Thrombosis in Cancer Patients COPS 2010
Transcript of Thrombosis in Cancer Patients COPS 2010
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Suthan ChanthawongSuthan ChanthawongDivision of Pharmacy Practice
Faculty of Pharmaceutical Sciences
Khon Kaen University
Thrombosis in Cancer Patients Thrombosis in Cancer Patients
33rdrd Clinical Oncology Pharmacy Symposium (COPS)Clinical Oncology Pharmacy Symposium (COPS)“PatientPatient--Centered Communication in Cancer CareCentered Communication in Cancer Care"
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Scope of PresentationScope of Presentation
�� EpidemiologyEpidemiology
��PathophysiologyPathophysiology
��Primary Prevention in VTEPrimary Prevention in VTE
��Treatment of VTETreatment of VTE
�� Secondary Prevention of VTESecondary Prevention of VTE
��Take Home MessagesTake Home Messages
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CancerCancer--associated Thrombosisassociated Thrombosis
�Potentially fatal complication
�Clinical impacts
�Risk factors
�Therapeutic interventions:
– Primary prevention
– Treatment
– Secondary prevention
Kakkar AK. Br J Cancer 2010;102:s1 Page � 4
��Why Such a Lack of ComplianceWhy Such a Lack of Compliance:
�Underestimation of risk
�Failure to assess clinical sings and risk
�Concern regarding anticoagulation-associated bleeding
�Inconvenience of available agents
�Lack of awareness of currently available clinical guideline
�Resistance to changing established practice pattern
Facts about VTEFacts about VTE
Kirwan CC, et al. BMA 2003;327:597-8.
Kakkar AK, et al. Oncologist 2003;8:381-8.
�Patients were not at risk of VTE: 27%
�HT or CMT were not increase risk of VTE: 60%
�Did not use thromboprophylaxis in HT or CMT: 80%
��FRONTLINE SurveyFRONTLINE Survey: Do not use thromboprophylaxis:
�Surgical cancer: 50% !!!
�Medical cancer: 95% !!!
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1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999
1
0
2
3
4National Hospital Discharge Survey
VT
E I
nc
ide
nc
e (
%)
VT
E I
nc
ide
nc
e (
%)
Cancer
No cancer
YearsYears
Stein PD, et al. Am J Med. 2006;119:60-68.
Incidence of VTE in US Patients:Incidence of VTE in US Patients: 19791979--19991999
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Incidence of VTE/PE in different Incidence of VTE/PE in different tumourtumour
LevitanLevitan N, et al. Medicine 1999;78:285N, et al. Medicine 1999;78:285
An analysis of 41.2 million US Medicare (age≥65) patients admitted
to the hospital with a malignancy
SiteSite Rate of DVT/PE per 10Rate of DVT/PE per 1044 ptspts
Head/neck, Bladder, Breast 16-22
Oesophagus, Uterus, Cervix 43-49
Prostate, Lung, Rectal, Liver 55-69
Colon, Leukaemia, Renal, Stomach 76-85
Lymphoma, Pancreas 96-110
Brain, Ovary 117-120
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00 2020 4040 6060 8080 100100 120120 140 160 180140 160 1800.000.00
0.200.20
0.400.40
1.001.00
0.800.80
0.600.60
DVT/PE and Malignant Disease
Malignant Disease
DVT/PE Only
Nonmalignant Disease
Number of Days
Pro
ba
bil
ity
of
De
ath
LevitanLevitan N, et al. Medicine 1999;78:285N, et al. Medicine 1999;78:285
Thrombosis and SurvivalThrombosis and Survival: Death After Hospitalization: Death After Hospitalization
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8
7
6
5
4
3
2
1
0
Chemotherapy
Risk of VTE in the cancer population
Remission
Risk of VTE in the general population
Time
Diagnosis
Metastasis
End of lifeHospitalization
Ris
k (
Od
ds
Ra
tio
)
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.
Risk of VTE Varies Over Natural History of CancerRisk of VTE Varies Over Natural History of Cancer
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Risk Factors for VTE in Patients with CancerRisk Factors for VTE in Patients with Cancer
Patient-related factors
o Older age
o Gender
o Race
o higher in African Americans
o Lower in Asians
o Patient comorbidities
o History of VTE
Cancer-related factors
o Site of cancer
o Advanced stage
o Initial period after diagnosis
Treatment-related factors
o Major surgery
o Hospitalization
o Chemotherapy
o Hormonal therapy
o Antiangiogenic agents
o ESAs, Transfusions
Biomarkers
o Platelet and leukocyte counts
o Tissue factor
o P-selectin
o D-dimer
Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007. Page � 10
Important Consequences of VTE in Cancer Patients
Noble S, et al. Br J Cancer. 2010;102:s2-9.
