VTE and Cancer
VTE Prophylaxis in the Cancer Patient
Scope, Trials, Guidelines and Solutions
VTE Prophylaxis in the Cancer Patient
Scope, Trials, Guidelines and Solutions
The Science and Medicine ofThe Science and Medicine ofCancer and Thrombosis ManagementCancer and Thrombosis Management
Samuel Z. Goldhaber, MDProfessor of Medicine
Harvard Medical SchoolCardiovascular Division
Director, Venous Thromboembolism Research GroupBrigham and Women’s Hospital
Boston, MA
Samuel Z. Goldhaber, MDProfessor of Medicine
Harvard Medical SchoolCardiovascular Division
Director, Venous Thromboembolism Research GroupBrigham and Women’s Hospital
Boston, MA
VTE and Cancer
Learning ObjectivesLearning Objectives
► Epidemiology/ Scope of the ProblemEpidemiology/ Scope of the Problem
► Prophylaxis Paradigm ShiftProphylaxis Paradigm Shift
► Surgeon General’s Call To ActionSurgeon General’s Call To Action
► Medicare’s “Never Events”Medicare’s “Never Events”
► Prophylaxis ModalitiesProphylaxis Modalities
► Electronic, Computerized AlertsElectronic, Computerized Alerts
► Human, Physician-to-Physician AlertsHuman, Physician-to-Physician Alerts
► Guidelines: NCCN, ASCO, ACCPGuidelines: NCCN, ASCO, ACCP
VTE and Cancer
Epidemiology: Epidemiology: Scope of the ProblemScope of the Problem
VTE and CancerICOPER Cumulative MortalityICOPER Cumulative Mortality
Mor
talit
y (%
)M
orta
lity
(%)
Days From DiagnosisDays From Diagnosis
17.5%17.5%
00
55
1010
1515
2020
2525
77 1414 3030 6060 9090
Lancet 1999;353:1386-1389Lancet 1999;353:1386-1389
VTE and Cancer
VTE and Cancer
► The high death rate from PE (exceeding The high death rate from PE (exceeding acute MI!) and the high frequency of acute MI!) and the high frequency of undiagnosed PE causing “sudden cardiac undiagnosed PE causing “sudden cardiac death” emphasize the need for death” emphasize the need for improved improved preventive efforts.preventive efforts.
► Failure to institute prophylaxis is a much Failure to institute prophylaxis is a much bigger problem with Medical Service bigger problem with Medical Service patients than Surgical Service patients.patients than Surgical Service patients.
At-Risk for VTEAt-Risk for VTE
VTE and Cancer
► Two quality improvement initiatives show Two quality improvement initiatives show that among at-risk-for-VTE Medical that among at-risk-for-VTE Medical Service patients, Medical Oncology Service patients, Medical Oncology patients are the least likely group to patients are the least likely group to receive VTE prophylaxis.receive VTE prophylaxis.
► 80% of omitted prophylaxis on Medical 80% of omitted prophylaxis on Medical Services occurred in Medical Oncology Services occurred in Medical Oncology
patientspatients. .
At-Risk for VTEAt-Risk for VTE
VTE and Cancer
Annual At-Risk for VTE:Annual At-Risk for VTE:U.S. HospitalsU.S. Hospitals
► 7.7 million Medical Service inpatients7.7 million Medical Service inpatients
► 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients
► Based upon ACCP guidelines for VTE Based upon ACCP guidelines for VTE
prophylaxisprophylaxis
Anderson FA Jr, et al. Am J Hematol; 2007; 82: 777-782Anderson FA Jr, et al. Am J Hematol; 2007; 82: 777-782
VTE and Cancer
Outpatient and Inpatient VTE Are LinkedOutpatient and Inpatient VTE Are Linked
► 74% of VTEs present in outpatients.74% of VTEs present in outpatients.
► 42% of outpatient VTE patients have had 42% of outpatient VTE patients have had recent surgery or hospitalization. recent surgery or hospitalization.
► Only 40% had received VTE prophylaxis.Only 40% had received VTE prophylaxis.
Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475
VTE and Cancer
ENDORSE : WORLDWIDE ENDORSE : WORLDWIDE (Lancet 2008; 371: 387-394)(Lancet 2008; 371: 387-394)
68,183 patients; 32 countries; 358 sitesFirst patient enrolled August 2, 2006;Last patient enrolled January 4, 2007
VTE and Cancer
MedicalMedicalSurgicalSurgical
ENDORSE: 68,183 PatientsENDORSE: 68,183 Patients
52%52% at risk for VTEat risk for VTE
(50% (50% receive ACCPreceive ACCPrecommended prophylaxis)recommended prophylaxis)
64% at risk for VTE
59% receive ACCP recommended
prophylaxis
42% at risk for VTE
40% receive ACCP recommended
prophylaxis
VTE and Cancer
VTE Prophylaxis VTE Prophylaxis Paradigm ShiftParadigm Shift
Cancer and Medical ConditionsCancer and Medical Conditionsin the Crosshairsin the Crosshairs
VTE and Cancer
Ten Years Ago…Ten Years Ago…
► Most Americans had not heard of DVT (deep Most Americans had not heard of DVT (deep vein thrombosis) or PE (pulmonary embolism)vein thrombosis) or PE (pulmonary embolism)
► Virtually no awarenessVirtually no awareness
► Media attention was limited to featuring a few Media attention was limited to featuring a few celebrities who were strickencelebrities who were stricken
► No state or congressional resolutionsNo state or congressional resolutions
► No patient advocacyNo patient advocacy
► No Medicare inputNo Medicare input
VTE and Cancer
VTE Awareness in 2009VTE Awareness in 2009
► Growing interest in VTE’s public health threatGrowing interest in VTE’s public health threat
► Known as the most preventable illness in hospitalized Known as the most preventable illness in hospitalized patientspatients
► Publicity is increasing among health care Publicity is increasing among health care professionals and the publicprofessionals and the public
► Patient advocacy is a realityPatient advocacy is a reality
► Congress and most States have adopted months for Congress and most States have adopted months for “Thrombosis Awareness”“Thrombosis Awareness”
► Medicare has declared certain DVTs or PEs as “Never Medicare has declared certain DVTs or PEs as “Never Events” and will not reimburseEvents” and will not reimburse
VTE and Cancer
Old Prophylaxis Paradigm Old Prophylaxis Paradigm
► MD individualizes prophylaxis prescription MD individualizes prophylaxis prescription and ultimately has complete “yes” or “no” and ultimately has complete “yes” or “no” authority to prescribe or withhold authority to prescribe or withhold prophylaxisprophylaxis
► Hospital, government auditors, patients, Hospital, government auditors, patients, and families do not challenge the MD’s and families do not challenge the MD’s decision to withhold prophylaxis. Instead, decision to withhold prophylaxis. Instead, they “defer to the physician’s medical they “defer to the physician’s medical judgment” judgment”
VTE and Cancer
New Prophylaxis ParadigmNew Prophylaxis Paradigm
► Hospital monitors VTE prophylaxis prescribing and insists Hospital monitors VTE prophylaxis prescribing and insists upon guideline-based practiceupon guideline-based practice
► Electronic reminders and automated electronic orders Electronic reminders and automated electronic orders ultimately ensure appropriate prophylaxis for at-risk ultimately ensure appropriate prophylaxis for at-risk patientspatients
► Hospital’s financial and medicolegal penalty for failure to Hospital’s financial and medicolegal penalty for failure to prophylax may be “passed on” to the responsible prophylax may be “passed on” to the responsible attending physicianattending physician
► Cancer patients represent high-risk, “must prophylax” Cancer patients represent high-risk, “must prophylax” subgroupsubgroup
VTE and Cancer
SURGEON SURGEON GENERAL:GENERAL:CALL TO CALL TO
ACTION TO ACTION TO PREVENT PREVENT
DVT AND PEDVT AND PE
September 15, 2008September 15, 2008
VTE and Cancer
Medicare’s Medicare’s “Never Events”“Never Events”
VTE and Cancer
Medicare’s most recent strategy to reduce Medicare’s most recent strategy to reduce medical errors is to withhold payment to medical errors is to withhold payment to hospitals for treatment of serious hospitals for treatment of serious preventable illnesses or complications preventable illnesses or complications termed “never events.” The initial 3 were:termed “never events.” The initial 3 were:1)1)Foreign object retained postopForeign object retained postop
2)2)Air embolism removing CVCAir embolism removing CVC
3)3)Blood transfusion incompatibilityBlood transfusion incompatibility
Medicare’s “Never Events”Medicare’s “Never Events”
VTE and Cancer
► On October 1, 2008, Medicare added:On October 1, 2008, Medicare added:
► DVT or pulmonary embolism occurring DVT or pulmonary embolism occurring after total knee or hip replacement. after total knee or hip replacement.
► Medicare will not pay the incremental Medicare will not pay the incremental cost to manage the complication. Nor cost to manage the complication. Nor will the patient be responsible. will the patient be responsible.
► The hospital will bear the additional The hospital will bear the additional financial burden.financial burden.
