Thrombosis in Cancer

An Update on Risk Assessment, Prevention

and Treatment

Agnes Lee, MD, MSc, FRCPC

University of British Columbia, Vancouver, BC
June 2011
Disclosure
• Leo Pharma
• Sanofi aventis
• Pfizer
• Bayer
• Boehringer Ingelheim
• Daiichi Sankyo
Cancer-Associated Thrombosis
• Common complication in patients with cancer
• Higher mortality among cancer patients with VTE
than without
• 2nd leading cause of death in cancer patients
• Activation of coagulation is important for tumour
progression and metastasis
• Effective prophylaxis and treatment will reduce
morbidity and may decrease overall mortality

Heit Arch Intern Med 2000. Heit Arch Intern Med 1999. Sorensen NEJM 2000. Pradoni N Engl J Med 1992. Sorensen N Engl J
Med 1988. Chew Arch Intern Med 2006. Khorana J Thromb Haemost 2007.
Objectives

To review evidence and updates in:

• Risk Assessment Models
• Prevention of VTE
• Treatment of Recurrent VTE
Objectives

To review evidence and updates in:

• Risk Assessment Models
• Prevention of VTE
• Treatment of Recurrent VTE
 Risk Factors for VTE in Cancer
• Risk varies from 1 – 30% depending on:
Patient-related Cancer-related Treatment-related
• Older age • Primary site • Surgery
• Race • Histology • Chemotherapy
• Prior VTE • Metastatic • Hormonal therapy
• Platelet count disease • Antiangiogenic
• Comorbid • Time interval therapy
conditions since diagnosis • ESA
• Hospitalization
• Catheters
Lyman et al. J Clin Oncol 2007.
Risk Stratification

Risk
of VTE

Patient-related
Risk Factors

7
Risk Stratification

RAM?
+/-
Biomarkers?

Patient-related
Risk Factors

8
Risk Assessment Models
• Khorana Model
 Ambulatory patients followed for febrile neutropenia
and other complications on new chemo regimen
 VTE not a predefined outcome

• Ay Model
 Ambulatory patients with new diagnosis of cancer or
progression of cancer followed in the Vienna CATS
 VTE is primary outcome and objectively verified
 Khorana model + D-dimer + soluble P-selectin
Khorana et al. Blood 2008. Ay et al Blood 2010.
Khorana Model for Outpatients

Patient Characteristic Score

Site of Cancer
Very high risk (stomach, pancreas) 2
High risk (lung, lymphoma, gynecologic, GU excluding prostate) 1

Pre-chemotherapy platelet count > 350,000/mm3 1

Hb < 10g/dL or use of ESA 1

Prechemotherapy leukocyte count > 11,000/mm3 1

BMI > 35 kg/m2 1

Khorana et al. Blood 2008.

Khorana Model Validation
• Prospective follow up of 819 patients
• Median observation time/follow-up: 656 days

Log-rank test P<0.001) 6-mo cumulative VTE rates:

Patients Events
n %
Score ≥3 93 17.7%

Score 2 221 9.6%

Score 1 229 3.8%

Score 0 276 1.5%

Ay et al Blood 2010.
Ay Model for Outpatients
• Addition of D-dimer and soluble P-selectin to Khorana model:

6-mo cumulative VTE rates:

Patients, n Events, %
Score ≥5 30 35%

Score 4 51 20.3%

Score 3 130 10.3%

Score 2 218 3.5%
Score 1 190 4.4%
Score 0 200 1.0%

Ay et al Blood 2010.
Objectives

To review evidence and updates in:

• Risk Assessment Models
• Prevention of VTE
• Treatment of Recurrent VTE
ASCO Guidelines on Prophylaxis
• Surgical Patients
 Prophylaxis with LMWH or LDUH, with or without
mechanical methods, for 7 – 10 days
 Up to 4 weeks in patients with high risk features
• Hospitalized Medical Patients
 Should be considered candidates for anticoagulant
prophylaxis in the absence of contraindications
• Ambulatory Patients
 Routine prophylaxis NOT recommended
 LMWH or warfarin recommended for myeloma patients on
IMiDs + chemo or dexamethasone

Lyman et al. J Clin Oncol 2007.