Increased morbidity
Increased mortality
Increased risk of recurrent VTE
Bleeding complications
Pulmonary Hypertension
Cancer treatment delays
Increased healthcare costs
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Homeostatic Cascade: Simplified OverviewHomeostatic Cascade: Simplified Overview
Colman RW, et al. J Exp Med 2006;203:493-5.
Vessel injuriesVessel injuries
VasoconstrictionVasoconstriction
Decrease Decrease
blood flowblood flow
Platelet Platelet
release reactionrelease reactionSerotoninSerotonin
Platelet aggregationPlatelet aggregation
TXATXA22, ADP, ADP
Primary haemostatic plugPrimary haemostatic plug
Stable haemostatic plugStable haemostatic plug
Tissue factorTissue factor
Coagulation Coagulation
cascadecascade
ThrombinThrombin
FibinFibin
phospholipidphospholipid
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Fibrinolytic activities:t-PA, u-PA, u-PAR,
PAI-1, PAI-2
Procoagulant Activities
FIBRIN
Endothelial cells
IL-1,
TNF-a,
VEGF
Tumor cellsTumor cells
Monocyte
PMN leukocyte
Activation of
coagulation
Platelets
Angiogenesis,
Basement matrix
degradation.
Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, 2007
Interface of Biology and CancerInterface of Biology and Cancer
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Virchow’s TriadVirchow’s Triad
VTEVTE
Hypercoagulability
Vascular injury
Stasis
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Virchow’s TriadVirchow’s Triad
Petralia G, et al. Informa Healthcare. 2008.
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Diagnosis of VTE OverviewDiagnosis of VTE Overview
SignSign and Symptomand Symptom
DVT � Leg pain, tenderness, ankle oedema, calf
tenderness, and swelling, dilated veins, and
Homan’s sign (a sharp pain on dorsiflexion of
the foot)
PE � The signs and symptoms are present to varying
degrees in patients with DVT
� That objective testing must be carried out to
confirm the diagnosis of DVT
Haeger K, et al. Angiology 1969;20:219-23. Page � 16
Calculating Risk of CMT Associated ThrombosisCalculating Risk of CMT Associated Thrombosis
Patient CharacteristicsPatient CharacteristicsOdds ratio Odds ratio
(95% CI)(95% CI)
VTE risk VTE risk
ScoreScore
Site of cancer
Very high risk: stomach, pancreas
High risk: lung, lymphoma, gynecologic, GU exclude prostate
Low risk: breast, colorectal, head and neck
4.3 (1.2-15.6)
1.5 (0.9-2.7)
1 (reference)
2
1
1
Pre CMT platelet count ≥ 350,000/mm3 1.8 (1.1-3.2) 1
Hemoglobin level < 10 g/dl or use red cell growth factors 2.4 (1.3-4.2) 1
Pre CMT leukocyte count > 11,000/mm3 2.2 (1.2-4) 1
BMI ≥ 35 kg/m2 2.5 (1.3-4.7) 1
Incidence of VTE over a median 2.5 months of F/U
Score 1-2: 0.3%
Score ≥ 3: 6.7%
Khorana AA, et al. Blood 2008;111:4902-7.
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Calculating Risk of CMT Associated ThrombosisCalculating Risk of CMT Associated Thrombosis
Khorana AA, et al. Blood 2008;111:4902-7. Page � 18
Well’s Score System: DVT
Clinical findingPoint
total
Paralysis, paresis, or recent orthopedic casting of LE 1
Recently bedridden (> 3 days) or major surgery within
past 4 weeks1
Localized tenderness in deep vein system 1
Swelling of entire leg 1
Calf swelling 3 cm > than other leg (as measured 10cm
below the tibial tuberosity)1
Pitting edema greater in the symptomatic leg 1
Collateral non-varicose superficial veins 1
Active cancer or cancer treated within 6 mo 1
Alternative dx > DVT (i.e., Baker’s cyst, cellulitis, SVT,
myositis, post-phlebitis, inguinal LAD, etc)-2
Point total
Probability
of DVT
Point
total
Low -2 to 0
Moderate 1 to 2
High 3 to 8
Wells PS, et al. Lancet. 1997;350(9094):1795-8
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Diagnosis of VTE OverviewDiagnosis of VTE Overview
Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.
Diagnostic algorithm using D-dimer and ultrasound in patients with
suspected DVT without consideration of clinical probability
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Diagnosis of VTE OverviewDiagnosis of VTE Overview
Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.
Diagnostic algorithm using clinical probability, D-dimer, and ultrasound in
patients with suspected DVT
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Diagnosis of VTE OverviewDiagnosis of VTE Overview
Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.