Medicare’s “Never Events”Medicare’s “Never Events”
VTE and Cancer
ProphylaxisProphylaxisModalitiesModalities
VTE and Cancer
VTE Prophylaxis in 19,958 Medical Patients/VTE Prophylaxis in 19,958 Medical Patients/9 Studies (Meta-Analysis)9 Studies (Meta-Analysis)
► 62% reduction in fatal PE62% reduction in fatal PE
► 57% reduction in fatal or nonfatal PE57% reduction in fatal or nonfatal PE
► 53% reduction in DVT53% reduction in DVT
Dentali F, et al. Ann Intern Med 2007; 146: 278-288Dentali F, et al. Ann Intern Med 2007; 146: 278-288
VTE and Cancer
VTE Prophylaxis in VTE Prophylaxis in Medical Patients is Cost-EffectiveMedical Patients is Cost-Effective
► $1,264 per patient for LMWH$1,264 per patient for LMWH
► $2,245 for No Prophylaxis$2,245 for No Prophylaxis
Deitelzweig et al. Thromb Haemostas 2008; 100: 810-820Deitelzweig et al. Thromb Haemostas 2008; 100: 810-820
VTE and Cancer
Intermittent Pneumatic CompressionIntermittent Pneumatic CompressionMeta-Analysis in Postop PatientsMeta-Analysis in Postop Patients
► 2,270 patients in 15 randomized trials2,270 patients in 15 randomized trials
► IPC devices reduced DVT risk by 60% IPC devices reduced DVT risk by 60% (Relative Risk 0.40, 95% CI 0.29-0.56, (Relative Risk 0.40, 95% CI 0.29-0.56, p< 0.001)p< 0.001)
Urbankova J. Thromb Haemost 2005; 94: 1181-5Urbankova J. Thromb Haemost 2005; 94: 1181-5
VTE and Cancer
Reversible Risk FactorsReversible Risk Factors
1.1. Nutrition: eat fruits, veggies, fish; less red meat Nutrition: eat fruits, veggies, fish; less red meat ((CirculationCirculation 2007;115:188-195)2007;115:188-195)
2.2. Quit cigarettesQuit cigarettes
3.3. Lose weight/ exerciseLose weight/ exercise
4.4. Prevent DM/ metabolic syndromePrevent DM/ metabolic syndrome
5.5. Control hypertension Control hypertension
6.6. Lower cholesterolLower cholesterol
7.7. Avoid air pollution Avoid air pollution
Arch Intern Med 2008; 168: 920-927)Arch Intern Med 2008; 168: 920-927)
VTE and Cancer
Statins Prevent Statins Prevent
PE and DVT!PE and DVT!
VTE and Cancer
JUPITERJUPITERTotal Venous ThromboembolismTotal Venous Thromboembolism
00 11 22 33 44
0.0
00
0.0
00
0.0
05
0.0
05
0.0
10
0.0
10
0.0
15
0.0
15
0.0
20
0.0
20
0.0
25
0.0
25
Cum
ulat
ive
Inci
denc
eC
umul
ativ
e In
cide
nce
Number at RiskNumber at Risk Follow-up (years)Follow-up (years)
RosuvastatinRosuvastatin
PlaceboPlacebo
8,9018,901 8,6488,648 8,4478,447 6,5756,575 3,9273,927 1,9861,986 1,3761,376 1,0031,003 548548 161161
8,9018,901 8,6528,652 8,4178,417 6,5746,574 3,9433,943 2,0122,012 1,3811,381 993993 556556 182182
HR 0.57, 95%CI 0.37-0.86HR 0.57, 95%CI 0.37-0.86P= 0.007P= 0.007
Placebo 60 / 8901
Rosuvastatin 34 / 8901
- 43 %- 43 %
Glynn et al NEJM 2009Glynn et al NEJM 2009
VTE and Cancer
JUPITERJUPITERVenous Thromboembolism – Unprovoked vs ProvokedVenous Thromboembolism – Unprovoked vs Provoked
HR 0.52, 95% CI 0.28-0.96HR 0.52, 95% CI 0.28-0.96P= 0.03P= 0.03
00 11 22 33 44
0.00
00.
000
0.00
50.
005
0.01
00.
010
0.01
50.
015
0.02
00.
020
Cum
ulat
ive
Inci
denc
eC
umul
ativ
e In
cide
nce
Follow-up (years)Follow-up (years)
00 11 22 33 44
0.00
00.
000
0.00
50.
005
0.01
00.
010
0.01
50.
015
0.02
00.
