VTE and Cancer A Systematic Analysis of VTE A Systematic Analysis of VTE Prophylaxis in the Setting Prophylaxis in the Setting of Cancer of Cancer Linking Science and Evidence to Linking Science and Evidence to Clinical Practice— Clinical Practice— What Do Trials Teach? What Do Trials Teach? Program Chairman Program Chairman Craig Kessler, MD MACP Craig Kessler, MD MACP Director, Division of Coagulation Director, Division of Coagulation Lombardi Comprehensive Cancer Center Lombardi Comprehensive Cancer Center Georgetown University Medical Center Georgetown University Medical Center Washington, DC Washington, DC Innovation ● Investigation ● Innovation ● Investigation ● Application Application
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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?
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VTE and Cancer
A Systematic Analysis of VTE A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Prophylaxis in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—Linking Science and Evidence to Clinical Practice—What Do Trials Teach?What Do Trials Teach?
A Systematic Analysis of VTE A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Prophylaxis in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—Linking Science and Evidence to Clinical Practice—What Do Trials Teach?What Do Trials Teach?
Program ChairmanProgram ChairmanCraig Kessler, MD MACPCraig Kessler, MD MACP
Director, Division of CoagulationDirector, Division of CoagulationLombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer Center
Georgetown University Medical CenterGeorgetown University Medical CenterWashington, DCWashington, DC
Program ChairmanProgram ChairmanCraig Kessler, MD MACPCraig Kessler, MD MACP
Director, Division of CoagulationDirector, Division of CoagulationLombardi Comprehensive Cancer CenterLombardi Comprehensive Cancer Center
Georgetown University Medical CenterGeorgetown University Medical CenterWashington, DCWashington, DC
VTE and Cancer: EpidemiologyVTE and Cancer: Epidemiology
► Of all cases of VTE:Of all cases of VTE:● About 20% occur in cancer patientsAbout 20% occur in cancer patients● Annual incidence of VTE in cancer Annual incidence of VTE in cancer
patients ≈ 1/250patients ≈ 1/250
► Of all cancer patients:Of all cancer patients:● 15% will have symptomatic VTE15% will have symptomatic VTE● As many as 50% have VTE at autopsyAs many as 50% have VTE at autopsy
► Compared to patients without cancer:Compared to patients without cancer:● Higher risk of first and recurrent VTEHigher risk of first and recurrent VTE● Higher risk of bleeding on anticoagulantsHigher risk of bleeding on anticoagulants● Higher risk of dyingHigher risk of dying
Lee AY, Levine MN. Lee AY, Levine MN. CirculationCirculation. 2003;107:23 Suppl 1:I17-I21. 2003;107:23 Suppl 1:I17-I21
VTE and Cancer
1.1. Ambrus JL et al. Ambrus JL et al. J MedJ Med. 1975;6:61-64. 1975;6:61-642.2. Donati MB. Donati MB. HaemostasisHaemostasis. 1994;24:128-131. 1994;24:128-1313.3. Johnson MJ et al. Johnson MJ et al. Clin Lab HaemClin Lab Haem. 1999;21:51-54. 1999;21:51-544.4. Prandoni P et al. Prandoni P et al. Ann Intern MedAnn Intern Med. 1996;125:1-7. 1996;125:1-7
DVT and PE in CancerDVT and PE in Cancer Facts, Findings, and Natural HistoryFacts, Findings, and Natural History
► VTE is the second leading cause of death VTE is the second leading cause of death in hospitalized in hospitalized cancer patientscancer patients1,21,2
► The risk of VTE in cancer patients undergoing surgery is The risk of VTE in cancer patients undergoing surgery is 3- 3- to 5-fold higher to 5-fold higher than those without cancerthan those without cancer22
► Up to Up to 50% of cancer patients 50% of cancer patients may have evidence of may have evidence of asymptomatic DVT/PEasymptomatic DVT/PE33
► Cancer patients with symptomatic DVT exhibit a Cancer patients with symptomatic DVT exhibit a high risk high risk for recurrent DVT/PE that persists for many yearsfor recurrent DVT/PE that persists for many years44
VTE and Cancer
Clinical Features of VTE in CancerClinical Features of VTE in Cancer
► VTE has significant negative impact on quality VTE has significant negative impact on quality of lifeof life