Diagnostic algorithm using clinical probability of DVT likely, D-dimer, and
ultrasound in patients with suspected DVT
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Laboratory testing and pretest probability: PE
� Abnormalities on ECG:
– Unexplained tachycardia
� Chest radiographs
� Arterial PO2 and the alveolar-arterial oxygen
� Elevation of D-dimer level
� Limitation: false positive
– Infection, cancer, trauma, and other inflammatory states
Tapson VF, et al. Am J Respir Crit Care Med 1999;160:1043-66.
Tapson VF. N Engl J Med 2008;358:1037-52.
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Well’s Score System: PE
Clinical findingPoint
total
Clinical S/S of DVT (minimum of leg swelling and
pain with palpation of the deep vein)3
PE as or more likely than an alternative diagnosis 3
HR > 100 1.5
Immobilization or surgery in the previous 4
weeks1.5
Previous DVT/PE 1.5
Hemoptysis 1
Malignancy (on Treatment, Treated in the last 6
mo or palliative)1
Point total
Probability
of PE
Point
total
Low < 2
Moderate 2.0-6.0
High > 6.0
PE unlikely ≤ 4.0
PE likely > 4.0
Wells PS, et al. Lancet. 1997;350(9094):1795-8 Page � 24
Diagnosis of VTE OverviewDiagnosis of VTE Overview
Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.
Strategy for diagnosis of PE using V/Q scanning in patients who are PE
unlikely
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Diagnosis of VTE OverviewDiagnosis of VTE Overview
Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.
Strategy for diagnosis of PE using CTPA in patients who are PE unlikely
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Diagnosis of VTE OverviewDiagnosis of VTE Overview
Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.
Strategy for diagnosis of PE using CTPA or V/Q in patients who are PE likely
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VTE initial prophylaxisVTE initial prophylaxis
Adult inpatient with diagnosis of or Adult inpatient with diagnosis of or
suspicion of cancersuspicion of cancer
Relative contraindication to AnticoagulantRelative contraindication to Anticoagulant
YesYes
MechanicalMechanical
NoNo
Pharmacological Pharmacological ±±MechanicalMechanical
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Pharmacologic(Prophylaxis & Treatment)
Low Molecular
Weight Heparin
(LMWH)
Nonpharmacologic(Prophylaxis)
Unfractionated
Heparin (UH)
Oral
Anticoagulants
Elastic
Stockings
Inferior
Vena Cava
Filter
Intermittent
Pneumatic
Compression
(IPC)
Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
Electrical calf
Stimulation (ECS)
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NonNon--pharmacologic Prophylaxispharmacologic Prophylaxis
� High risk hemorrhagic complication
� Adjunct to pharmacological therapy
Intermittent Pneumatic CompressionIntermittent Pneumatic Compression Elastic stockingElastic stocking
Electrical calf stimulationElectrical calf stimulation
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Pharmacologic ProphylaxisPharmacologic Prophylaxis
� Aspirin
� Warfarin
� Unfractionated heparin (UFH)
� Low molecular weight heparin (LMWH)
� Fondaparinux
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ORALORAL PARENTERALPARENTERAL
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
AT
Adapted from Adapted from WeitzWeitz & Bates,& Bates, J J ThrombThromb HaemostHaemost 20072007
New AnticoagulantsNew Anticoagulants
TTP889
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
Betrixaban
TAK 442
Dabigatran
TFPI (tifacogin)
APC (drotrecogin alfa)
sTM (ART-123)
Fondaparinux
Idraparinux
DX-9065a
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Aspirin Aspirin
Limited evidence in cancer
In general; Should not be used
as a 1st pharmacological modality
Geerts WH, et al. Chest 2008;133:381s-453s.
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WarfarinWarfarin: Oral Vitamin K antagonist : Oral Vitamin K antagonist
� Rapidly absorption
� Long t1/2 36-42 hrs
� Inter-individual variation
� Narrow therapeutic window
� Drug-Drug interaction
Zacharski LR, et al. Oncologist 2005;10:72-9.
Hutten BA, et al. J Clin Oncol 2000;18:3078-83.
� Retrospective study in 2000
� Cancer VS non-cancer
� Intervention: Warfarin 3 mos (keep INR 2-3)
� Results: increased incidence of
� Recurrence: 27.1/100 vs 9.0/100 pt-yr
� Bleeding: 13.3/100 vs 2.1/100 pt-yr
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WarfarinWarfarin: Mechanism of action: Mechanism of action
Martin JH. Aust Prescr 2009;32:76-80
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WarfarinWarfarin: : InterindividualInterindividual VariabilityVariability
Redman AR, Pharmacotherapy, 2001; 21:235–242 Page � 36
UnfractionatedUnfractionated HeparinHeparin
� Sulphated-mucopolysaccharides
� 3000-30,000 Da (mean 15,000 Da)
� Continuous infusion or SQ
Hirsh J, et al. Chest 2008;133:141s-159s.