020
Cum
ulat
ive
Inci
denc
eC
umul
ativ
e In
cide
nce
Provoked Venous ThromboembolismProvoked Venous Thromboembolism
HR 0.61, 95% CI 0.35-1.09HR 0.61, 95% CI 0.35-1.09P= 0.09P= 0.09
Unprovoked Venous ThromboembolismUnprovoked Venous Thromboembolism
Follow-up (years)Follow-up (years)
Clear clinical benefit in the absence of any bleeding hazardClear clinical benefit in the absence of any bleeding hazard (hemorrhagic events: rosuvastatin 258, placebo 275, P=0.45)(hemorrhagic events: rosuvastatin 258, placebo 275, P=0.45)
PlaceboPlaceboPlaceboPlacebo
RosuvastatinRosuvastatin
RosuvastatinRosuvastatin
Glynn et al NEJM 2009Glynn et al NEJM 2009
VTE and Cancer
Electronic and “Human” Electronic and “Human” Prophylaxis AlertsProphylaxis Alerts
Implications for Cancer PatientsImplications for Cancer Patients
VTE and Cancer
Randomization in ALERT StudyRandomization in ALERT Study
Kucher N, et al. NEJM 2005;352:969-977Kucher N, et al. NEJM 2005;352:969-977
VTE risk score > 4No prophylaxis
N = 2,506
INTERVENTION:Single alertN = 1,255
CONTROLNo computer alert
N = 1,251
VTE and Cancer
VTE and Cancer
Primary End PointPrimary End Point
InterventionIntervention
ControlControl
NNumberumber at risk at risk12551255 977977 900900 853853
12511251 976976 893893 839839
InterventionIntervention
Control Control
Time Time ((daysdays))00 3030 6060 9090%
Fre
edom
fro
m D
VT
/%
Fre
edom
fro
m D
VT
/ PE
PE
9090
9292
9494
9696
9898
100100
Kucher N, et al. NEJM 2005;352:969-977Kucher N, et al. NEJM 2005;352:969-977
VTE and Cancer
Electronic AlertsElectronic Alerts Halve Rate of PE and Maintain EffectivenessHalve Rate of PE and Maintain Effectiveness
VTE Rate: VTE Rate:
Pre-AlertPre-Alert 2005—3.3/10002005—3.3/1000
Post-AlertPost-Alert 2006—1.7/10002006—1.7/1000
Post-AlertPost-Alert 2007—1.7/10002007—1.7/1000
Thromb Haemost 2008; 100: 699-704Thromb Haemost 2008; 100: 699-704
VTE and Cancer
““Human” Physician AlertHuman” Physician Alert
► As we planned a multicenter randomized trial As we planned a multicenter randomized trial applying the electronic alert strategy to a broad array applying the electronic alert strategy to a broad array of hospitals across the U.S., we learned that of hospitals across the U.S., we learned that replication of our electronic alert was not feasible. replication of our electronic alert was not feasible.
► Therefore, we crafted a strategy that employed a Therefore, we crafted a strategy that employed a “human” rather than electronic alerting system. “human” rather than electronic alerting system.
► The physician alert consisted of a direct page from a The physician alert consisted of a direct page from a hospital staff member to the Attending Physician. hospital staff member to the Attending Physician.
► The primary end point was reduction in symptomatic The primary end point was reduction in symptomatic VTE within 90 days of randomization.VTE within 90 days of randomization.
VTE and Cancer
Physician Alert: ResultsPhysician Alert: Results
► 2493 patients (82% on Medical Services) from 25 study 2493 patients (82% on Medical Services) from 25 study sites were randomized to the intervention (n=1238) versus sites were randomized to the intervention (n=1238) versus the control group (n=1255). the control group (n=1255).
► Patients whose physicians were alerted were more than Patients whose physicians were alerted were more than twice as likely to receive VTE prophylaxis (46.0% versus twice as likely to receive VTE prophylaxis (46.0% versus 20.6%, p<0.0001). 20.6%, p<0.0001).
► The symptomatic VTE rate was lower in the intervention The symptomatic VTE rate was lower in the intervention group (2.7% versus 3.4%; hazard ratio, 0.79; 95% group (2.7% versus 3.4%; hazard ratio, 0.79; 95% confidence interval, 0.50 to 1.25), but the difference did confidence interval, 0.50 to 1.25), but the difference did not achieve statistical significance. not achieve statistical significance.
► Major bleeding at 30 days in the alert group was similar to Major bleeding at 30 days in the alert group was similar to the control groupthe control group. .
