PowerPoint PresentationVTE and Cancer
A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—
What Do Trials Teach?
About 20% occur in cancer patients
Annual incidence of VTE in cancer
patients ≈ 1/250
As many as 50% have VTE at autopsy
Compared to patients without cancer:
Higher risk of first and recurrent VTE
Higher risk of bleeding on anticoagulants
Higher risk of dying
VTE and Cancer
Donati MB. Haemostasis. 1994;24:128-131
DVT and PE in Cancer
Facts, Findings, and Natural History
VTE is the second leading cause of death in hospitalized cancer patients1,2
The risk of VTE in cancer patients undergoing surgery is 3- to 5-fold higher than those without cancer2
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Let’s continue examining the association between DVT/PE and cancer.
Consider these statistics. DVT/PE is the second leading cause of death in hospitalized cancer patients. Up to twenty percent of all DVT/PE cases occur in cancer patients and up to fifty percent of cancer patients may have evidence of asymptomatic DVT/PE.
As I previously mentioned, surgery is a well-known risk factor; however cancer patients undergoing surgery compound that risk to 3 to 5-times greater than surgery patients without cancer.
Finally, cancer patients are at higher risk of developing a recurrent DVT or PE following a primary experience than patients without cancer.
VTE and Cancer
VTE has significant negative impact on quality of life
VTE may be the presenting sign of occult malignancy
10% with idiopathic VTE develop cancer within 2 years
20% have recurrent idiopathic VTE
25% have bilateral DVT
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Levitan N, et al. Medicine 1999;78:285
0 20 40 60 80 100 120 140 160 180
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0.20
0.40
1.00
0.80
0.60
Incidence of VTE and Colon Cancer Stage
White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40
Days after Cancer Diagnosis
7%
6%
5%
4%
3%
2%
1%
0%
Counterintuitively, Magnitude of Effect on Survival is Greatest with
Local Stage Disease
VTE and Cancer
VTE Associated with Accelerated Death in Breast Cancer Does Symptomatic VTE Reflect Presence or Emergence
of Metastatic, Aggressive Cancer?
VTE and Cancer
Recurrent Ovarian 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)
VTE and Cancer
Khorana, JCO, 2006
Cancer
Type
Women: breast, ovary, lung
Patient
New Agents: e.g.
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Several classes of agents have been used for prophylaxis and treatment of VTE
Nonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filter
Most commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs)
VTE and Cancer
Francis, NEJM, 2007
CANCER RECEIVE ANTICOAGULATION FOR
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.
VTE and Cancer
Cancer and Thrombosis
VTE and Cancer
Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis:
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
Incidence of VTE in Surgical Patients
No Cancer N=16,954
The @RISTOS Registry
Tracked 30-day incidence of VTE in 2373 patients
Type of surgery
Most events occur after hospital discharge
Most common cause of 30-day post-op death
Agnelli, Ann Surg 2006; 243: 89-95
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Abdominal or pelvic surgery for cancer (mostly colorectal)
LMWH once daily vs. UFH tid for 7–10 days post-op
DVT on venography at day 7–10 and symptomatic VTE
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
475
double-blind
13.9%
P=0.052
5.1%
1.8%
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
ENOXACAN II
A multicenter, prospective, assessor-blinded, open-label, randomized trial: Dalteparin administered for 28 days after major abdominal surgery compared to 7 days of treatment
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).
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.
Major Abdominal Surgery: FAME Investigators—Dalteparin Extended
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All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis.
Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis.
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.
VTE and Cancer
Thrombosis is a potential complication of central venous catheters, including these events:
Fibrin sheath formation
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Prophylaxis for Venous Catheters
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
Study
Regimen
N
CRT (%)
285 140
155 155
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Tolerability of Low-Dose Warfarin
95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin daily
INR measured at baseline and four time points
10% of all recorded INRs >1.5
Patients with elevated INR
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No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)
Chest Jun 2008: 454S–545S
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The Ambulatory Patient
Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian)
Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.)
VTE and Cancer
Medical Oncology Patients
Stage, grade, and extent of cancer
Metastatic disease, venous stasis due to bulky disease
Type of antineoplastic treatment
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Heit JA et al. Thromb Haemost. 2001;86:452-463
Risk Factor/Characteristic
3.04
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Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study.
This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data.
Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included.
What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE.
Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of 4.05. In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE.
VTE and Cancer
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
Oncology Setting
VTE Incidence
0.2%
2%
8%
3%
6%
9%
Not universally recommended for outpatients, but there are exceptions
New data for certain agents
Heterogeneous population
VTE Risk with Bevacizumab in Colorectal Cancer
Approaches Risk of Antiangiogenesis in Myeloma
VTE and Cancer
Bevacizumab Increases Risk of
VTE and Cancer
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
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 P Value
(95% CI)
High-dose dexamethasone
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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
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Randomization
Secondary Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Dalteparin
Dalteparin
Dalteparin
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
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5
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20
25
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Dalteparin N=338
OAC N=335
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in Cancer – Bottom Line
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
New Development
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Dalteparin
OAC
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
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Patients balanced for age, gender, stage, smoking history, ECOG performance status
LMWH for Small Cell Lung Cancer
Turkish Study
CEV = cyclophosphamide, epirubicin, vincristine;
Chemotherapyplus Dalteparin
Chemo alone
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
Cancer:
Rate of Appropriate Prophylaxis, %
5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
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VTE prophylaxis is underused in patients with cancer
The Fundamental Research in Oncology and Thrombosis (FRONTLINE) survey was a questionnaire distributed globally to clinicians involved in cancer care and accessible on a dedicated Web site1
Data from 3891 completed questionnaires were available for analysis1
The results indicated that 52% of respondents would routinely utilize thromboprophylaxis for surgical oncology patients, and that most respondents only considered thromboprophlyaxis in approximately 5% of their medical oncology patients1
These results can be compared with prophylaxis rates in other patient groups as determined by other recent studies
A retrospective record review in 10 US teaching or community-based hospitals of patients undergoing major surgeries (major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement) showed VTE prophylaxis was used in 89% of patients2
A retrospective record review of patients aged 65 and older in 20 Oklahoma hospitals undergoing major abdominothoracic surgery indicated that prophylaxis was used in 38% of patients3
A retrospective record review at 2 Canadian hospitals of medical inpatients indicated that prophylaxis was used in 33% of patients4
In the DVT-FREE prospective registry of patients with ultrasound-confirmed DVT, among 5451 patients, 42% had received prophylaxis5
[1/Kakkar.
Oncologist.2003/
p259/c1/line A1-A10;
p261/c2/line 6-8]
1. Kakkar AK, Levine M, Pinedo HM, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8:381-388.
2. Stratton MA, Anderson FA, Bussey HI, et al. Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients. Arch Intern Med. 2000;160:334-340.
3. Bratzler DW, Raskob GE, Murray CK, Bumpus LJ, Piatt DS. Underuse of venous thromboembolism prophylaxis for general surgery patients: physician practices in the community hospital setting. Arch Intern Med. 1998;158:1909-1912.
4. Rahim SA, Panju A, Pai M, Ginsberg J. Venous thromboembolism prophylaxis in medical inpatients: a retrospective chart review. Thromb Res. 2003;111:215-219.
5. Goldhaber SZ, Tapson VF, for the DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol. 2004;93:259-262.
Chart1
VTE and Cancer
Conclusions and Summary
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