� Important Limitations:� High protein binding
� Non-linear pharmacokinetic
� Heparin-induced thrombocytopenia (HIT)
� Osteoporosis
� Narrow therapeutic window:
� aPTT monitoring
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UnfractionatedUnfractionated HeparinHeparin
www.ecconline.info Page � 38
MOA: UFH, LMWH, MOA: UFH, LMWH, FondaparinuxFondaparinux
http://www.ashpmedia.org/popup/anticoagulation_additional.html
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MOA: UFH, LMWH, MOA: UFH, LMWH, FondaparinuxFondaparinux
Weitz JI. N Engl J Med 1997;337:688-98. Page � 40
Low Molecular Weight HeparinLow Molecular Weight Heparin
� Enzymatic depolymerization
� 4000-5,000 Da
� Dalteparin, Enoxaparin, Tinzaparin,
Nadroparin, Bemiparin
� Once daily, Fixed or Wt-base
� Regular monitoring is not indicated� Excepts in obese, renal insufficiency
Hirsh J, et al. Chest 2008;133:141s-159s.
� Benefits:� Improve anticogulant effect
� Improve PK profile
� Reduced propensity: � Osteoporosis
� HIT
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FondaparinuxFondaparinux
� AT-binding polysaccharide
� Act through AT-mediating selective
inhibition of factor Xa
� Fixed dose 2.5 mg S.Q.
� Regular monitoring is not indicated
Hirsh J, et al. Chest 2008;133:141s-159s. Page � 42
VTE Prophylaxis and TreatmentVTE Prophylaxis and Treatment
Prophylaxis in
Hospitalized Patient
Prophylaxis in
ambulatory patients
Prophylaxis in patients
undergoing surgery
Treatment of VTE and
prevention of recurrent
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MetaMeta--analyses: LMWH and UFH treatment analyses: LMWH and UFH treatment
Leizorovicz A. Drugs 1996;52: suppl7:30-7.
Lensing AW, et al. Arch Intern Med 1995;155:601-7.
Siragusa S, et al. Am J Med 1996;100:269-77.
Hettiarachchi RJ, et al. Curr Opin Pulm Med 1998;4:220-5.
Gould MK, et al. Ann Intern Med 1999;130:800-9.
Dolovich LR, et al. Arch Intern Med 2000;160:181-8.
Van Dongen CJ, et al. Cochrane Database Syst Rev 2004:CD001100Page � 44
� Open-label, randomized trial was conducted to compare
the efficacy of a fixed dose of LMWH administered
subcutaneously with oral-dose warfarin in patients with
cancer and VTE for secondary prophylaxis
� A recent meta-analysis showed initial
treatment with LMWH caused a 40%
reduction in mortality rate among
patients with cancer compared with
patients who received initial treatment
with unfractionated heparin (UFH)
� Previous studies have suggested that
LMWH can be safely administered for
3 months
LMWH: Gap of KnowledgeLMWH: Gap of Knowledge
Meyer G, et al. Arch Intern Med 2002;162:1729-35.
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EnoxaparinEnoxaparin: Secondary Prevention: Secondary Prevention
�Cancer and DVT, PE, or both were eligible
� Interventions:
– A subcutaneous dose of enoxaparin (1.5 mg/kg/d)
– Enoxaparin and warfarin (6 to 10 mg orally) for 3 months (adjusted to
achieve an INR between 2.0 and 3.0)
�Outcome Measures
– The primary end point: the composite of treatment failure, defined as symptomatic
and objectively confirmed recurrent VTE and/or major bleeding within the 3
month treatment period
– Secondary end points: 3- and-6-month mortality, evolution of underlying cancer at
6 months, major and minor bleeding, heparin-induced thrombocytopenia, and
recurrent thromboembolism during the 6-month study period
Meyer G, et al. Arch Intern Med 2002;162:1729-35. Page � 46
EnoxaparinEnoxaparin: Outcomes: Outcomes
�During the 3-month treatment period, 15 (21.1%) and 7
(10.5%) patients in the warfarin and enoxaparin groups,
respectively, experienced major hemorrhage or recurrent VTE
(P=.09)
�A total of 21 (29.6%) and 13 (19.4%) patients who received
warfarin and enoxaparin treatment experienced major
hemorrhage, recurrent VTE, or died
Meyer G, et al. Arch Intern Med 2002;162:1729-35.
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Recurrent VTE or major hemorrhageRecurrent VTE or major hemorrhage
Meyer G, et al. Arch Intern Med 2002;162:1729-35.
P=0.04
Page � 48
Mortality OutcomeMortality Outcome
Meyer G, et al. Arch Intern Med 2002;162:1729-35.
