Transcript Document

Innovation ● Investigation ● Application
VTE and Cancer
A Systematic Analysis of VTE
Prophylaxis in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—
What Do Trials Teach?
Program Chairman
Craig Kessler, MD MACP
Director, Division of Coagulation
Lombardi Comprehensive Cancer Center
Georgetown University Medical Center
Washington, DC
VTE and Cancer: Epidemiology
VTE and Cancer
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Of all cases of VTE:
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Of all cancer patients:
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About 20% occur in cancer patients
Annual incidence of VTE in cancer
patients ≈ 1/250
15% will have symptomatic VTE
As many as 50% have VTE at autopsy
Compared to patients without cancer:
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Higher risk of first and recurrent VTE
Higher risk of bleeding on anticoagulants
Higher risk of dying
Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
DVT and PE in Cancer
VTE and Cancer
Facts, Findings, and Natural History
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VTE is the second leading cause of death in hospitalized
cancer patients1,2
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The risk of VTE in cancer patients undergoing surgery is 3to 5-fold higher than those without cancer2
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Up to 50% of cancer patients may have evidence of
asymptomatic DVT/PE3
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Cancer patients with symptomatic DVT exhibit a high risk
for recurrent DVT/PE that persists for many years4
1. Ambrus JL et al. J Med. 1975;6:61-64
2. Donati MB. Haemostasis. 1994;24:128-131
3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4. Prandoni P et al. Ann Intern Med. 1996;125:1-7
Clinical Features of VTE in Cancer
VTE and Cancer
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VTE has significant negative impact on quality
of life
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VTE may be the presenting sign of occult
malignancy
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•
•
10% with idiopathic VTE develop cancer within
2 years
20% have recurrent idiopathic VTE
25% have bilateral DVT
Bura et. al., J Thromb Haemost 2004;2:445-51
Thrombosis and Survival
Likelihood of Death After Hospitalization
VTE and Cancer
1.00
Probability of Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20 40
60
80 100 120140 160 180
Number of Days
Levitan N, et al. Medicine 1999;78:285
Incidence of VTE and Colon Cancer Stage
VTE and Cancer
7%
Local
Regional
Remote
Incidence of VTE (%)
6%
5%
4%
3%
2%
1%
0%
0
50
100
150
200
250
300
Days after Cancer Diagnosis
White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40
350
400
Symptomatic VTE in Cancer Reduces Survival
VTE and Cancer
Counterintuitively, Magnitude of Effect on Survival is Greatest with
Local Stage Disease
VTE Associated with Accelerated Death in Breast Cancer
VTE and Cancer
Does Symptomatic VTE Reflect Presence or Emergence
of Metastatic, Aggressive Cancer?
White, et al. Thromb Res,120 suppl. 2 (2007)
Recurrent Ovarian Cancer
VTE and Cancer
• 7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)
• 78% of VTE in ROC occur within 2 months of second line chemo regimen: cisplatin-related
• Ascites is the only independent risk factor for VTE (HR=2.2)
Fotopoulou C et al. Thromb Res 2009
Hospital Mortality With or Without VTE
Mortality (%)
VTE and Cancer
N=66,016
Khorana, JCO, 2006
N=20,591
N=17,360
Thrombosis Risk In Cancer
VTE and Cancer
Primary Prophylaxis
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Medical Inpatients
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Surgery
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Radiotherapy
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Central Venous Catheters
Risk Factors for Cancer-Associated VTE
VTE and Cancer
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Cancer
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Type
• Men: prostate, colon, brain, lung
• Women: breast, ovary, lung
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Stage
Treatments
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Surgery
• 10-20% proximal DVT
• 4-10% clinically evident PE
• 0.2-5% fatal PE
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Chemotherapy
Central venous catheters (~4% generate clinically
relevant VTE)
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Patient
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Prior VTE
Comorbidities
Genetic background
Cancer and Thrombosis
VTE and Cancer
Medical Inpatients
Antithrombotic Therapy: Choices
VTE and Cancer
Nonpharmacologic
(Prophylaxis)
Intermittent
Pneumatic
Compression
Elastic
Stockings
Inferior
Vena Cava
Filter
Pharmacologic
(Prophylaxis & Treatment)
Unfractionated
Heparin (UH)
Low Molecular
Weight
Heparin
(LMWH)
Oral
Anticoagulants
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
Prophylaxis Studies in Medical Patients
Rate of VTE (%)
VTE and Cancer
Relative
risk
reduction
63%
Relative
risk
reduction
44%
Placebo Enoxaparin Placebo Dalteparin
MEDENOX Trial
PREVENT
Francis, NEJM, 2007
Relative
risk
reduction
47%
Placebo Fondaparinux
ARTEMIS
ASCO Guidelines
VTE and Cancer
1. SHOULD HOSPITALIZED PATIENTS WITH
CANCER RECEIVE ANTICOAGULATION FOR
VTE PROPHYLAXIS?