VTE and Cancer
Physician Alert: ResultsPhysician Alert: Results
Piazza G. Piazza G. CirculationCirculation 2009;119: 2196-2201 2009;119: 2196-2201
100%100%
98%98%
96%96%
94%94%
92%92%
90%90%0 7 14 21 28 35 42 49 56 63 70 77 84 900 7 14 21 28 35 42 49 56 63 70 77 84 90
Time after initial enrollment (days)Time after initial enrollment (days)
Fre
edo
m fr
om P
rim
ary
End
poi
nt
Fre
edo
m fr
om P
rim
ary
End
poi
nt
Wilcoxon P-value: 0.307; Long-Rank P-value: 0.309Wilcoxon P-value: 0.307; Long-Rank P-value: 0.309
Human AlertHuman Alert No AlertNo Alert
VTE and Cancer
Current Status of ASCO and Current Status of ASCO and NCCN Guidelines for VTENCCN Guidelines for VTE
Prophylaxis in Cancer PatientsProphylaxis in Cancer Patients
VTE and Cancer
ASCO Guidelines ASCO Guidelines Hospitalized Patients with CancerHospitalized Patients with Cancer
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
Patients with cancer should be Patients with cancer should be considered candidates for VTE considered candidates for VTE prophylaxis with anticoagulants prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in (UFH, LMWH, or fondaparinux) in the absence of bleeding or other the absence of bleeding or other contraindications to anticoagulationcontraindications to anticoagulation
Multiple RCTs of hospitalized Multiple RCTs of hospitalized medical patients with subgroups of medical patients with subgroups of patients with cancer. The 8th ACCP patients with cancer. The 8th ACCP guidelines strongly recommend guidelines strongly recommend (1A) prophylaxis with either low-(1A) prophylaxis with either low-dose heparin or LMWH for dose heparin or LMWH for bedridden patients with active bedridden patients with active cancer.cancer.
VTE and Cancer
Ambulatory Patients with Cancer Without VTE Ambulatory Patients with Cancer Without VTE Receiving Systemic ChemotherapyReceiving Systemic Chemotherapy
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
Routine prophylaxis with an Routine prophylaxis with an antithrombotic agents is not antithrombotic agents is not recommended recommended except as noted belowexcept as noted below
Routine prophylaxis in ambulatory Routine prophylaxis in ambulatory patients receiving chemotherapy is not patients receiving chemotherapy is not recommended due to conflicting trials, recommended due to conflicting trials, potential bleeding, the need for potential bleeding, the need for laboratory monitoring and dose laboratory monitoring and dose adjustment, and the relatively low adjustment, and the relatively low incidence of VTE.incidence of VTE.
LMWH or adjusted dose warfarin (INR LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma ~ 1.5) is recommended in myeloma patients on thalidomide or lenalidomide patients on thalidomide or lenalidomide plus chemotherapy or dexamethasoneplus chemotherapy or dexamethasone
This recommendation is based on This recommendation is based on nonrandomized trial data and nonrandomized trial data and extrapolation from studies of extrapolation from studies of postoperative prophylaxis in orthopedic postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose surgery and a trial of adjusted-dose warfarin in breast cancerwarfarin in breast cancer
VTE and Cancer
Patients with Cancer Undergoing SurgeryPatients with Cancer Undergoing Surgery
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
All patients undergoing major surgical All patients undergoing major surgical intervention for malignant disease intervention for malignant disease should be considered for should be considered for thromboprophylaxis with low- dose thromboprophylaxis with low- dose UFH, LMWH, or fondaparinux starting UFH, LMWH, or fondaparinux starting as early as possible for at least 7-10 as early as possible for at least 7-10 days unless contraindicated.days unless contraindicated.
RCTs of UFH and those comparing RCTs of UFH and those comparing the effects of LMWH and UFH on DVT the effects of LMWH and UFH on DVT rates on patients with cancer indicate rates on patients with cancer indicate broadly similar prophylactic efficacies broadly similar prophylactic efficacies for these two agentsfor these two agents
Mechanical methods may be added to Mechanical methods may be added to anticoagulation in very high risk anticoagulation in very high risk patients but should not be used alone patients but should not be used alone unless anticoagulation in unless anticoagulation in contraindicated.contraindicated.
A Cochrane review of 19 studiesA Cochrane review of 19 studies
VTE and Cancer
Patients with Cancer Patients with Cancer Undergoing Surgery Undergoing Surgery (continued)(continued)
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
LMWH for up to 4 weeks may be LMWH for up to 4 weeks may be considered after major considered after major abdominal/pelvic surgery with residual abdominal/pelvic surgery with residual malignant disease, obesity, and a malignant disease, obesity, and a previous history of VTEprevious history of VTE
Recent RCTs suggest that prolonging Recent RCTs suggest that prolonging prophylaxis up to 4 weeks is more prophylaxis up to 4 weeks is more effective than short-course prophylaxiseffective than short-course prophylaxis in reducing postoperative VTE.in reducing postoperative VTE.