22.7% and 11.3%, P=0.07
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Adverse Event and 6 month F/UAdverse Event and 6 month F/U
�Bleeding:
– 16.0% vs 7.0% (warfarin and enoxaparin) experienced major hemorrhage
– No patients in the enoxaparin gr. and 8.0% in warfarin gr. died due to bleeding
�Six Month Follow-up
– At the end of the 3-month treatment period, 121 patients were alive and were
followed for an additional 3 months
– A total of 29 (38.7%) and 22 (31.0%) patients in the warfarin and enoxaparin
groups died during the 6-month follow-up
– Cancer progressed in 27 (36.0%) and 24 (33.8%) patients during the 6-month
follow-up, respectively
Meyer G, et al. Arch Intern Med 2002;162:1729-35. Page � 50
ConclusionsConclusions
Meyer G, et al. Arch Intern Med 2002;162:1729-35.
� Warfarin was associated with a high bleeding rate in
patients with VTE and cancer
� The LMWH enoxaparin was as effective as warfarin
and was associated with a substantially lower bleeding
rate
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Vitamin K antagonist (INR 2.0 Vitamin K antagonist (INR 2.0 -- 3.0)3.0)
>> 3 months3 months
LMWH or UFH LMWH or UFH
5 to 7 days5 to 7 daysInitial treatment
Long-term therapy
Standard Treatment of VTEStandard Treatment of VTECan We Do Better Than This?Can We Do Better Than This?
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This multicenter, RCT was conducted to compare the efficacy of
dalteparin, an LMWH, with short-term dalteparin followed by
long-term oral anticoagulation with a coumarin in preventing
recurrent VTE in patients with cancer
At the time of this study, short-term LMWH
treatment, followed by long-term oral
anticoagulation, was the standard of care
For prevention of recurrent VTE in patients
with cancer
While providing some efficacy, oral
anticoagulation is associated with a number
of limitations, some of which are specific to
patients with cancer
Gap of Knowledge before 2003Gap of Knowledge before 2003
Lee AYY, et al. N Engl J Med 2003;349:146-53.
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CLOT TrialCLOT Trial
�Experienced acute, symptomatic DVT, PE, or both
� Intervention:
– Dalteparin (200 IU/kg once daily for 5 to 7 days) followed by a coumarin
derivative for 6 months (oral anticoagulant group)
– Dalteparin alone for 6 months (200 IU/kg once daily for 1 month, followed
by 150 IU/kg for 5 months)
�End points:
– Primary end point: the first episode of objectively documented,
symptomatic, recurrent DVT, PE, or both during the 6-month study period
– Secondary outcomes: clinically overt bleeding and death
Lee AYY, et al. N Engl J Med 2003;349:146-53. Page � 54
5 to 7 days
Dalteparin
200 IU/kg OD
Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo
Control GroupControl Group
Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo
Experimental GroupExperimental Group
1 month 6 months
Lee AY, et al. N Engl J Med. 2003;349:146-153.
The CLOT TrialThe CLOT Trial
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Primary efficacy outcome Primary efficacy outcome
Lee AYY, et al. N Engl J Med 2003;349:146-53. Page � 56
Probability of symptomatic recurrent VTEProbability of symptomatic recurrent VTE
Lee AYY, et al. N Engl J Med 2003;349:146-53.
52% reduced risk for recurrent VTE9% and 17% in the dalteparin and oral anticoagulant groups
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Secondary OutcomesSecondary Outcomes
� Safety
• There was no significant difference between the dalteparin
and oral anticoagulant groups in
• The rate of major bleeding (6% vs 4%, respectively)
• Or any bleeding (14% vs 19%, respectively)
� Mortality
• During the 6 month treatment period, 130 and 136 patients
died in the dalteparin and oral anticoagulant groups,
respectively
Lee AYY, et al. N Engl J Med 2003;349:146-53.
Lee AYY. et al. J Clin Oncol; 23:2123-2129 2005Page � 58
CLOT Trial: ConclusionsCLOT Trial: Conclusions
Lee AYY, et al. N Engl J Med 2003;349:146-53.
� An only-dalteparin regimen was more effective than a
regimen consisting of short-term dalteparin followed
by oral anticoagulation in reducing the risk of
recurrent VTE
� The two regimens produced approximately equivalent
risks for hemorrhagic complications
� Long-term self-injection of LMWH was acceptable to
patients enrolled in this study
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Long Term LMWH Long Term LMWH vsvs Usual careUsual care
� CA and acute symptomatic proximal-vein thrombosis
� Intervention:
• Treatment with tinzaparin or
• Long-term vitamin K antagonist therapy for 3 months
� Primary outcome measures:
• Objectively documented recurrent VTE or death at 3
months
• Patients were followed by telephone at 1 year for
objectively documented recurrent VTE or death
Hull RD, et al. Am J Med 2006;119:1062-72. Page � 60
Clinical OutcomesClinical Outcomes
� At 3 months, new episodes of VTE:
• 6% and 10% of tinzaparin and usual care patients
� At 12-month follow-up:
• There remained an excess risk for recurrent VTE among
patients who received usual care (16%) compared with
those who received tinzaparin (P=0.044)
� No difference between the 2 groups:
• All bleeding, major bleeding, minor bleeding or death
Hull RD, et al. Am J Med 2006;119:1062-72.
