Cancer-Associated Thrombosis

Guidelines for Treatment

Professor Mark Levine, MD, MScMcMaster University

Juravinski Cancer Centre Hamilton, Ontario, Canada

Why do we treat proximal DVT?– To improve symptoms– To prevent progression and recurrence– To prevent pulmonary embolism– To prevent post-phlebitic syndrome

Why do we treat pulmonary embolism?– To improve symptoms– To prevent pulmonary hypertension– To prevent death

Adapted from Barritt and Jordan Lancet 1960.

• Patients with pulmonary embolism diagnosed clinically.

• Randomized to heparin 10,000 units Q6H x 6 doses plus concurrent nicoumalone for 14 days (target PT 2-3x control) or no treatment.

• In the 1st 35 patients, 0 of 16 anticoagulant patients died compared to 5 of 19 control patients, P=0.036 and 5 additional control patients had recurrent PE based on clinical diagnosis.

• 3 minor bleeds on anticoagulant therapy.

• Randomization was discontinued and then 38 additional patients were treated with anticoagulants with no adverse outcomes.

Adapted from Barritt and Jordan Lancet 1960.

Initial Therapy: Unfractionated or Low Molecular

Weight Heparin?

UFH Molecular weight =16,000 Da

DEPOLYMERISATION

LMWHMolecular weight =4,500-5,000 Da

High affinity for AT III

Depolymerisation of UFH

Advantages of LMWH over UFH

• Binds less avidly to plasma proteins, platelets, and cells

• Dose-independentrenal clearance

• Good bioavailabilityafter sc injection

• Experimentally less bleeding

• Once-daily sc injection

• Weight-adjusted dosing

• No laboratory monitoring

• Less HIT

• Outpatient therapy

HIT = heparin-induced thrombocytopenia; sc = subcutaneous

Initial treatment of VTE LMWH vs UFH

Adapted from Gould et al., Ann Intern Med 1999;130:800-9.

All studies (REM)

All studies (FEM)

0.01 0.1 1 10 100 0.01 0.1 1 10 100

OR 0.71 (P=0.25)

OR 0.57 (P=0.047)

OR 0.87 (P=0.40)

OR 0.85 (P=0.28)

FavoursLMWH

Oddsratio

FavoursUFH

FavoursLMWH

Oddsratio

FavoursUFH

Columbus (1997)Luomanmaki (1996)Fiessinger (1996)Koopman (1996)Levine (1996)Lindmarker (1994)Simonneau (1993)Lopaciuk (1992)Prandoni (1992)Hull (1992)Duroux (1991)Primary studies

Major bleeding(n=3,674)

Recurrent thromboembolism(n=3,566)

Initial treatment of VTEOutpatient LMWH vs inpatient UFH

Adapted from: 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators. N Engl J Med 1997;337:657-62. 3. Koopman et al., N Engl J Med 1996;334:682-87.

Levine1 Columbus2 Koopman3

UFH n=253

Enoxap

n=247UFH n=511

Reviparin n=510

UFH n=198

Nadroparin n=202

Recurrent VTE (%)

6.7 5.3 4.9 5.3 8.6 6.9

Major bleeding (%)

1.2 2.0 2.3 3.1 2.0 0.5

Initial treatment of VTE Outpatient LMWH vs inpatient UFH (cont’d)

† Significantly fewer hospital days in LMWH group.

Levine1 Columbus2 Koopman3

UFH n=253

Enoxap n=247

UFH n=511

Reviparin n=510

UFH n=198

Nadroparin n=202

Hospital days (mean)

6.5 1.1† 9.4 6.4† 8.1 2.7†

Entirely outpatienttreatment

0.0 49% 0.0 27% 0.0 36%

Adapted from 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators. N Engl J Med 1997;337:657-62. 3. Koopman et al. N Engl J Med 1996;334:682-87.

Cumulative Incidence of Recurrent VTE During Anticoagulant Therapy

0

181661

1

160631

2 3

129602

4 5 6

92161

7 8 9

73120

10 11 12

64115

0

10

20

30

Cu

mu

lati

ve p

rop

ort

ion

recu

rren

t th

rom

bo

emb

olis

m (

%)

Hazard ratio 3.2

Cancer

No cancer

CancerNo cancer

Time (months)

Adapted from Prandoni et al., Blood 2002;100:3484-8.

Cumulative Incidence of Clinically Important Bleeding During Anticoagulant Therapy

0

181661

1

170636

2 3

141615

4 5 6

102170

7 8 9

81127

10 11 12

68124

CancerNo cancer

0

10

20

30

Cu

mu

lati

ve p

rop

ort

ion

maj

or

ble

edin

g (

%)

Hazard ratio 2.2

Cancer

No cancer

Time (months)

Adapted from Prandoni et al., Blood 2002;100:3484-8.

Oral Anticoagulant Therapy in Cancer Patients

• Warfarin therapy is complicated:

– difficult to maintain tight therapeutic control(anorexia, vomiting, drug interactions).

– frequent interruptions for thrombocytopenia and procedures.

– venous access difficult.– increased risk of recurrence and bleeding.