Recommendation. Hospitalized patients with
cancer should be considered candidates for
VTE prophylaxis with anticoagulants in the
absence of bleeding or other contraindications
to anticoagulation.
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
Cancer and Thrombosis
VTE and Cancer
Surgical Patients
Incidence of VTE in Surgical Patients
VTE and Cancer
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Cancer patients have 2-fold risk of post-operative
DVT/PE and >3-fold risk of fatal PE despite prophylaxis:
No Cancer
Cancer
N=16,954
N=6124
Post-op VTE
0.61%
1.26%
<0.0001
Non-fatal PE
0.27%
0.54%
<0.0003
Autopsy PE
0.11%
0.41%
<0.0001
Death
0.71%
3.14%
<0.0001
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
P-value
Natural History of VTE in Cancer Surgery:
The @RISTOS Registry
VTE and Cancer
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Web-Based Registry of Cancer Surgery
Tracked 30-day incidence of VTE in 2373 patients
Type of surgery
• 52% General
• 29% Urological
• 19% Gynecologic
82% received in-hospital thromboprophylaxis
31% received post-discharge thromboprophylaxis
Findings
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2.1% incidence of clinically overt VTE (0.8% fatal)
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Most events occur after hospital discharge
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Most common cause of 30-day post-op death
Agnelli, Ann Surg 2006; 243: 89-95
Prophylaxis in Surgical Patients
VTE and Cancer
LMWH vs. UFH
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Abdominal or pelvic surgery for cancer (mostly colorectal)
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LMWH once daily vs. UFH tid for 7–10 days post-op
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DVT on venography at day 7–10 and symptomatic VTE
Study
N
Design
Regimens
ENOXACAN 1
631
double-blind
enoxaparin vs. UFH
Canadian Colorectal
DVT Prophylaxis 2
475
double-blind
enoxaparin vs. UFH
1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103
2. McLeod R, et al. Ann Surg 2001;233:438-444
Prophylaxis in Surgical Patients
VTE and Cancer
Incidence of Outcome Event
16.9%
P=0.052
Canadian Colorectal
DVT Prophylaxis Trial
13.9%
N=234
N=241
1.5% 2.7%
VTE
(Cancer)
McLeod R, et al. Ann Surg 2001;233:438-444
Major Bleeding
(All)
Extended Prophylaxis in
Surgical Patients
Incidence of Outcome Event
VTE and Cancer
12.0%
ENOXACAN II
P=0.02
N=167
5.1%
4.8%
N=165
3.6%
1.8%
0.6%
VTE
Prox
DVT
0% 0.4%
NNT = 14
Any
Major
Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
VTE and Cancer
Major Abdominal Surgery: FAME
Investigators—Dalteparin Extended
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A multicenter, prospective, assessor-blinded, open-label,
randomized trial: Dalteparin administered for 28 days
after major abdominal surgery compared to 7 days of
treatment
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RESULTS: Cumulative incidence of VTE was reduced
from 16.3% with short-term thromboprophylaxis (29/178
patients) to 7.3% after prolonged thromboprophylaxis
(12/165) (relative risk reduction 55%; 95% confidence
interval 15-76; P=0.012).
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CONCLUSIONS: 4-week administration of dalteparin,
5000 IU once daily, after major abdominal surgery
significantly reduces the rate of VTE, without increasing
the risk of bleeding, compared with 1 week of
thromboprophylaxis.
Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.
ASCO Guidelines: VTE Prophylaxis
VTE and Cancer
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All patients undergoing major surgical intervention
for malignant disease should be considered for
prophylaxis.
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Patients undergoing laparotomy, laparoscopy, or
thoracotomy lasting > 30 min should receive
pharmacologic prophylaxis.
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Prophylaxis should be continued at least 7 – 10
days post-op. Prolonged prophylaxis for up to 4
weeks may be considered in patients undergoing
major surgery for cancer with high-risk features.
