1. Cancer-Associated Thrombosis
Guidelines for Treatment
Professor Mark Levine, MD, MSc
McMaster University
Juravinski Cancer Centre
Hamilton, Ontario, Canada

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

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

4. 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.
Adapted from Barritt and Jordan Lancet 1960.

5. 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.

6. Initial Therapy: Unfractionated or Low Molecular Weight Heparin?

7. Depolymerisation of UFH
Molecular weight =
16,000 Da
DEPOLYMERISATION
LMWH
Molecular weight =
4,500-5,000 Da
High affinity for AT III

8. Advantages of LMWH over UFH
Once-daily sc injection
Weight-adjusted dosing
No laboratory monitoring
Less HIT
Outpatient therapy
Binds less avidly to plasma proteins, platelets, and cells
Dose-independent renal clearance
Good bioavailability after sc injection
Experimentally less bleeding
HIT = heparin-induced thrombocytopenia; sc = subcutaneous

9. Initial treatment of VTE LMWH vs UFH
Major bleeding (n=3,674)
Recurrent thromboembolism (n=3,566)
Primary studies
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)
OR 0.85 (P=0.28)
All studies (REM)
OR 0.71 (P=0.25)
OR 0.87 (P=0.40)
0.01
0.1 1 10
100
0.01
0.1 1 10
100
Favours LMWH
Odds ratio
Favours UFH
Favours LMWH
Odds ratio
Favours UFH
Adapted from Gould et al., Ann Intern Med 1999;130:800-9.

10. 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
8.6
6.9
Major bleeding (%)
1.2
2.0
2.3
3.1
0.5
Adapted from: 1. Levine et al., N Engl J Med 1996;334: The Columbus Investigators.
N Engl J Med 1997;337: Koopman et al., N Engl J Med 1996;334:

11. Initial treatment of VTE Outpatient LMWH vs inpatient UFH (cont’d)
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 outpatient treatment
0.0
49%
27%
36%
† Significantly fewer hospital days in LMWH group.
Adapted from 1. Levine et al., N Engl J Med 1996;334: The Columbus Investigators.
N Engl J Med 1997;337: Koopman et al. N Engl J Med 1996;334:

12. Cumulative Incidence of Recurrent VTE During Anticoagulant Therapy
181
661 1
160
631 2 3
129
602 4 5 6 92
161 7 8 9 73
120 10 11 12 64
115 20 30
Cumulative proportion recurrent thromboembolism (%)
Hazard ratio 3.2
Cancer
No cancer
Time (months)
Adapted from Prandoni et al., Blood 2002;100:

13. Cumulative proportion major bleeding (%)
Cumulative Incidence of Clinically Important Bleeding During Anticoagulant Therapy
181
661 1
170
636 2 3
141
615 4 5 6
102 7 8 9 81
127 10 11 12 68
124
Cancer
No cancer 20 30
Cumulative proportion major bleeding (%)
Hazard ratio 2.2
Time (months)
Adapted from Prandoni et al., Blood 2002;100:

14. 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.

15. Long-term Anticoagulant Therapy with LMWH
Does not require laboratory monitoring
Once- or twice-daily subcutaneous injection
Effective in warfarin resistance
Potentially less bleeding

16. 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.

17. Outcome (recurrent VTE and/or major bleeding
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

18. CLOT Trial R Cancer patients with acute DVT and/or PE Dalteparin
Oral anticoagulant
DVT, deep vein thrombosis; PE, pulmonary embolism.
Adapted from Lee et al., NEJM 2003;349:

19. 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/kg sc once daily Month 2–6: 75–80% of full dose
OAC, oral anticoagulant.
Adapted from Lee et al. CLOT Trial 2003

20. Baseline Characteristics
LMWH OAC N = 338 N = 338
Female gender
Age, mean (years) 62 63
Outpatient
Qualifying VTE
DVT only
PE ± DVT
ECOG score

21. Baseline Characteristics
LMWH OAC N = 338 N = 338
Extent of solid tumour
no evidence 36 33
localised 39 43
metastatic
Haematological malignancy 40 30
Cancer treatment
Central venous catheter 46 40
Previous VTE 39 36

22. Days post-randomization Probability of recurrent VTE (%)5 10 15 20 25
Days post-randomization 30 60 90
120
150
180
210
Probability of recurrent VTE (%)
Risk reduction = 52% P=0.0017
Dalteparin
OAC
Adapted from Lee et al., NEJM 2003;349:

23. Bleeding Events LMWH OAC P* N = 336 N = 336
Major bleed (5.6%) (3.6%) 0.27
Any bleed (13.6%) (18.5%) 0.093
* Fisher’s exact test

24. 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).

25. 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,

26. 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,

27. 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,

28. Thrombolytic therapy in selected patients
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.

29. 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.

30. Weight adjusted LMWH or IV UFH
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,

31. So Where are We in 2008?
Has there been much research progress since 2003 in terms of treatment of VTE in Cancer?

32. Recurrent VTE Risk reduction = 52% P = 0.00175 10 15 20 25
Days post-randomization 30 60 90
120
150
180
210
Probability of recurrent VTE (%)
Risk reduction = 52% P =
Dalteparin
OAC
Adapted from Lee et al., NEJM 2003;349:

33. 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?