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Cancer-Associated
Thrombosis
Guidelines for Treatment
Professor Mark Levine, MD, MSc
McMaster 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
• 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.
Adapted from Barritt and Jordan Lancet 1960.
• 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?
Depolymerisation of UFH
UFH
Molecular weight =
16,000 Da
DEPOLYMERISATION
LMWH
Molecular weight =
4,500-5,000 Da
High affinity for AT III
Advantages of LMWH over UFH
• Binds less avidly to
plasma proteins,
platelets, and cells
• Dose-independent
renal clearance
• Good bioavailability
after 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
Primary studies
Major bleeding
(n=3,674)
Recurrent thromboembolism
(n=3,566)
Duroux (1991)
Hull (1992)
Prandoni (1992)
Lopaciuk (1992)
Simonneau (1993)
Lindmarker (1994)
Levine (1996)
Koopman (1996)
Fiessinger (1996)
Luomanmaki (1996)
Columbus (1997)
All studies (FEM)
OR 0.57 (P=0.047)
All studies (REM)
OR 0.71 (P=0.25)
0.01
0.1
Favours
LMWH
1
Odds
ratio
10
100
Favours
UFH
Adapted from Gould et al., Ann Intern Med 1999;130:800-9.
OR 0.85 (P=0.28)
OR 0.87 (P=0.40)
0.01
0.1
Favours
LMWH
1
Odds
ratio
100
10
Favours
UFH
Initial treatment of VTE
Outpatient LMWH vs inpatient UFH
Levine1
Columbus2
Koopman3
UFH
n=253
Enoxap
n=247
UFH
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
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.
Initial treatment of VTE
Outpatient LMWH vs inpatient UFH (cont’d)
Levine1
UFH
n=253
Enoxap
n=247
Hospital
days
(mean)
6.5
1.1†
Entirely
outpatient
treatment
0.0
49%
†
Columbus2
Koopman3
UFH Reviparin UFH
n=511
n=510
n=198
Nadroparin
n=202
9.4
6.4†
8.1
2.7†
0.0
27%
0.0
36%
Significantly fewer hospital days in LMWH group.
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
30
Hazard ratio 3.2
20
Cancer
10
No cancer
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time (months)
181
661
160
631
129
602
Adapted from Prandoni et al., Blood 2002;100:3484-8.
92
161
73
120
64
115
Cancer
No cancer
Cumulative Incidence of Clinically Important
Bleeding During Anticoagulant Therapy
Cumulative proportion
major bleeding (%)
30
Hazard ratio 2.2
20
Cancer
10
No cancer
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time (months)
181
661
170
636
141
615
Adapted from Prandoni et al., Blood 2002;100:3484-8.
102
170
81
127
68
124
Cancer
No cancer
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=0.09
5 bleeds in LMWH and 12 in Warfarin
CLOT Trial
Cancer patients with
acute DVT and/or PE
Dalteparin
Dalteparin
Dalteparin
Oral anticoagulant
R
DVT, deep vein thrombosis; PE, pulmonary embolism.
Adapted from Lee et al., NEJM 2003;349:146-53.
CLOT Trial
Group
Initial treatment
(5–7 days)
Long-term therapy
(6 months)
OAC
Dalteparin 200 IU/kg
sc once daily
Warfarin or acenocoumarol
(target INR 2.5)
LMWH
Dalteparin 200 IU/kg
sc once daily
OAC, oral anticoagulant.
Adapted from Lee et al. CLOT Trial 2003
Month 1: dalteparin 200 IU/kg
Month 2–6: 75–80% of full dose
Baseline Characteristics
LMWH
N = 338
OAC
N = 338
Female gender
179
169
Age, mean (years)
62
63
Outpatient
169
156
DVT only
235
230
PE ± DVT
103
108
0
80
63
1
135
150
2
118
122
Qualifying VTE
ECOG score
Baseline Characteristics
LMWH
N = 338
OAC
N = 338
Extent of solid tumour
no evidence
localised
metastatic
298
36
39
223
308
33
43
232
Haematological malignancy
Cancer treatment
40
266
30
259
Central venous catheter
Previous VTE
46
39
40
36
Probability of recurrent VTE (%)
Recurrent VTE
Risk reduction = 52%
P=0.0017
25
20
OAC
15
Dalteparin
10
5
0
0
30
60
90
120
150
Days post-randomization
Adapted from Lee et al., NEJM 2003;349:146-53.
180
210
Bleeding Events
Major bleed
Any bleed
* Fisher’s exact test
LMWH
N = 336
OAC
N = 336
19 (5.6%)
46 (13.6%)
12 (3.6%)
62 (18.5%)
P*
0.27
0.093
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
Adapted from JCO 2007;25,5490-505.
• 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.
Treatment: ASCO
• What is the best
treatment for patients
with cancer with
established VTE to
prevent recurrent VTE.
Adapted from JCO 2007;25,5490-505.
• 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.
Treatment: ASCO 2007
• What is the best
treatment for patients
with cancer with
established VTE to
prevent recurrent VTE.
Adapted from JCO 2007;25,5490-505.
• 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.
ESMO Guidelines
Initial Therapy
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
Adapted from Ann Oncol 2008.
ESMO Guidelines
Long Term
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
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?
Probability of recurrent VTE (%)
Recurrent VTE
Risk reduction = 52%
P = 0.0017
25
20
OAC
15
Dalteparin
10
5
0
0
30
60
90
120
150
Days post-randomization
Adapted from Lee et al., NEJM 2003;349:146-53.
180
210
Progress in Treatment?
• 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?