A Systematic Analysis of VTE Prophylaxis in the Setting of 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

Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application

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

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

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

Thrombosis and SurvivalThrombosis and SurvivalLikelihood of Death After HospitalizationLikelihood of Death After Hospitalization

00 20 20 40 40 60 60 80 80 100 100 120 120140 160 180140 160 1800.000.00

0.200.20

0.400.40

1.001.00

0.800.80

0.600.60

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

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

Inci

denc

e of

VT

E (

%)

Inci

denc

e of

VT

E (

%)

0 50 100 150 200 250 300 350 4000 50 100 150 200 250 300 350 400

7%7%

6%6%

5%5%

4%4%

3%3%

2%2%

1%1%

0%0%

Local Regional RemoteLocal Regional Remote

R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40R.H. White et al. Thombosis Research 120 Suppl. 2 (2007) S29-S40

Cancer typeCancer typeHazard ratio (95% CI) for death within one year, cases Hazard ratio (95% CI) for death within one year, cases

with VTE diagnosed in year 1 vs. no VTE, by stagewith VTE diagnosed in year 1 vs. no VTE, by stage

LocalLocal RegionalRegional RemoteRemote

ProstateProstate 5.6 (3.8-8.5)5.6 (3.8-8.5)‡‡ 4.7 (1.9-11.5)4.7 (1.9-11.5) ‡ ‡ 2.8 (1.5-5.0)2.8 (1.5-5.0) †

BreastBreast 6.6 (3.7-11.8)6.6 (3.7-11.8) ‡ ‡ 2.4 (1.3-4.5)2.4 (1.3-4.5) ‡ ‡ 1.8 (1.1-2.9)*1.8 (1.1-2.9)*

LungLung 3.1 (2.1-4.5)3.1 (2.1-4.5) ‡ ‡ 2.9 (2.3-3.5)2.9 (2.3-3.5) ‡ ‡ 2.5 (2.3-2.7)2.5 (2.3-2.7) ‡ ‡

Colon/rectumColon/rectum 3.2 (1.8-5.5)3.2 (1.8-5.5) ‡ ‡ 2.2 (1.7-3.0)2.2 (1.7-3.0) ‡ ‡ 2.0 (1.7-2.4)2.0 (1.7-2.4) ‡ ‡

MelanomaMelanoma 14.4 (4.6-45.2)14.4 (4.6-45.2) ‡ ‡ N/AN/A 2.8 (1.5-5.3)2.8 (1.5-5.3) †

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma 3.2 (1.9-5.3)3.2 (1.9-5.3) ‡ ‡ 2.0 (1.3-3.2)2.0 (1.3-3.2) † 2.3 (1.7-3.1)2.3 (1.7-3.1) ‡ ‡

UterusUterus 7.0 (3.4-14.2)7.0 (3.4-14.2) ‡ ‡ 9.1 (4.8-17.2)9.1 (4.8-17.2) ‡ ‡ 1.7 (1.0-3.0)*1.7 (1.0-3.0)*

BladderBladder 3.2 (1.7-6.2)3.2 (1.7-6.2) ‡ ‡ 3.3 (1.7-6.4)3.3 (1.7-6.4) ‡ ‡ 3.3 (1.8-6.2)3.3 (1.8-6.2) ‡ ‡

PancreasPancreas 2.3 (1.2-4.6)*2.3 (1.2-4.6)* 3.8 (2.8-5.1)3.8 (2.8-5.1) ‡ ‡ 2.3 (1.9-2.7)2.3 (1.9-2.7) ‡ ‡

StomachStomach 2.4 (1.1-5.1)*2.4 (1.1-5.1)* 1.5 (1.0-2.1)*1.5 (1.0-2.1)* 1.8 (1.4-2.3)1.8 (1.4-2.3) ‡ ‡

OvaryOvary 11.3 (2.5-51.7)11.3 (2.5-51.7) † 4.8 (1.1-20.4)*4.8 (1.1-20.4)* 2.3 (1.7-3.0)2.3 (1.7-3.0) ‡ ‡

KidneyKidney 3.2 (1.2-8.8)*3.2 (1.2-8.8)* 1.4 (0.6-3.2)1.4 (0.6-3.2) 1.3 (0.9-2.0)1.3 (0.9-2.0)

* p<0.05; * p<0.05; †p<0.01); p<0.01); ‡ p<0.001)p<0.001)

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 Disease Local Stage Disease

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)White, et al. Thromb Res,120 suppl. 2 (2007)White, et al. Thromb Res,120 suppl. 2 (2007)