Extended Prophylaxis After Surgery
placebo/no prophylaxis LMWH
20%

P=0.02 P=0.01 P=0.06

15%

10%

5%
NS NS NS
0%
VTE Maj Bleed VTE Maj Bleed VTE Maj Bleed
ENOXACAN II FAME CANBESURE
No. Cancer Pt 332 199 625
Bergqvist et al. N Engl J Med 2002. Rasmussen et al J Thromb Haemost 2006. Kakkar et al J Thromb Haemost 2010.
Surgical Cancer Patients
12
@RISTOS
10
Prospective cohort
Incidence of VTE, No.

8 N=2373
6 symptomatic VTE 2.1%
overall mortality 1.7%
4

0 46% due to
1-5 5-10 11-15 16-20 21-25 25-30 >30
Days post surgery fatal PE
Agnelli et al. Ann Surg 2006.
Surgical Cancer Patients
@RISTOS
Risk factors for VTE
previous history of VTE
anesthesia lasting > 2 hours
bed rest post-op > 4 days
advanced tumour
age > 60
Agnelli et al. Ann Surg 2006.
Odds Ratio (95% CI)
6.0 (2.1 – 16.8)
4.5 (1.1 – 19.0)
4.4 (2.5 – 7.8)
2.7 (1.4 – 5.2)
2.6 (1.2 – 5.7)
 Million Women Study
• 947,454 middle aged women in UK 1996-2001
• Prospectively followed for PE, DVT or death from VTE
using national hospital admission databases
• In first 12 weeks after surgery, risk of VTE:
 1 in 45 for hip or knee replacement
 1 in 85 for cancer surgery
 1 in 115 for vascular surgery
 1 in 140 for any surgery

Sweetland et al. BMJ 2009

 Million Women Study

91-fold

peak incidence at 3 weeks

53-fold

risk of PE higher than DVT

34-fold
Sweetland et al. BMJ 2009
ASCO Guidelines on Prophylaxis
• Surgical Patients
 Prophylaxis with LMWH or LDUH, with or without
mechanical methods, for 7 – 10 days
 Up to 4 weeks in patients with high risk features
• Hospitalized Medical Patients
 Should be considered candidates for anticoagulant
prophylaxis in the absence of contraindications
• Ambulatory Patients
 Routine prophylaxis NOT recommended
 LMWH or warfarin recommended for myeloma patients on
IMiDs + chemo or dexamethasone

Lyman et al. J Clin Oncol 2007.

Prophylaxis of Oncology Inpatients
• Major guidelines recommend standard prophylaxis
• No studies focused on cancer patients for inpatient
prophylaxis during medical admission
• A post hoc analysis (MEDENOX trial) reported non-
significant reduction in VTE with enoxaparin (RR
0.50; 0.14 – 1.72) in cancer subgroup (N~35/group)
• Compliance is poor at ~25%

Alikhan et al. Blood Coagul Fibrinolysis 2003. Amin et al J Clin Onco 2007 (abstract).
In hospital Prophylaxis

• Introduced VTE prophylaxis as a

Required Organizational Practice
• Five tests of compliance
• Reviews started January 2011
• Identified as a Clinical Care
Management priority by MoH

http://www.accreditation.ca/uploadedFiles/CHAR-2009-EN.pdf
ASCO Guidelines on Prophylaxis
• Surgical Patients
 Prophylaxis with LMWH or LDUH, with or without
mechanical methods, for 7 – 10 days
 Up to 4 weeks in patients with high risk features
• Hospitalized MedicalPatients
 Should be considered candidates for anticoagulant
prophylaxis in the absence of contraindications
• Ambulatory Patients
 Routine prophylaxis NOT recommended
 LMWH or warfarin recommended for myeloma patients on
IMiDs + chemo or dexamethasone

Lyman et al. J Clin Oncol 2007.