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
Central Venous Catheters
VTE and Cancer
Thrombosis is a potential complication of central
venous catheters, including these events:
–Fibrin sheath formation
–Superficial phlebitis
–Ball-valve clot
–Deep vein thrombosis (DVT)
Geerts W, et al. Chest Jun 2008: 381S–453S
Prophylaxis for Venous Catheters
VTE and Cancer
Placebo-Controlled Trials
Study
Regimen
N
CRT (%)
Reichardt*
2002
Dalteparin 5000 U daily
placebo
285
140
11 (3.7)
5 (3.4)
Couban*
2002
Warfarin 1mg daily
placebo
130
125
6 (4.6)
5 (4.0)
ETHICS†
2004
Enoxaparin 40 mg daily
placebo
155
155
22 (14.2)
28 (18.1)
*symptomatic outcomes; †routine venography at 6 weeks
Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et
al. Proc ASCO 2004;23:730
Central Venous Catheters: Warfarin
VTE and Cancer
Tolerability of Low-Dose Warfarin
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95 cancer patients receiving FU-based infusion
chemotherapy and 1 mg warfarin daily
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INR measured at baseline and four time points
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10% of all recorded INRs >1.5
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Patients with elevated INR
2.0–2.9
6%
3.0–4.9
19%
>5.0
7%
Masci et al. J Clin Oncol. 2003;21:736-739
8th ACCP Consensus Guidelines
VTE and Cancer
No routine prophylaxis to prevent
thrombosis secondary to central
venous catheters, including LMWH
(2B) and fixed-dose warfarin (1B)
Chest Jun 2008: 454S–545S
Primary Prophylaxis in Cancer Radiotherapy
VTE and Cancer
The Ambulatory Patient
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No recommendations from ACCP
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No data from randomized trials (RCTs)
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Weak data from observational studies in
high risk tumors (e.g. brain tumors;
mucin-secreting adenocarcinomas:
Colorectal, pancreatic, lung, renal cell,
ovarian)
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Recommendations extrapolated from
other groups of patients if additional risk
factors present (e.g., hemiparesis in brain
tumors, etc.)
Risk Factors for VTE in
Medical Oncology Patients
VTE and Cancer
► Tumor
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Ovary, brain, pancreas, lung, colon
► Stage,
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grade, and extent of cancer
Metastatic disease, venous stasis due to
bulky disease
Type of antineoplastic treatment
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type
Multiagent regimens, hormones,
anti-VEGF, radiation
Miscellaneous VTE risk factors
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Previous VTE, hospitalization, immobility,
infection, thrombophilia
Independent Risk Factors for DVT/PE
VTE and Cancer
Risk Factor/Characteristic
O.R.
Recent surgery with institutionalization
21.72
Trauma
12.69
Institutionalization without recent surgery
7.98
Malignancy with chemotherapy
6.53
Prior CVAD or pacemaker
5.55
Prior superficial vein thrombosis
4.32
Malignancy without chemotherapy
4.05
Neurologic disease w/ extremity paresis
3.04
Serious liver disease
0.10
Heit JA et al. Thromb Haemost. 2001;86:452-463
VTE Incidence In Various Tumors
VTE and Cancer
Oncology Setting
VTE
Incidence
Breast cancer (Stage I & II) w/o further treatment
0.2%
Breast cancer (Stage I & II) w/ chemo
2%
Breast cancer (Stage IV) w/ chemo
8%
Non-Hodgkin’s lymphomas w/ chemo
3%
Hodgkin’s disease w/ chemo
6%
Advanced cancer (1-year survival=12%)
9%
High-grade glioma
26%
Multiple myeloma (thalidomide + chemo)
28%
Renal cell carcinoma
43%
Solid tumors (anti-VEGF + chemo)
47%
Wilms tumor (cavoatrial extension)
4%
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
Primary VTE Prophylaxis
VTE and Cancer
►Recommended for hospitalized
cancer patients
►Not universally recommended for
outpatients, but there are exceptions
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New data for certain agents
Heterogeneous population
Need for risk stratification
VTE and Cancer
VTE Risk with Bevacizumab in Colorectal Cancer
Approaches Risk of Antiangiogenesis in Myeloma
Naluri SR et al. JAMA. 2008;300:2277
VTE and Cancer
Bevacizumab Increases Risk of
Symptomatic VTE by 33% vs Controls
Naluri SR et al. JAMA. 2008;300:2277
VTE and Cancer
Incidence of VTE: USA and Canada Greater
than Israel, Australia, and Europe
Multivariate Analysis of the Risk of Thrombosis Associated with
Lenalidomide plus High-Dose Dexamethasone and Concomitant
Erythropoietin for the Treatment of Multiple Myeloma
Treatment
Odds Ratio
(95% CI)
P Value
Lenalidomide plus
High-dose dexamethasone
3.51 (1.77-6.97)
<0.001
Concomitant erythropoietin
3.21 (1.72-6.01)
<0.001
Knight: N Engl J Med.2006,354:2079
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►
►
rEPO used
more in USA
and Canada
L+Dex: 23%
VTE with EPO
vs 5% w/o
EPO
Placebo + Dex:
7% VTE with
EPO vs 1%
without EPO
Oral Anticoagulant Therapy
in Cancer Patients: Problematic
VTE and Cancer
► Warfarin
●
●
●
●
►
therapy is complicated by:
Difficulty maintaining tight therapeutic control, due
to anorexia, vomiting, drug interactions, etc.
