thrombosis in cancer an update on risk assessment, prevention and treatment agnes lee, md, msc,...
TRANSCRIPT
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