Recurrent Ovarian CancerRecurrent Ovarian Cancer

Fotopoulou C et al. Thromb Res 2009Fotopoulou C et al. Thromb Res 2009

• • 7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)• 78% of VTE in ROC occur within 2 months of second line chemo regimen: • 78% of VTE in ROC occur within 2 months of second line chemo regimen: cisplatin-relatedcisplatin-related• Ascites is the only independent risk factor for VTE (HR=2.2) • Ascites is the only independent risk factor for VTE (HR=2.2)

• • 7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)7% symptomatic VTE (2.8-6.1% in primary ovarian Cancer)• 78% of VTE in ROC occur within 2 months of second line chemo regimen: • 78% of VTE in ROC occur within 2 months of second line chemo regimen: cisplatin-relatedcisplatin-related• Ascites is the only independent risk factor for VTE (HR=2.2) • Ascites is the only independent risk factor for VTE (HR=2.2)

Hospital Mortality With or Without VTEHospital Mortality With or Without VTE

Khorana, JCO, 2006Khorana, JCO, 2006

Mor

talit

y (%

)M

orta

lity

(%)

Mor

talit

y (%

)M

orta

lity

(%)

N=66,016N=66,016 N=20,591N=20,591 N=17,360N=17,360

Thrombosis Risk In Cancer Thrombosis Risk In Cancer

Primary ProphylaxisPrimary Prophylaxis► Medical InpatientsMedical Inpatients

► SurgerySurgery

► RadiotherapyRadiotherapy

► Central Venous CathetersCentral Venous Catheters

Risk Factors for Cancer-Associated VTERisk Factors for Cancer-Associated VTE

► CancerCancer● Type Type

• Men: prostate, colon, brain, lungMen: prostate, colon, brain, lung• Women: breast, ovary, lungWomen: breast, ovary, lung

● StageStage► TreatmentsTreatments

● SurgerySurgery• 10-20% proximal DVT10-20% proximal DVT• 4-10% clinically evident PE4-10% clinically evident PE• 0.2-5% fatal PE0.2-5% fatal PE

● ChemotherapyChemotherapy● Central venous cathetersCentral venous catheters (~4% generate clinically (~4% generate clinically

relevant VTE)relevant VTE)► PatientPatient

● Prior VTEPrior VTE● ComorbiditiesComorbidities● Genetic backgroundGenetic background

Medical InpatientsMedical Inpatients

Cancer and ThrombosisCancer and Thrombosis

PharmacologicPharmacologic(Prophylaxis & Treatment)(Prophylaxis & Treatment)

NonpharmacologicNonpharmacologic(Prophylaxis)(Prophylaxis)

Antithrombotic Therapy: ChoicesAntithrombotic Therapy: Choices

IntermittentPneumaticCompression

Elastic Stockings

InferiorVena CavaFilter

OralAnticoagulants

UnfractionatedHeparin (UH)

Low Molecular Weight Heparin (LMWH)

New Agents: e.g. Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?

Prophylaxis Studies in Medical PatientsProphylaxis Studies in Medical Patients

Francis, NEJM, 2007Francis, NEJM, 2007

Placebo EnoxaparinPlacebo Enoxaparin MEDENOX TrialMEDENOX Trial

Placebo DalteparinPlacebo Dalteparin PREVENTPREVENT

Placebo FondaparinuxPlacebo Fondaparinux ARTEMISARTEMIS

Rat

e of

VT

E (

%)

Rat

e of

VT

E (

%)

Relative Relative risk risk

reduction reduction 63%63%





ASCO GuidelinesASCO Guidelines

1. SHOULD HOSPITALIZED PATIENTS WITH1. SHOULD HOSPITALIZED PATIENTS WITHCANCER RECEIVE ANTICOAGULATION FORCANCER RECEIVE ANTICOAGULATION FORVTE PROPHYLAXISVTE PROPHYLAXIS??

Recommendation. Recommendation. 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.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

Surgical PatientsSurgical Patients

Cancer and ThrombosisCancer and Thrombosis

► 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 prophylaxis:and >3-fold risk of fatal PE despite prophylaxis:

Kakkar AK, et al. Kakkar AK, et al. Thromb HaemostThromb Haemost 2001; 86 (suppl 1): OC1732 2001; 86 (suppl 1): OC1732

Incidence of VTE in Surgical PatientsIncidence of VTE in Surgical Patients

No CancerNo CancerN=16,954N=16,954

CancerCancerN=6124N=6124

P-valueP-value

Post-op VTEPost-op VTE 0.61%0.61% 1.26%1.26% <0.0001<0.0001

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

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

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

Canadian Canadian Colorectal DVT Colorectal DVT Prophylaxis TrialProphylaxis Trial13.9%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 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

