thrombosis in cancer patients cops 2010

1

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"

Page � 2

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

Page � 3

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% !!!

Page � 5

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

Page � 6

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

2

Page � 7

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

Page � 8

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

Page � 9

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

Page � 11

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

Page � 12

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

3

Page � 13

Virchow’s TriadVirchow’s Triad

VTEVTE

Hypercoagulability

Vascular injury

Stasis

Page � 14

Virchow’s TriadVirchow’s Triad

Petralia G, et al. Informa Healthcare. 2008.

Page � 15

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.

Page � 17

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

4

Page � 19


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

Page � 20



Diagnostic algorithm using clinical probability, D-dimer, and ultrasound in

patients with suspected DVT

Page � 21



Diagnostic algorithm using clinical probability of DVT likely, D-dimer, and

ultrasound in patients with suspected DVT

Page � 22

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.

Page � 23

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



Strategy for diagnosis of PE using V/Q scanning in patients who are PE

unlikely

5

Page � 25



Strategy for diagnosis of PE using CTPA in patients who are PE unlikely

Page � 26



Strategy for diagnosis of PE using CTPA or V/Q in patients who are PE likely

Page � 27

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

Page � 28

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)

Page � 29

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

Page � 30

Pharmacologic ProphylaxisPharmacologic Prophylaxis

� Aspirin

� Warfarin

� Unfractionated heparin (UFH)

� Low molecular weight heparin (LMWH)

� Fondaparinux

6

Page � 31

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

Page � 32

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.

Page � 33

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

Page � 34

WarfarinWarfarin: Mechanism of action: Mechanism of action

Martin JH. Aust Prescr 2009;32:76-80

Page � 35

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

7

Page � 37

UnfractionatedUnfractionated HeparinHeparin

www.ecconline.info Page � 38

MOA: UFH, LMWH, MOA: UFH, LMWH, FondaparinuxFondaparinux

http://www.ashpmedia.org/popup/anticoagulation_additional.html

Page � 39

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

Page � 41

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

8

Page � 43

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.

Page � 45

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


Page � 47

Recurrent VTE or major hemorrhageRecurrent VTE or major hemorrhage


P=0.04

Page � 48

Mortality OutcomeMortality Outcome


22.7% and 11.3%, P=0.07

9

Page � 49

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


� 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

Page � 51

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?

Page � 52

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.

Page � 53

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

10

Page � 55

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


52% reduced risk for recurrent VTE9% and 17% in the dalteparin and oral anticoagulant groups

Page � 57

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. J Clin Oncol; 23:2123-2129 2005Page � 58

CLOT Trial: ConclusionsCLOT Trial: Conclusions


� 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

Page � 59

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.

11

Page � 61

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

Page � 63

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

Page � 65

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


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


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


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


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


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


Page � 77


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


thrombosis in cancer patients cops 2010

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