► VTE may be the presenting sign of occult VTE may be the presenting sign of occult malignancymalignancy• 10% with idiopathic VTE develop cancer within 10% with idiopathic VTE develop cancer within
2 years2 years• 20% have recurrent idiopathic VTE20% have recurrent idiopathic VTE• 25% have bilateral DVT25% have bilateral DVT
Bura Bura et. al.,et. al., J Thromb HaemostJ Thromb Haemost 2004;2:445-51 2004;2:445-51
VTE and Cancer
Thrombosis and SurvivalThrombosis and SurvivalLikelihood of Death After HospitalizationLikelihood of Death After Hospitalization
DVT/PE and Malignant DiseaseDVT/PE and Malignant Disease
Malignant DiseaseMalignant Disease
DVT/PE OnlyDVT/PE Only
Nonmalignant DiseaseNonmalignant Disease
Number of DaysNumber of Days
Pro
bab
ility
of D
ea
thP
roba
bili
ty o
f De
ath
Levitan N, et al. Medicine 1999;78:285Levitan N, et al. Medicine 1999;78:285
VTE and Cancer
Incidence of VTE and Colon Cancer StageIncidence of VTE and Colon Cancer StageIncidence of VTE and Colon Cancer StageIncidence of VTE and Colon Cancer Stage
White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40
Days after Cancer DiagnosisDays after Cancer Diagnosis
Symptomatic VTE in Cancer Reduces Survival Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Counterintuitively, Magnitude of Effect on Survival is Greatest with
Local Stage DiseaseLocal Stage Disease
VTE and Cancer
VTE Associated with Accelerated Death in Breast Cancer VTE Associated with Accelerated Death in Breast Cancer Does Symptomatic VTE Reflect Presence or Emergence Does Symptomatic VTE Reflect Presence or Emergence
of Metastatic, Aggressive Cancer?of Metastatic, Aggressive Cancer?
White, et al. Thromb Res,120 suppl. 2 (2007)White, et al. Thromb Res,120 suppl. 2 (2007)
VTE and Cancer
Recurrent Ovarian CancerRecurrent Ovarian Cancer
Fotopoulou C et al. Thromb Res 2009
• 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)
• 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
Hospital Mortality With or Without VTEHospital Mortality With or Without VTE
1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITHCANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FORVTE PROPHYLAXISVTE PROPHYLAXIS??
RecommendationRecommendation. . Hospitalized patients with Hospitalized patients with cancer should be considered candidates for cancer should be considered candidates for VTE prophylaxis with anticoagulants in the VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications absence of bleeding or other contraindications to anticoagulation.to anticoagulation.
► Cancer patients have Cancer patients have 2-fold risk of post-operative DVT/PE 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxisand >3-fold risk of fatal PE despite prophylaxis::
Non-fatal PENon-fatal PE 0.27%0.27% 0.54%0.54% <0.0003<0.0003
Autopsy PEAutopsy PE 0.11%0.11% 0.41%0.41% <0.0001<0.0001
DeathDeath 0.71%0.71% 3.14%3.14% <0.0001<0.0001
VTE and Cancer
Natural History of VTE in Cancer Surgery: Natural History of VTE in Cancer Surgery: The @RISTOS RegistryThe @RISTOS Registry
► Web-Based Registry of Cancer SurgeryWeb-Based Registry of Cancer Surgery Tracked 30-day incidence of VTE in 2373 patientsTracked 30-day incidence of VTE in 2373 patients
Type of surgeryType of surgery • • 52% General 52% General • • 29% Urological29% Urological • • 19% Gynecologic19% Gynecologic
82% received in-hospital thromboprophylaxis82% received in-hospital thromboprophylaxis
31% received post-discharge thromboprophylaxis31% received post-discharge thromboprophylaxis
FindingsFindings
► 2.1% incidence of clinically overt VTE (0.8% fatal)2.1% incidence of clinically overt VTE (0.8% fatal)
► Most events occur after hospital discharge Most events occur after hospital discharge
► Most common cause of 30-day post-op deathMost common cause of 30-day post-op death
Agnelli, Ann Surg 2006; 243: 89-95Agnelli, Ann Surg 2006; 243: 89-95
VTE and Cancer
LMWH vs. UFHLMWH vs. UFH► Abdominal or pelvic surgery for cancer (mostly colorectal)Abdominal or pelvic surgery for cancer (mostly colorectal)
► LMWH once daily vs. UFH tid for 7–10 days post-opLMWH once daily vs. UFH tid for 7–10 days post-op
► DVT on venography at day 7–10 and symptomatic VTEDVT on venography at day 7–10 and symptomatic VTE