Frequent interruptions for thrombocytopenia and
procedures
Difficulty in venous access for monitoring
Increased risk of both recurrence and bleeding
Is it reasonable to substitute long-term LMWH
for warfarin ? When? How? Why?
CLOT: Landmark Cancer/VTE Trial
VTE and Cancer
Dalteparin
CANCER PATIENTS WITH
ACUTE DVT or PE
[N = 677]
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►
Dalteparin
Randomization
Dalteparin
Oral Anticoagulant
Primary Endpoints: Recurrent VTE and Bleeding
Secondary Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Landmark CLOT Cancer Trial
Reduction in Recurrent VTE
Probability of Recurrent VTE, %
VTE and Cancer
25
Risk reduction = 52%
p-value = 0.0017
Recurrent VTE
20
OAC
15
10
Dalteparin
5
0
0
Lee, Levine, Kakkar, Rickles et.al. N
Engl J Med, 2003;349:146
30
60
90
120
150
Days Post Randomization
180
210
Bleeding Events in CLOT
VTE and Cancer
Dalteparin
OAC
N=338
N=335
Major bleed
19 ( 5.6%)
12 ( 3.6%)
0.27
Any bleed
46 (13.6%)
62 (18.5%)
0.093
* Fisher’s exact test
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
P-value*
Treatment of Cancer-Associated VTE
VTE and Cancer
Study
Design
Length of
Therapy
(Months)
N
Recurrent
Major
Death
VTE
Bleeding
(%)
(%)
(%)
6
4
NS
39 NS
41
0.09
7
16
0.09
11 0.03
23
0.03
6
8
NS
23 NS
22
CLOT Trial
(Lee 2003)
Dalteparin
OAC
6
336
336
9
17
0.002
CANTHENOX
(Meyer 2002)
Enoxaparin
OAC
3
67
71
11
21
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
3
80
87
6
11
ONCENOX
(Deitcher ISTH
2003)
Enox (Low)
Enox (High)
OAC
6
32
36
34
3.4
3.1
6.7
NS
NS
NR
VTE and Cancer
Treatment and 2° Prevention of VTE
in Cancer – Bottom Line
New Development
►
New standard of care is LMWH at therapeutic doses
for a minimum of 3-6 months (Grade 1A
recommendation—ACCP)
►
NOTE: Dalteparin is only LMWH approved (May,
2007) for both the treatment and secondary
prevention of VTE in cancer
►
Oral anticoagulant therapy to follow for as long as
cancer is active (Grade 1C recommendation—
ACCP)
Chest Jun 2008: 454S–545S
CLOT 12-month Mortality
All Patients
VTE and Cancer
Probability of Survival, %
100
90
80
70
Dalteparin
60
OAC
50
40
30
20
10
0
HR 0.94 P-value = 0.40
0
30 60 90 120
180
240
300
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
360
Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
VTE and Cancer
Patients Without Metastases (N=150)
Probability of Survival, %
100
Dalteparin
90
80
70
OAC
60
50
40
30
20
10
HR = 0.50 P-value = 0.03
0
0
30 60 90 120 150 180
240
300
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
360
LMWH for Small Cell Lung Cancer
Turkish Study
VTE and Cancer
►
84 patients randomized: Chemo +/- LMWH (18 weeks)
►
Patients balanced for age, gender, stage, smoking
history, ECOG performance status
Chemotherapy
plus Dalteparin
Chemo alone
P-value
1-y overall survival, %
51.3
29.5
0.01
2-y overall survival, %
17.2
0.0
0.01
Median survival, m
13.0
8.0
0.01
CEV = cyclophosphamide, epirubicin, vincristine;
LMWH = Dalteparin, 5000 units daily
Altinbas et al. J Thromb Haemost 2004;2:1266.
VTE Prophylaxis Is Underused
in Patients With Cancer
Rate of Appropriate Prophylaxis, %
VTE and Cancer
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Cancer:
Surgical
Major
Surgery2
Major
Abdominothoracic
Surgery (Elderly)3
Medical
Inpatients4
Confirmed DVT
(Inpatients)5
Cancer:
Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388
4. Rahim SA et al. Thromb Res. 2003;111:215-219
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
Conclusions and Summary
VTE and Cancer
► Risk factors for VTE in the setting of cancer have
been well characterized: solid tumors, chemotherapy,
surgery, thrombocytopenia
► Long-term secondary prevention with LMWH has
been shown to produce better outcomes than warfarin
► Guidelines and landmark trials support administration
of LMWH in at risk patients
► Cancer patients are under-prophylaxed for VTE
► Health system pharmacists can play a pivotal role in
improving clinical outcomes in this patient population