VTE and Cancer
Treatment of Patients with Established Treatment of Patients with Established VTE to Prevent RecurrenceVTE to Prevent Recurrence
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
LMWH is the preferred approach for the initial LMWH is the preferred approach for the initial 5-10 days in cancer patient with established 5-10 days in cancer patient with established VTE.VTE.
LMWH for 3-6 months is LMWH for 3-6 months is more effective than vitamin K more effective than vitamin K antagonists given for a antagonists given for a similar duration for similar duration for preventing recurrent VTE.preventing recurrent VTE.
LMWH for at least 6 months is preferred for LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are antagonists with a targeted INR of 2-3 are acceptable when LMWH is not available. The acceptable when LMWH is not available. The CLOT study demonstrated a relative risk CLOT study demonstrated a relative risk reduction of 49% with LMWH vs. a vitamin K reduction of 49% with LMWH vs. a vitamin K antagonist. Dalteparin sodium approved by the antagonist. Dalteparin sodium approved by the FDA for extended treatment of symptomatic FDA for extended treatment of symptomatic VTE to reduce the risk of recurrence of VTE in VTE to reduce the risk of recurrence of VTE in patients with cancerpatients with cancer (FDA 2007) (FDA 2007)
VTE and Cancer
Treatment of Patients with Established Treatment of Patients with Established VTE to Prevent Recurrence VTE to Prevent Recurrence (continued)(continued)
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
Anticoagulation for an indefinite period Anticoagulation for an indefinite period should be considered for patients with should be considered for patients with active cancer (metastatic disease, active cancer (metastatic disease, continuing chemotherapy)continuing chemotherapy)
In the absence of clinical trials, In the absence of clinical trials, benefits and risks of benefits and risks of continuing LMWH continuing LMWH beyond 6 months is a clinical beyond 6 months is a clinical judgment in the individual patient.judgment in the individual patient. Caution is urged in elderly patients Caution is urged in elderly patients and those with intracranial and those with intracranial malignancy.malignancy.
Inferior vena cava filters are reserved Inferior vena cava filters are reserved for those with contraindications to for those with contraindications to anticoagulation or PE despite anticoagulation or PE despite adequate long-term LMWH.adequate long-term LMWH.
Consensus recommendations due to Consensus recommendations due to lack of date in cancer-specific lack of date in cancer-specific populationspopulations
VTE and Cancer
Anticoagulants in the Absence of Anticoagulants in the Absence of Established VTE to Improve SurvivalEstablished VTE to Improve Survival
Role of VTE ProphylaxisRole of VTE Prophylaxis EvidenceEvidence
Anticoagulants are not currently Anticoagulants are not currently recommended to improve survival in recommended to improve survival in patients with cancer without VTE.patients with cancer without VTE.
RCTs and meta-analysis of warfarin, RCTs and meta-analysis of warfarin, UFH and LMWH have reported UFH and LMWH have reported encouraging but variable results encouraging but variable results generally showing clinical benefit only generally showing clinical benefit only in subgroup analyses.in subgroup analyses.
VTE and Cancer
Summary of the Guidelines UpdatesSummary of the Guidelines Updates
Summary of Major Changes in the Summary of Major Changes in the 1.2009 Version of the Venous 1.2009 Version of the Venous
Thromboembolic Disease GuidelinesThromboembolic Disease Guidelines
VTE and Cancer
Changes in 2009 NCCN GuidelinesChanges in 2009 NCCN Guidelines
Stage 1 Immediate:Stage 1 Immediate:► ““Stage 1 Immediate: Concomitant with diagnosis or while diagnosis Stage 1 Immediate: Concomitant with diagnosis or while diagnosis
and risk assessment (heparin phase)” changed to “Stage 1 and risk assessment (heparin phase)” changed to “Stage 1 Immediate: At diagnosis or during diagnostic evaluation”Immediate: At diagnosis or during diagnostic evaluation”
► Low –molecular-weight-heparin: New footnote “6” was added that Low –molecular-weight-heparin: New footnote “6” was added that states, states, “Although each of the low molecular weight heparins “Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer (LMWH), have been studies in randomized control trials in cancer patients, dalteparin’s efficacy in this population is supported by the patients, dalteparin’s efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the highest quality evidence and it is the only LMWH approved by the FDA for this indicationFDA for this indication.”.”