Oncology Outpatient Prophylaxis
20%

18% Placebo anticoagulant

16%
Incidence of VTE

14% RRR=85%
Not significant
12% P=0.03
10%

8%

6%

4%

2%

0%
Breast (IV) Breast (III/IV) NSCLC (III/IV) Glioma (III/IV)
Active: warfarin certoparin certoparin dalteparin
drug

Levine et al. Lancet 1994. Haas et al. JTH 2005. Perry et al. J Clin Oncol 2007.
PROTECHT Study
• Multicentre, double-blind, placebo-controlled 2:1 RCT
• Advanced lung, breast, GI, pancreas, ovary, H+N
• Nadroparin vs placebo for duration of chemo (up to 4m)

Nadroparin Placebo P-value

No. Patients 769 381

1° endpoint: VTE + ATE 2.0% 3.9% 0.02*

Major bleeding 0.7% 0 0.18

1-yr mortality 43% 41%

Agnelli et al. Lancet Oncol 2009.

*1-sided
 CONKO 004 Trial
• 312 patients receiving no treatment enoxaparin
chemotherapy for APC 10%
9.9%
• Randomized to gemcitabine 8%
or gemcitabine + enoxaparin P<0.01
6%
• Enoxaparin 1 mg/kg once daily
P=0.6
x 12 weeks then 40 mg once 4%
daily 3.8%
2% 2.6%
• Primary outcome: 1.3%
symptomatic VTE and fatal PE 0%
at 12 weeks VTE bleeding

Riess et al. ASCO May 2009.

 FRAGEM Trial
• 123 patients receiving no treatment dalteparin
chemotherapy for APC 35%

• Randomized to gemcitabine or 30%

31%
gemcitabine + dalteparin 25%
P=0.02
20%
• Dalteparin 200 U/kg once daily
x 1 month then 150 U/kg x 2 15%
P=0.03
months 10% 12%
5%
9%
• Primary outcome:
0%
0%
symptomatic VTE and fatal PE fatal PE or
VTE
at 3 months sudden death
Maraveyas et al. ESMO 2009.
 Prophylaxis in Oncol Outpatients
Statistics for each study MH risk ratio and 95% CI
MH risk Lower Upper
ratio limit limit p-Value

FAMOUS 0.77 0.21 2.84 0.70

TOPIC-1 1.01 0.36 2.81 0.99

TOPIC-2 0.53 0.25 1.11 0.09

PRODIGE 0.66 0.29 1.49 0.32

PROTECHT 0.50 0.22 1.13 0.10

SIDERAS 0.82 0.23 2.94 0.76

Other Cancers 0.64 0.44 0.94 0.02

CONKO004 0.35 0.16 0.75 0.01

FRAGEM 0.37 0.17 0.81 0.01

Pancreas 0.36 0.20 0.62 <.001

Efficacy outcome: VTE 0.1 0.2 0.5 1 2 5 10

LMWH Control
Kuderer et al. ASH 2009.
Objectives

To review evidence and updates in:

• Risk Assessment Models
• Prevention of VTE
• Treatment of Recurrent VTE
 Long Term Treatment
RCTs of LMWH vs Vit K antagonists in cancer
Pt, Rec VTE, Major
Study Long-Term Treatment Death, % P-value
No. % Bleed, %
Meyer 71 Warfarin 21.1 22.7 NS
2002 67 Enoxaparin 1.5 mg/kg 10.5 11.3
Lee 336 Warfarin 17 4 41 0.002
2003 336 Dalteparin 200/150 IU/kg 9 6 39
30 Warfarin 10 2.9 8.8 NS
Deitcher
29 Enoxaparin 1.0 mg/kg 6.9 6.5 6.5
2006
32 Enoxaparin 1.5 mg/kg 6.3 11.1 19.4
Hull 100 Warfarin 10 7 19 NS
2006 100 Tinzaparin 175 IU/kg 6 7 20

