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

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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

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ive

Inci

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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.