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Patients were randomized to receive 1 of 3 treatment regimens: � Low-dose enoxaparin:
� BID enoxaparin (1.0 mg/kg) for 5 d � OD enoxaparin (1.0 mg/kg) for 175 d
� High-dose enoxaparin:
� BID enoxaparin (1.0 mg/kg) for 5 d � OD enoxaparin (1.5 mg/kg) for 175 d
� Oral anticoagulation:
� BID enoxaparin (1.0 mg/kg) for 5 d until stable INR 2-3 on oral warfarin
begun on day 2 of enoxaparin
The efficacy and safety of extended-duration
(6 month) low- or high-dose enoxaparin,
compared with initial enoxaparin followed
by warfarin in the secondary prevention of
VTE in patients with cancer was examined
in the ONCENOXONCENOX study
ONCENOX studyONCENOX study
Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-96. Page � 62
ONCENOX: Clinical OutcomesONCENOX: Clinical Outcomes
� The incidence of recurrent VTE (ITT population):
– There was no difference between the low- and high-dose
enoxaparin groups
� Major hemorrhagic events:
– 1 patient (3%) in the warfarin group
– 2 (6%) in the low-dose enoxaparin group
– 4 (11%) in the high-dose enoxaparin group
Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-96.
These data suggest that enoxaparin, administered for
6 months in patients with cancer, is safe
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Acute Continue
Heparin or LMWH
together with a
VKA (e.g. warfarin)
untill an INR of 2.0-3.0
is achieved
VKA (e.g. warfarin)
INR 2.0-3.0
3-6-12 months or lifelong
Risk of VTE (5-7%/year)
vs.
Risk of bleeding (3-4%/year)
How long?
Treatment and secondary prevention of VTE Treatment and secondary prevention of VTE
Page � 64
Geerts WH, et al. Chest 2008;133(6 suppl):381s-453s.
88thth ACCP: ACCP: LongLong--term treatment for DVT or PEterm treatment for DVT or PE
�� Initial management of DVTInitial management of DVT
� Secondary prevention in patients with cancer � LMWH for the first 3 to 6 months of long-term anticoagulant therapy
� Duration of therapy � Warfarin or LMWH: indefinitely or until the cancer is resolved
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Study of VTE Prophylaxis in cancerStudy of VTE Prophylaxis in cancer
Trial N Intervention VTE Major
Bleeding
SurgicalSurgical patientspatients
Bergqvist et al.1 2070 Dalteparin 5000 IU qd
Dalteparin 2500 IU qd
8.5% vs 14.9%,
p<0.001
4.6% vs 3.6%,
NS
ENOXACAN2 631 Enoxaparin 40 mg qd,
UFH tid
14.7% vs 18.2% -
McLeod et al.3 475 Enoxaparin 40 mg qd,
UFH 5000 U tid
13.9% vs 16.9%,
p=0.052
NR
ENOXACAN II4 332 Enoxaparin 40 mg qd X 6-10 d
Then Enoxaparin 40 mg qd or
placebo X 19-21 d
E/E 4.8% vs E/P
12%, p=0.02;
E/E 5.5% vs E/P
13.8%, p=0.01
E/E 0.8% vs
E/P 0.4%,
p>0.99; E/E
1.2% vs E/P
0.4%, p=0.62
FAME5 198 Dalteparin 5000 IU qd X 1 week,
Dalteparin 5000 IU qd X 4 weeks
19.6% vs 8.8%,
p=0.03
NR
1. Bergqvist D, et al. Br J Surg 1995;82:496-501.
2. ENOXACAN Study Group. Br J Surg 1997;84:1099-103.
3. McLeod RS, et al. Ann Surg 2001;233:438-44.
4. Bergqvist D, et al. N Eng J Med 2002;346:975-80.
5. Rasmussen MS, et al. J Thromb Haemost 2003;1(suppl1): (Abstr 0C399).
Page � 66
Study of VTE Prophylaxis in cancerStudy of VTE Prophylaxis in cancer
Trial N Intervention VTE Major
Bleeding
MedicalMedical patients (Immobilized medical inpatients)patients (Immobilized medical inpatients)
ARTEMIS1 849 (131
CA:15.4%)
Fondaparinux 2.5 mg qd X 14 d,
Placebo X 6-14 d
5.6% vs 10.5%,
p=0.029
0.2% vs 0.2%,
MEDENOX2 118 Enoxaparin 40 mg qd X 6-14 d,
Placebo X 6-14 d
9.7% vs 19.5%,
p=0.4
NR
PREVENT3 3706 (190
CA:5.1%)