Lee et al N Engl J Med 2003. Meyer et al Arch Intern Med 2002. Deitcher et al Clin Appl Thromb Hemost 2006. Hull et al Am J
Med 2006.
CLOT Recurrent VTE
risk reduction = 52%
25 HR 0.48 (95% CI 0.30, 0.77)
log-rank p = 0.002
Probability of Recurrent VTE, %

20

15 VKA, 17%

10

dalteparin, 9%
5

0 30 60 90 120 150 180 210

Days Post Randomization
Lee et al. New Engl J Med 2003.
Treatment of Recurrent VTE
• LMWH dose escalation is effective in cancer patients
with recurrent VTE on anticoagulation
 90% respond to 25-50% dose escalation
 Fewer than 5% experience any bleeding
• DO NOT INSERT IVC FILTER
 Does not treat hypercoagulability or reduce symptoms
 Can lead to more DVT, venous gangrene, limb loss
 No data to show reduction in mortality or hospitalization
• No evidence for other anticoagulants
Carrier et al. J Thromb Haemost 2009. White et al. Arch Intern Med 2000.
Approach to Recurrent VTE
Symptomatic recurrent VTE

Failure on Warfarin Failure on LMWH

Increase LMWH by ~25% or back

Switch to full dose LMWH*
up to full dose*

Reassess in 5-7 days†

No improvement Symptomatic improvement

Check peak anti-Xa level Continue same dose

Increase LMWH dose accordingly to aim for: Resume usual follow-

1.6 – 2.0 U/mL for once daily dosing or up
0.8 – 1.0 U/ml for twice daily dosing

*full dose refers to the recommended weight-adjusted dose of LMWH for the initial therapy of VTE.
†Reassessment should consist of clinical evaluation of symptoms. Radiological imaging is not required except
when deterioration is noted and further extension or new thrombosis is suspected.

Lee. Hematology Education Program Book 2010.

Treatment in Thrombocytopenia/Bleeding
• LMWH dose reduction is effective in patients with
thrombocytopenia (< 50 x 109/L)
• consider platelet transfusion if VTE is acute
• reduce dose to 50% if count 20 – 50 x 109/L
• prophylactic or withhold dose if count <20 x 109/L

• LMWH should be withheld if active bleeding

• treat underlying bleeding source whenever possible

• THERAPEUTIC ANTICOAGULATION DOES NOT CAUSE

BLEEDING – LOOK FOR BLEEDING SOURCE
Lee. J Clin Oncol 2009;27:4895-4901.
PharmaCare Coverage
• New Special Authority Criterion added March 17, 2011
• For treatment, dalteparin is approved for:
“Associated with cancer, in patients who have either failure or are
unable to tolerate oral therapy with warfarin (up to 6 months)”
 Not available for other LMWH due to lack of data

• For prophylaxis, all LMWHs are also approved for:

“patients with thrombophilia (up to 3 months)”
 Can be used for continuing prophylaxis after hospital discharge
following surgery for cancer

http://www.health.gov.bc.ca/pharmacare/sa/criteria/restricted/dalteparin.html
Other Take Home Messages …
• Patients tolerate long-term LMWH very well
• Important to apply pressure to injection site for at least 2
minutes to reduce hematomas
• LMWH should be stored at room temperature
 refrigeration, freezing, heat will deactivate drug

• PharmaCare coverage can be obtained immediately by

phone at 1-877-657-1188, press #1
• Thrombosis Clinic referral fax: 604-875-5071
Thrombosis in Cancer Summary
• VTE is a very common complication that increase morbidity
and mortality in cancer patients
• Use a validated RAM to estimate risk of VTE in ambulatory
patients with new or progressive disease
• Selected cancer patients benefit from extended prophylaxis
after surgery
• Prophylaxis in hospitalized patients is a patient safety priority
• LMWH is the “best” agent available for prevention and
treatment