► Unfractionated heparin (IV): target aPTT range changed from “2.0-Unfractionated heparin (IV): target aPTT range changed from “2.0-2.9 x control) to “2.0-2.5 x control…” (Also for VTE-H) in these 2.9 x control) to “2.0-2.5 x control…” (Also for VTE-H) in these patients.patients.
VTE and Cancer
Changes in 2009 NCCN GuidelinesChanges in 2009 NCCN Guidelines
Stage 3 Chronic:Stage 3 Chronic:
► ““Third bullet: “Consider indefinite anticoagulation….” Third bullet: “Consider indefinite anticoagulation….” changed to “changed to “Recommend indefinite anticoagulation….”Recommend indefinite anticoagulation….”
► Fourth bullet: “For catheter associated thrombosis, Fourth bullet: “For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at anticoagulate as long as catheter is in place and for at least 3 months after catheter removal”.least 3 months after catheter removal”.
VTE and Cancer
Changes in 2009 NCCN GuidelinesChanges in 2009 NCCN Guidelines
► 66Although each of the low molecular weight heparins Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled (LMWH) have been studied in randomized controlled trials in cancer patients, trials in cancer patients, dalteparin’s efficacy in this dalteparin’s efficacy in this population is supported by the highest quality evidence population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this and is the only LMWH approved by the FDA for this indicationindication..
Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous heparin versus a coumarin for the prevention of recurrent venous thromboembolism on patients with cancer. New Eng J Med 2003;349(2): thromboembolism on patients with cancer. New Eng J Med 2003;349(2): 146-153.146-153.
VTE and Cancer
(VTE-D): (VTE-D): Therapeutic Anticoagulation Therapeutic Anticoagulation Treatment for VenousThromboembolismTreatment for VenousThromboembolism
► The NCCN panel recommends VTE thromboprophylaxis for all The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. VTE should be maintained for cancer patients. Following Following hospital discharge, it is recommended that patients at high-risk hospital discharge, it is recommended that patients at high-risk of VTE (e.g. cancer surgery patients) continue to receive VTE of VTE (e.g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation.prophylaxis for up to 4 weeks post-operation. Careful Careful evaluation and follow-up of cancer patients in whom VTE is evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of of the patient is assessed and the risks and benefits of treatment are considered. treatment are considered.
VTE and Cancer
(VTE-D): (VTE-D): Therapeutic Anticoagulation Therapeutic Anticoagulation Treatment for VenousThromboembolismTreatment for VenousThromboembolism
Stage 1 Stage 1 ImmediateImmediate: At diagnosis or during diagnostic : At diagnosis or during diagnostic evaluation:evaluation:
► Low-molecular-weight heparin (LMWH)Low-molecular-weight heparin (LMWH)• Dalteparin (200 units/kg subcutaneous daily)Dalteparin (200 units/kg subcutaneous daily)• Enoxaparin (1 mg/kg subcutaneous every 12 hours)Enoxaparin (1 mg/kg subcutaneous every 12 hours)• Tinzaparin (175 units/kg subcutaneous daily)Tinzaparin (175 units/kg subcutaneous daily)
► Fondaparinux (5 mg [<50 kg]; 7.5 mg [50-100 kg]; 10 mg [> 100 kg] Fondaparinux (5 mg [<50 kg]; 7.5 mg [50-100 kg]; 10 mg [> 100 kg] subcutaneous dailysubcutaneous daily
► Unfractionated heparinUnfractionated heparin (IV) (80 units/kg load, then 18 (IV) (80 units/kg load, then 18 units/kg per hour, target aPTT of 2.0-2.5 x control or per units/kg per hour, target aPTT of 2.0-2.5 x control or per hospital SOP)hospital SOP)
VTE and Cancer
(VTE-D): (VTE-D): Therapeutic Anticoagulation Therapeutic Anticoagulation Treatment for VenousThromboembolismTreatment for VenousThromboembolism
► Additional VTE risk factors for surgical oncology patients Additional VTE risk factors for surgical oncology patients with a previous episode of VTE include anesthesia times with a previous episode of VTE include anesthesia times longer than 2 hours, advanced stage disease, bed rest, longer than 2 hours, advanced stage disease, bed rest, >> 44 days and patients age 60 years or older. Extended days and patients age 60 years or older. Extended prophylaxis out to prophylaxis out to 44 weeks post-surgery was associated weeks post-surgery was associated with a greater than 50% reduction in venographic VTEwith a greater than 50% reduction in venographic VTE
VTE and Cancer
(VTE-D): (VTE-D): Therapeutic Anticoagulation Therapeutic Anticoagulation Treatment for VenousThromboembolismTreatment for VenousThromboembolism
