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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?