Dalteparin 5000 IU qd X 14 d,
Placebo X 14 d
2.77% vs 4.96%,
p=0.0015
0.49% vs 0.16%
1. Cohen AT, et al. BMJ 2006;332:325-9.
2. Alikhan R. Blood Coagul Fibrinolysis 2003;14:341-6.
3. Leizorovicz A, et al. Circulation 2004;110:874-9.
12
Page � 67
Study of VTE Treatment in cancerStudy of VTE Treatment in cancer
Trial N Intervention VTE Major
Bleeding
FRAXODI1 - Nadroparin bid, Dalteparin qd 7.2% vs 4.1% 1.2% vs 1.3%
Merli et al2 141 Enoxaparin bid, Enoxaparin qd,
UFH
6.4% vs 12.2%
vs 6.7% vs
21.1%, p=0.09
1.3% vs 1.7%
vs 2.1% vs 7%
vs 16%, p=0.09
CANTANOX3 146 Enoxaparin, warfarin 10.5% vs 21.1%,
p=0.09
7% vs 16%,
p=0.09
CLOT4 672 Dalteparin qd X 5-7 d + warfarin
X 6 mo, Dalteparin qd X 6 mo
15.8% vs 8%,
p=0.002
6% vs 4%,
p=0.27
LITE5 200 Tinzaparin, UFH + warfarin X 6 d,
then warfarin
T 6% vs W 10%,
T 7% vs W 16%,
p=0.04
T 7% vs W 7%
ONCENOX6 122 Enoxaparin X 5d then LD
Enoxaparin, HD Enoxaparin,
warfarin
LD 6.9% vs HD
6.3% vs W 10%
LD 6.5% vs HD
11.1% vs 2.9%
1. Charbonnier BA, et al. Thromb Haemost 1998;79:897-901.
2. Merli G, et al. Ann Intern Med 2001;134:191-202.
3. Meyer G, et al. et al. Arch Intern Med 2002;162:1729-35.
4. Lee AY, et al. N Eng J Med 2003;349:146-53.
5. Hull RD, et al. Am J Med 2006;119: 1062-72.
6. Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-96.
Page � 68
Anticoagulant regimens: Recommendation Anticoagulant regimens: Recommendation
NCCN Clinical Practice Guideline in Oncology. VTE 2010.
Lyman GH, et al. J Clin Oncol 2007;25:5490-505.
Management PhaseManagement Phase DosageDosage
Prophylaxis(duration: until ambulatory or D/C)
UFH
Dalteparin
Enoxaparin
Fondaparinux
Tinzaparin
5000 U SC q 8 hr
5000 U SC daily
40 mg SC daily
2.5 mg SC daily
4500 U SC or 75 U/kg SC daily
Treatment: initial (5-7 days for minimum)
UFH
Dalteparin
Enoxaparin
Fondaparinux
Tinzaparin
80 U/kg IV push then 18 U/kg/hr
100 U/kg SC q 12 hr; 200 U/kg SC daily
1 mg/kg SC q 12 hr; 1.5 mg/kg SC daily
< 50 kg: 2.5-5 mg SC daily;
50-100 kg: 5-7.5 mg SC daily
> 100 kg: 7.5-10 mg SC daily
175 U/kg SC daily
Treatment: long term(3-6 mo for DVT, 6-12 mo for PE)
Dalteparin(preferred in advanced or metastatic cancer)
Warfarin
200 U/kg SC daily X 1 mo � 150 U/kg SC daily
5-10 mg PO daily
Page � 69
IssuesIssues ASCOASCO ACCPACCP NCCNNCCN
Prophylaxis in hospitalized � All pts � High risk pts, bed ridden � All pts without CI
Prophylaxis in ambulatory � Not recommend for
routine
� LMWH or warfarin
recommend in MM
receiving thalidomide or
lenalidomide + CMT or
dexamethasone
� LMWH or warfarin
recommend in MM
receiving thalidomide or
lenalidomide + CMT or
dexamethasone
Prophylaxis in undergoing
surgery
� Major surgery: low dose
UFH or LMWH without
CI, ASAP in
postoperative period
� Higher-risk surgery:
low dose UFH TID or
LMWH or Fondaparinux
without CI,
Treatment of VTE and
prevention of recurrence
� LMWH initial 5-10 days
with cancer established
VTE,
� 6mo treatment in active
cancer,
� Vena cava filter only
indicated in
anticoagulant CI and
resistant
anticoagulation therapy
� LMWH for 1st 3-6 mo of
long term coagulation
therapy
� Subsequent treatment
by warfarin or LMWH
until cancer is resolved
� Evaluation risk-benefit
ratio periodically
� Initial treatment:
LMWH or Fondaparinux
� LMWH without warfarin
if prefer for proximal
DVT , PE in active cancer
� LMWH or warfarin (INR
2-3)
� Minimum duration
3-6 mo (DVT),
6-12 mo in PE
� Lifelong for active
cancer or persistent risk
factors
Guideline SummaryGuideline Summary
Lyman GH, et al. Am J Hematol 2007;82:777-82.
