranted in specific surgical cancer populations ► Prophylaxis in hospitalized non-surgical cancerProphylaxis in hospitalized non-surgical cancer patients is suboptimalpatients is suboptimal ► Compliance with ACCP and NCCN guidelines isCompliance with ACCP and NCCN guidelines is poorpoor

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