Long-term Anticoagulant Therapy with LMWH

• Does not require laboratory monitoring

• Once- or twice-daily subcutaneous injection

• Effective in warfarin resistance

• Potentially less bleeding

CANTHANOX Trial

• Cancer patients with proximal DVT and/ or PE received initial enoxaparin 1.5 mg/kg subcu daily for at least four days.

• Randomized to continue enoxaparin at same dose or warfarin.

• Duration of therapy was three months.

Adapted from Meyer et al., Arch Intern Med 2002;162,1729.

CANTHANOX

Treatment Outcome (recurrent VTE and/or major

bleeding

LMWH (n=71) 7 (9%)

Warfarin (n=75) 15 (20%)

P=0.095 bleeds in LMWH and 12 in Warfarin

CLOT Trial

Oral anticoagulant

Adapted from Lee et al., NEJM 2003;349:146-53.

Cancer patients with

acute DVT and/or PER

Dalteparin

Dalteparin

Dalteparin

DVT, deep vein thrombosis; PE, pulmonary embolism.

Adapted from Lee et al. CLOT Trial 2003

Group Initial treatment Long-term therapy(5–7 days) (6 months)

OAC Dalteparin 200 IU/kg Warfarin or acenocoumarol sc once daily (target INR 2.5)

LMWH Dalteparin 200 IU/kg Month 1: dalteparin 200 IU/kgsc once daily Month 2–6: 75–80% of full

dose

OAC, oral anticoagulant.

CLOT Trial

Baseline Characteristics

LMWH OACN = 338 N = 338

Female gender 179 169

Age, mean (years) 62 63

Outpatient 169 156

Qualifying VTE

DVT only 235 230

PE ± DVT 103 108

ECOG score

0 80 63

1 135 150

2 118 122

Baseline Characteristics

LMWH OACN = 338 N = 338

Extent of solid tumour 298 308 no evidence 36 33 localised 39 43 metastatic 223 232

Haematological malignancy 40 30Cancer treatment 266 259

Central venous catheter 46 40Previous VTE 39 36

Recurrent VTE

0

5

10

15

20

25

Days post-randomization

0 30 60 90 120 150 180 210

Pro

bab

ilit

y o

f re

curr

ent

VT

E (

%) Risk reduction = 52%P=0.0017

Dalteparin

OAC

Adapted from Lee et al., NEJM 2003;349:146-53.

Bleeding Events

LMWH OAC P*N = 336 N = 336

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

Any bleed 46 (13.6%) 62 (18.5%) 0.093

* Fisher’s exact test

Treatment of VTE: Long-term

• Long-term LMWH “simplifies” treatment.

• In the CLOT trial each patient who received oral anticoagulants had on average 23 INRs performed (maximum 83).

American Society of Clinical Oncology Guidelines: Treatment of VTE

• What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE

• LMWH is the preferred choice for the initial treatment.

• LMWH given for at least six months is preferred for long term.

• Vitamin K antagonist INR (2-3) when LMWH not available.

Adapted from JCO 2007;25,5490-505.

Treatment: ASCO

• What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE.

• After six months, indefinite anticoagulant therapy for selected patients with active cancer e.g. metastases.

• IVC Filter only in patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite LMWH therapy.

Adapted from JCO 2007;25,5490-505.

Treatment: ASCO 2007

• What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE.

• For CNS malignancy, same therapy as for other cancers. However avoid anticoagulants if active intracranial bleeding, low platelets, etc.

• For elderly patient with cancer and VTE same approach as for other age groups.

Adapted from JCO 2007;25,5490-505.

ESMO Guidelines

dalteparin 200 IU/kg daily or enoxaparin 100 IU/kg BID

daily or UFH by IV continuous infusion

If severe renal failure (creatinine clearance < 30), IV UFH or LMWH monitored

by anti Xa monitoring

Thrombolytic therapy in selected patients

Initial Therapy

Adapted from Ann Oncol 2008.

ESMO Guidelines

long-term treatment for 6 months with

75–80% of the initial dose of LMWH

IVC filter in

recurrent PE despite adequate anticoagulant Rx or with a contraindication to

anticoagulants

Long Term

Adapted from Ann Oncol 2008.

Consensus Statement: International Union of Angiology and Union Internationale de Phlebologie

Initial Therapy Secondary Prevention

Weight adjusted LMWH or IV UFH

dalteparin LMWH 200 IU/kg subcu for four

weeks followed by five months of 75% of dose

Adapted from Int Angiol 2006;25,101-61.

So Where are We in 2008?

Has there been much research progress since 2003 in terms of

treatment of VTE in Cancer?

Recurrent VTE

0

5

10

15

20

25

Days post-randomization

0 30 60 90 120 150 180 210

Pro

babi

lity

of r

ecur

rent

VT

E (

%) Risk reduction = 52%

P = 0.0017

Dalteparin

OAC

Adapted from Lee et al., NEJM 2003;349:146-53.

• Can we do better than 8% recurrence at six months?

• Has long term LMWH been adopted?

• What is the duration of long term treatment?

• How should a patient who develops recurrent VTE on LMWH be treated?

Progress in Treatment?