Geerts WH, et al. Chest 2008;133(6 suppl):381s-453s.
NCCN Guideline. VTE 2010.Page � 70
Take Home MassagesTake Home Massages
�Management of VTE remains a challenge
�LMWH preferred use as the initial treatment and
secondary prevention
�Minimum of 6 months and longer duration if the
cancer remains active
�Both recurrent thrombosis and bleeding remain
problems
�Need to make research more for the advent of new
anticoagulants
Page � 71
Important Questions to be AnsweredImportant Questions to be Answered
�How large and how consistent is any survival benefit?
�Which patients (tumour type, stage, prognostic
category) are most likely to benefit from therapy?
�Which anticoagulant is most effective?
�What duration of treatment is needed?
�How large is the risk of significant adverse effects?
Kakkar AK, et al. Br J Cancer. 2010;102(s1):s24-29
13
Page � 73
CLINICAL SCENARIOSCLINICAL SCENARIOS
Treatment of limb VTE:
Acute management• Commence LMWH in preference to UFH
- Dalteparin 200U/kg once daily s.c.
- Tinzaparin 175U/kg once daily s.c.
- Enoxaparin 1.5mg/kg once daily s.c.
(alternatively, enoxaparin 1mg/kg every 12 h s.c.)
• Fondaparinux may be considered
- Fondaparinux 5mg (<50 kg); 7.5mg (50–100 kg); 10mg (>100 kg) daily s.c.
Maintenance treatment• Continue LMWH at 75–80% treatment dose
• Alternatively, administer warfarin at a dose to achieve an INR of 2–3 if not on
myelosuppressive chemotherapy or complex supportive/concomitant medications
• Continue for at least 6 months. Indefinite treatment recommended if active
metastatic disease is observed or there is continued exposure to potentially
thrombogenic anticancer therapy
Coleman R, et al. Br J Cancer. 2010;102(s1):s17-23 Page � 74
CLINICAL SCENARIOSCLINICAL SCENARIOS
Treatment of limb VTE:
Anticoagulant Contraindication• Recent central nervous system bleed
• Active major bleed (42U in 24 h)
• Platelets < 50 X 109/l
• Severe platelet dysfunction
• Known bleeding tendency, e.g., haemophilia
• Elevated PT or aPTT above therapeutic target level
• Severely limited life expectancy or no palliative benefit
• Patient refusal
Coleman R, et al. Br J Cancer. 2010;102(s1):s17-23
Page � 75
CLINICAL SCENARIOSCLINICAL SCENARIOS
Treatment of PE:
� Assess severity, including ECHO or CT angiography if necessary for right
heart enlargement. Consider as high risk for death (15%) if systolic BP
<90mmHg
� High-risk massive embolus
- Oxygen
- Commence heparin 80U/kg and infuse at 18U/kg/h to maintain aPTT
between 2.0 and 2.5
- Commence thrombolyis with rtPA 100mg over 2 h or up to 50mg over
15min if rapidly deteriorating
� Uncomplicated
- Treat as for VTE
Coleman R, et al. Br J Cancer. 2010;102(s1):s17-23 Page � 76
CLINICAL SCENARIOSCLINICAL SCENARIOS
CVC-related thrombosis:
� Preservation of catheter access not essential
- Remove line and anticoagulate for 3 months
� Preservation of catheter access clinically important
- Anticoagulate with line in situ and for at least 3 months after removal.
Removal of line and reinsertion at a later date may be necessary if
symptoms worsen (e.g., recurrent emboli or increasing arm swelling)
Vena cava filter placement:� Contraindications to anticoagulation
� Failure of anticoagulation
� Non-compliance
� Documented multiple PE and chronic pulmonary hypertension
Coleman R, et al. Br J Cancer. 2010;102(s1):s17-23
Page � 77
CLINICAL SCENARIOSCLINICAL SCENARIOS
Therapeutic anticoagulant failure:
� During vitamin K antagonist therapy* Check compliance
* Increase target INR to 3–4
* Change to LMWH
* Consider vena caval filter
� During LMWH therapy* Check compliance
* Increase 75 to 80% maintenance dose to full-treatment dose
* Consider increase from treatment dose by 20–25%
* Convert once-daily to twice-daily administration
* Consider vena caval filter
Coleman R, et al. Br J Cancer. 2010;102(s1):s17-23