1. ENOXACAN Study Group. 1. ENOXACAN Study Group. Br J SurgBr J Surg 1997;84:1099–103 1997;84:1099–1032. McLeod R, et al. 2. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-444 2001;233:438-444
Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients
StudyStudy NN DesignDesign RegimensRegimens
ENOXACAN ENOXACAN 11 631631 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH
Canadian Colorectal Canadian Colorectal DVT Prophylaxis DVT Prophylaxis 22 475475 double-blinddouble-blind enoxaparin vs. UFHenoxaparin vs. UFH
VTE and Cancer
Canadian Colorectal Canadian Colorectal DVT Prophylaxis TrialDVT Prophylaxis Trial
13.9%13.9%
1.5% 2.7%1.5% 2.7%
16.9%16.9%
N=234N=234
N=241N=241
McLeod R, et al. McLeod R, et al. Ann SurgAnn Surg 2001;233:438-444 2001;233:438-444
P=0.052P=0.052
In
cide
nce
of O
utco
me
Eve
ntIn
cide
nce
of O
utco
me
Eve
nt
VTEVTE Major BleedingMajor Bleeding(Cancer) (All)(Cancer) (All)
Prophylaxis in Surgical PatientsProphylaxis in Surgical Patients
VTE and Cancer
VTE Prox Any MajorVTE Prox Any Major DVT Bleeding BleedingDVT Bleeding Bleeding
P=0.02
5.1%
1.8%
Bergqvist D, et al. (for the ENOXACAN II investigators) Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J MedN Engl J Med 2002;346:975-980 2002;346:975-980
► A multicenter, prospective, assessor-blinded, open-label, A multicenter, prospective, assessor-blinded, open-label, randomized trial: randomized trial: Dalteparin administered for 28 days Dalteparin administered for 28 days after major abdominal surgeryafter major abdominal surgery compared to 7 days of compared to 7 days of treatmenttreatment
► RESULTS:RESULTS: Cumulative Cumulative incidence of VTE was reduced incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3%patients) to 7.3% after prolonged thromboprophylaxis after prolonged thromboprophylaxis (12/165) ((12/165) (relative risk reduction 55%;relative risk reduction 55%; 95% confidence 95% confidence interval 15-76; P=0.012).interval 15-76; P=0.012).
► CONCLUSIONS:CONCLUSIONS: 4-week administration of dalteparin, 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTEsignificantly reduces the rate of VTE, without increasing , without increasing the risk of bleeding, compared with 1 week of the risk of bleeding, compared with 1 week of thromboprophylaxis.thromboprophylaxis.
► All patients undergoing major surgical intervention All patients undergoing major surgical intervention for malignant disease should be considered for for malignant disease should be considered for prophylaxis.prophylaxis.
► Patients undergoing laparotomy, laparoscopy, or Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive thoracotomy lasting > 30 min should receive pharmacologic prophylaxis.pharmacologic prophylaxis.
► Prophylaxis should be continued at least 7 – 10 Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing weeks may be considered in patients undergoing major surgery for cancer with high-risk features.major surgery for cancer with high-risk features.
Thrombosis is a potential complication of central Thrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events:
No routine prophylaxis to prevent No routine prophylaxis to prevent thrombosis secondary to central thrombosis secondary to central venous catheters, including LMWH venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)(2B) and fixed-dose warfarin (1B)
ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S
VTE and Cancer
Primary Prophylaxis in Cancer RadiotherapyPrimary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient The Ambulatory Patient
► No recommendations from ACCPNo recommendations from ACCP
► No data from randomized trials (RCTs)No data from randomized trials (RCTs)
► Weak data from observational studies in Weak data from observational studies in high risk tumors (e.g. brain tumors; high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, Colorectal, pancreatic, lung, renal cell, ovarian)ovarian)
► Recommendations extrapolated from Recommendations extrapolated from other groups of patients if additional risk other groups of patients if additional risk factors present (e.g., hemiparesis in brain factors present (e.g., hemiparesis in brain tumors, etc.)tumors, etc.)