Stage 2 Acute: Short term, during transition to chronic Stage 2 Acute: Short term, during transition to chronic phase:phase:
► LMWH (category 1) is preferred as monotherapyLMWH (category 1) is preferred as monotherapy without without warfarin in patients with proximal DVT or PE and warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or prevention of recurrent VTE in patients with advanced or metastatic cancermetastatic cancer
► If UFH or factor Xa antagonist, transition to LMWH or If UFH or factor Xa antagonist, transition to LMWH or warfarinwarfarin
► Warfarin (2.5-5 mg every day initially, subsequent dosing Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2.0-3.0)based on INR value; target INR 2.0-3.0)
VTE and Cancer
Therapeutic Anticoagulation FailureTherapeutic Anticoagulation Failure
Therapeutic INR
Switch to heparin (LMWH
preferred) or fondaparinux
Increase warfarin dose and treat with
parenteral agent until INR target achieved or consider switching
to heparin (LMWH preferred) or fondaparinux
Patient on
warfarin
Check INR
Sub-therapeutic
INR
VTE and Cancer
Therapeutic Anticoagulation FailureTherapeutic Anticoagulation Failure
Therapeutic aPTT
Increase dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HIT
Increase dose of heparin to reach therapeutic level
Patient on
heparin
Check aPTT levels
Sub-therapeutic
aPTT
VTE and Cancer
Improving VTE Prophylaxis in CancerImproving VTE Prophylaxis in Cancer
► ““Immunize” cancer patients Immunize” cancer patients with LMWH with LMWH unless MD “opts out”—analogous to flu unless MD “opts out”—analogous to flu vaccine or pneumonia vaccinevaccine or pneumonia vaccine
► Pay attention to the Pay attention to the Continuum of Care Continuum of Care and to VTE risk at the time of Discharge—and to VTE risk at the time of Discharge—Order discharge LMWHOrder discharge LMWH
► Withhold payments Withhold payments to hospitals when DVT/ to hospitals when DVT/ PE develops after total hip or knee PE develops after total hip or knee replacement—Medicare began this replacement—Medicare began this practice in October 2008practice in October 2008
VTE and Cancer
ConclusionsConclusions
1.1. VTE prophylaxis has enjoyed a paradigm shift. Gone are VTE prophylaxis has enjoyed a paradigm shift. Gone are the days when the imperial physician reigned unchallenged the days when the imperial physician reigned unchallenged on VTE prophylaxis decisions. Hospitals and Medicare are on VTE prophylaxis decisions. Hospitals and Medicare are scrutinizing implementation of prophylaxis. scrutinizing implementation of prophylaxis.
2.2. Hospital-acquired VTE is not supposed to happen any Hospital-acquired VTE is not supposed to happen any longer. Medicare is declaring some VTEs “Never Events” longer. Medicare is declaring some VTEs “Never Events” and will not reimburse hospitals for additional treatment. and will not reimburse hospitals for additional treatment.
3.3. Effective VTE prophylaxis in cancer patients usually Effective VTE prophylaxis in cancer patients usually requires anticoagulation with LMWH but when bleeding risk requires anticoagulation with LMWH but when bleeding risk is too high, use mechanical measures. is too high, use mechanical measures.
4.4. DVT prophylaxis in cancer patients is under-utilized and DVT prophylaxis in cancer patients is under-utilized and requires increased vigilance and prophylaxis-focused requires increased vigilance and prophylaxis-focused interventionintervention
VTE and Cancer
ConclusionsConclusions
5.5. DVT prophylaxis following cancer surgery for four DVT prophylaxis following cancer surgery for four weeks is recommended; longer periods may be weeks is recommended; longer periods may be necessary depending on risk assessmentnecessary depending on risk assessment
6.6. DVT prophylaxis following established DVT in cancer for DVT prophylaxis following established DVT in cancer for at least 6 months is recommended and for longer, at least 6 months is recommended and for longer, indefinite periods with active cancer and/or indefinite periods with active cancer and/or chemotherapy.chemotherapy.
7.7. Heart healthy lifestyle and statins reduce VTE riskHeart healthy lifestyle and statins reduce VTE risk8.8. Electronic, computerized alerts can reduce symptomatic Electronic, computerized alerts can reduce symptomatic
VTE by at least 40%.VTE by at least 40%.9.9. When “human” alerts are used, symptomatic VTE is When “human” alerts are used, symptomatic VTE is
reduced by about 20%. reduced by about 20%. 10.10. PE/ DVT patients with cancer warrant LMWH PE/ DVT patients with cancer warrant LMWH
monotherapy.monotherapy.
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