Thrombosis in Cancer An Update on Risk Assessment, Prevention and Treatment Agnes Lee, MD, MSc, FRCPC University of British Columbia, Vancouver, BC June.

Thrombosis in CancerAn Update on Risk Assessment, Prevention

and Treatment

Agnes Lee, MD, MSc, FRCPCUniversity of British Columbia, Vancouver, BCJune 2011

Disclosure

• Leo Pharma• Sanofi aventis• Pfizer• Bayer• Boehringer Ingelheim• Daiichi Sankyo

• 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.

Cancer-Associated Thrombosis

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

Patient-related

• Older age• Race• Prior VTE• Platelet count• Comorbid

conditions

Lyman et al. J Clin Oncol 2007.

Cancer-related

• Primary site• Histology • Metastatic

disease• Time interval

since diagnosis

Treatment-related

• Surgery• Chemotherapy• Hormonal therapy• Antiangiogenic

therapy• ESA• Hospitalization• Catheters

• Risk varies from 1 – 30% depending on:

7

Risk Stratification

Canc

er-re

late

dRi

sk Fa

ctor

s

Patient-relatedRisk Factors

Treatment-related

Risk Factors

Risk of VTE

8

Risk Stratification

Canc

er-re

late

dRi

sk Fa

ctor

s

Patient-relatedRisk Factors

Treatment-related

Risk Factors

Biomarkers?

RAM?+/-

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-selectinKhorana et al. Blood 2008. Ay et al Blood 2010.

Patient Characteristic Score

Site of Cancer Very high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, GU excluding prostate)

21

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 Model for Outpatients

Khorana et al. Blood 2008.

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

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.

Khorana Model Validation

Log-rank test P<0.001)

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%

• Addition of D-dimer and soluble P-selectin to Khorana model:

Ay Model for Outpatients

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

Lyman et al. J Clin Oncol 2007.

• 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

Bergqvist et al. N Engl J Med 2002. Rasmussen et al J Thromb Haemost 2006. Kakkar et al J Thromb Haemost 2010.

0%

5%

10%

15%

20%placebo/no prophylaxis LMWH

Extended Prophylaxis After Surgery

P=0.02 P=0.01 P=0.06

ENOXACAN II FAME CANBESURENo. Cancer Pt 332 199 625

VTE Maj Bleed VTE Maj Bleed VTE Maj Bleed

NS NS NS

Surgical Cancer Patients

0

2

4

6

8

10

12 @RISTOSProspective cohort

N=2373

symptomatic VTE 2.1%

overall mortality 1.7%

In

cide

nce

of V

TE, N

o.

Agnelli et al. Ann Surg 2006.

1-5 5-10 11-15 16-20 21-25 25-30 >30

Days post surgery

46% due tofatal PE

@RISTOSRisk factors for VTE Odds Ratio (95% CI)

previous history of VTE 6.0 (2.1 – 16.8)

anesthesia lasting > 2 hours 4.5 (1.1 – 19.0)

bed rest post-op > 4 days 4.4 (2.5 – 7.8)

advanced tumour 2.7 (1.4 – 5.2)

age > 60 2.6 (1.2 – 5.7)

Agnelli et al. Ann Surg 2006.

Surgical Cancer Patients

Million Women Study

Sweetland et al. BMJ 2009

• 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

Million Women Study

Sweetland et al. BMJ 2009

91-fold

53-fold

34-fold

peak incidence at 3 weeks

risk of PE higher than DVT

ASCO Guidelines on Prophylaxis

Lyman et al. J Clin Oncol 2007.

• 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

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

Lyman et al. J Clin Oncol 2007.

• 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

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

Breast (IV) Breast (III/IV) NSCLC (III/IV) Glioma (III/IV)

Placebo anticoagulant

RRR=85%

P=0.03

Levine et al. Lancet 1994. Haas et al. JTH 2005. Perry et al. J Clin Oncol 2007.

I

ncid

ence

of

VT

E

Active: warfarin certoparin certoparin dalteparindrug

Not significant

Oncology Outpatient Prophylaxis

• 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.

PROTECHT Study

*1-sided

CONKO 004 Trial• 312 patients receiving

chemotherapy for APC

• Randomized to gemcitabine or gemcitabine + enoxaparin

• Enoxaparin 1 mg/kg once daily x 12 weeks then 40 mg once daily

• Primary outcome: symptomatic VTE and fatal PE at 12 weeks

Riess et al. ASCO May 2009.

0%

2%

4%

6%

8%

10%

no treatment enoxaparin

VTE bleeding

P<0.01

P=0.6

9.9%

1.3%

2.6%3.8%

0%

5%

10%

15%

20%

25%

30%

35%

no treatment dalteparin

FRAGEM Trial• 123 patients receiving

chemotherapy for APC

• Randomized to gemcitabine or gemcitabine + dalteparin

• Dalteparin 200 U/kg once daily x 1 month then 150 U/kg x 2 months

• Primary outcome: symptomatic VTE and fatal PE at 3 months

Maraveyas et al. ESMO 2009.

VTE

P=0.02

P=0.03

fatal PE or sudden death

31%

12%9%

0%

Pancreas

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

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

0.36 0.20 0.62 <.001

0.1 0.2 0.5 1 2 5 10

LMWH Control

Other Cancers

Kuderer et al. ASH 2009.

Prophylaxis in Oncol Outpatients

Efficacy outcome: VTE

Objectives

To review evidence and updates in:

• Risk Assessment Models

• Prevention of VTE

• Treatment of Recurrent VTE

Long Term TreatmentRCTs of LMWH vs Vit K antagonists in cancer

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.

Study Pt, No. Long-Term Treatment Rec VTE,

%Major

Bleed, % Death, % P-value

Meyer2002

71 Warfarin 21.1 22.7 NS

67 Enoxaparin 1.5 mg/kg 10.5 11.3

Lee2003

336 Warfarin 17 4 41 0.002

336 Dalteparin 200/150 IU/kg 9 6 39

Deitcher2006

30 Warfarin 10 2.9 8.8 NS

29 Enoxaparin 1.0 mg/kg 6.9 6.5 6.5

32 Enoxaparin 1.5 mg/kg 6.3 11.1 19.4

Hull2006

100 Warfarin 10 7 19 NS

100 Tinzaparin 175 IU/kg 6 7 20

CLOT Recurrent VTE

Lee et al. New Engl J Med 2003.

0

5

10

15

20

25

Days Post Randomization

0 30 60 90 120 150 180 210

Prob

abili

ty o

f Rec

urre

nt V

TE, %

dalteparin, 9%

VKA, 17%

risk reduction = 52%HR 0.48 (95% CI 0.30, 0.77)log-rank p = 0.002

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 anticoagulantsCarrier et al. J Thromb Haemost 2009. White et al. Arch Intern Med 2000.

Approach to Recurrent VTE

*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.

Symptomatic recurrent VTE

Failure on Warfarin Failure on LMWH

Switch to full dose LMWH* Increase LMWH by ~25% or back up to full dose*

Reassess in 5-7 days†

No improvement Symptomatic improvement

Check peak anti-Xa level

Increase LMWH dose accordingly to aim for:1.6 – 2.0 U/mL for once daily dosing or

0.8 – 1.0 U/ml for twice daily dosing

Continue same dose

Resume usual follow-up

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

• 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

Thrombosis in Cancer Summary