VTE and Cancer
Risk Factors for VTE inRisk Factors for VTE inMedical Oncology PatientsMedical Oncology Patients
► Stage, grade, and extent of cancerStage, grade, and extent of cancer● Metastatic disease, venous stasis due to Metastatic disease, venous stasis due to
bulky diseasebulky disease
► Type of antineoplastic treatmentType of antineoplastic treatment● Multiagent regimens, hormones,Multiagent regimens, hormones,
Heit JA et al. Heit JA et al. Thromb HaemostThromb Haemost. 2001;86:452-463. 2001;86:452-463
VTE and Cancer
VTE Incidence In Various TumorsVTE Incidence In Various Tumors
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
► Recommended for hospitalized Recommended for hospitalized cancer patientscancer patients
► Not universally recommended for Not universally recommended for outpatients, but there are exceptionsoutpatients, but there are exceptions● New data for certain agentsNew data for certain agents● Heterogeneous populationHeterogeneous population
Need for risk stratificationNeed for risk stratification
VTE and Cancer
Naluri SR et al. JAMA. 2008;300:2277
VTE Risk with Bevacizumab in Colorectal Cancer VTE Risk with Bevacizumab in Colorectal Cancer Approaches Risk of Antiangiogenesis in Approaches Risk of Antiangiogenesis in
MyelomaMyeloma
VTE and Cancer
Naluri SR et al. JAMA.Naluri SR et al. JAMA. 2008;300:2277 2008;300:2277
Bevacizumab Increases Risk of Bevacizumab Increases Risk of Symptomatic VTE by 33% vs ControlsSymptomatic VTE by 33% vs Controls
VTE and Cancer
Knight: N Engl J Med.2006,354:2079Knight: N Engl J Med.2006,354:2079
► rEPO used rEPO used more in USA more in USA and Canadaand Canada
► L+Dex:L+Dex: 23% 23% VTE with EPO VTE with EPO vs 5% w/o vs 5% w/o EPOEPO
► Placebo + Dex:Placebo + Dex: 7% VTE with 7% VTE with EPO vs 1% EPO vs 1% without EPOwithout EPO
Incidence of VTE: USA and Canada Greater Incidence of VTE: USA and Canada Greater than Israel, Australia, and Europethan Israel, Australia, and Europe
Multivariate Analysis of the Risk of Thrombosis Associated with Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma Erythropoietin for the Treatment of Multiple Myeloma
TreatmentTreatment Odds RatioOdds Ratio P ValueP Value(95% CI)(95% CI)
Lenalidomide plusLenalidomide plus 3.51 (1.77-6.97)3.51 (1.77-6.97) <0.001<0.001High-dose dexamethasoneHigh-dose dexamethasone
Multivariate Analysis of the Risk of Thrombosis Associated with Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and Concomitant Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Myeloma Erythropoietin for the Treatment of Multiple Myeloma
TreatmentTreatment Odds RatioOdds Ratio P ValueP Value(95% CI)(95% CI)
Lenalidomide plusLenalidomide plus 3.51 (1.77-6.97)3.51 (1.77-6.97) <0.001<0.001High-dose dexamethasoneHigh-dose dexamethasone
Oral Anticoagulant TherapyOral Anticoagulant Therapyin Cancer Patients: Problematicin Cancer Patients: Problematic
► Warfarin therapy is complicated by:Warfarin therapy is complicated by:
● Difficulty maintaining tight therapeutic control, due Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. to anorexia, vomiting, drug interactions, etc.
● Frequent interruptions for thrombocytopenia and Frequent interruptions for thrombocytopenia and proceduresprocedures
● Difficulty in venous access for monitoringDifficulty in venous access for monitoring● Increased risk of both recurrence and bleedingIncreased risk of both recurrence and bleeding
► Is it reasonable to substitute long-term LMWH Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?for warfarin ? When? How? Why?
Treatment and 2Treatment and 2° Prevention of VTE ° Prevention of VTE in Cancer – Bottom Linein Cancer – Bottom Line
► New standard of care is LMWH at therapeutic doses New standard of care is LMWH at therapeutic doses for a for a minimum of 3-6 monthsminimum of 3-6 months (Grade 1A (Grade 1A recommendation—ACCP)recommendation—ACCP)
► NOTENOTE:: Dalteparin is only LMWH approved (May, Dalteparin is only LMWH approved (May, 2007) for both the 2007) for both the treatment and secondary treatment and secondary preventionprevention of VTE in cancer of VTE in cancer
► Oral anticoagulant therapy to follow for as long as Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—cancer is active (Grade 1C recommendation—ACCP)ACCP)
ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S
VTE Prophylaxis Is Underused VTE Prophylaxis Is Underused in Patients With Cancer in Patients With Cancer
1.Kakkar AK et al. Oncologist. 2003;8:381-3882.Stratton MA et al. Arch Intern Med. 2000;160:334-3403.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
4.Rahim SA et al. Thromb Res. 2003;111:215-2195.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
VTE and Cancer
Conclusions and SummaryConclusions and Summary
► Risk factors for VTE in the setting of cancer have Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, been well characterized: solid tumors, chemotherapy, surgery, thrombocytopeniasurgery, thrombocytopenia
► Long-term secondary prevention with LMWH has Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinbeen shown to produce better outcomes than warfarin
► Guidelines and landmark trials support administration Guidelines and landmark trials support administration of LMWH in at risk patientsof LMWH in at risk patients
► Cancer patients are under-prophylaxed for VTECancer patients are under-prophylaxed for VTE
► Health system pharmacists can play a pivotal role in Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient populationimproving clinical outcomes in this patient population