ENOXACAN IIENOXACAN II

In

cide

nce

of O

utco

me

Eve

ntIn

cide

nce

of O

utco

me

Eve

nt

N=167

N=165

0% 0.4%

12.0%

4.8%

NNT = 140.6%

3.6%

Extended Prophylaxis inExtended Prophylaxis inSurgical PatientsSurgical Patients

► A multicenter, prospective, assessor-blinded, open-label, A multicenter, prospective, assessor-blinded, open-label, randomized trial: randomized trial: Dalteparin administered for 28 days after Dalteparin administered for 28 days after major abdominal surgery major abdominal surgery compared to 7 days of treatmentcompared to 7 days of treatment

► RESULTS:RESULTS: Cumulative Cumulative incidence of VTE was reduced from incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 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, 5000 4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly IU once daily, after major abdominal surgery significantly reduces the rate of VTEreduces the rate of VTE, without increasing the risk of , without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis.bleeding, compared with 1 week of thromboprophylaxis.

Major Abdominal Surgery: FAME InvestigatorsMajor Abdominal Surgery: FAME Investigators—Dalteparin Extended —Dalteparin Extended

Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.Rasmussen, J Thromb Haemost. 2006 Nov;4(11):2384-90. Epub 2006 Aug 1.

ASCO Guidelines: VTE ProphylaxisASCO Guidelines: VTE Prophylaxis

► 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.

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

Thrombosis is a potential complication of central Thrombosis is a potential complication of central venous catheters, including these events:venous catheters, including these events:

–Fibrin sheath formationFibrin sheath formation

–Superficial phlebitisSuperficial phlebitis

–Ball-valve clotBall-valve clot

–Deep vein thrombosis (DVT)Deep vein thrombosis (DVT)

Central Venous CathetersCentral Venous Catheters

Geerts W, et al. Geerts W, et al. ChestChest Jun 2008: 381S–453S Jun 2008: 381S–453S

Placebo-Controlled TrialsPlacebo-Controlled Trials

StudyStudy RegimenRegimen NN CRT (%)CRT (%)

Reichardt* Reichardt* 20022002

Dalteparin 5000 U dailyDalteparin 5000 U dailyplaceboplacebo

285285140140

11 (3.7)11 (3.7) 5 (3.4)5 (3.4)

Couban*Couban*20022002

Warfarin 1mg dailyWarfarin 1mg dailyplaceboplacebo

130130125125

6 (4.6)6 (4.6) 5 (4.0)5 (4.0)

ETHICSETHICS††

20042004Enoxaparin 40 mg dailyEnoxaparin 40 mg daily

placeboplacebo155155155155

22 (14.2)22 (14.2)28 (18.1)28 (18.1)

**symptomatic outcomessymptomatic outcomes;; ††routine venography at 6 weeksroutine venography at 6 weeks

Prophylaxis for Venous CathetersProphylaxis for Venous Catheters

Reichardt P, et al. Reichardt P, et al. Proc ASCOProc ASCO 2002;21:369a; Couban S, et al, 2002;21:369a; Couban S, et al, BloodBlood 2002;100:703a; Agnelli G, et 2002;100:703a; Agnelli G, et al. al. Proc ASCOProc ASCO 2004;23:730 2004;23:730

Young AM et al. Lancet 2009;373:567Young AM et al. Lancet 2009;373:567Young AM et al. Lancet 2009;373:567Young AM et al. Lancet 2009;373:567

Thrombotic Thrombotic EventsEvents

Warfarin evaluationWarfarin evaluation Dose evaluationDose evaluation

No No warfarin warfarin (n=404)(n=404)

Warfarin Warfarin (n=408)(n=408)

Relative risk Relative risk (95% CI, p value)(95% CI, p value)

Fixed-Fixed-dose dose

warfarin warfarin (n=471)(n=471)

Dose-Dose-adjusted adjusted warfarin warfarin (n=473)(n=473)


Catheter-Catheter-related related

thrombotic thrombotic eventsevents

24 24 (6%)(6%)

24 24 (6%)(6%)

0.990.99(0.57-1.72, 0.98)(0.57-1.72, 0.98)

34 34 (7%)(7%)

13 13 (3%)(3%)

0.38 0.38 (0.20-0.71,0.002)(0.20-0.71,0.002)

No catheter-No catheter-related eventrelated event

370 370 (92%)(92%)

372 372 (91%)(91%) --

433 433 (92%)(92%)

448 448 (95%)(95%) --

Not knownNot known 10 10 (2%)(2%)

12 12 (3%)(3%)

4 4 (<1%)(<1%)

12 12 (3%)(3%)

All thrombotic All thrombotic eventsevents

38 38 (9%)(9%)

30 30 (7%)(7%)

0.78 0.78 (0.50-1.24), 0.30(0.50-1.24), 0.30

37 37 (8%)(8%)

26 26 (6%)(6%)

0.70 0.70 (0.43-1.14, 0.15)(0.43-1.14, 0.15)

WARP: Prophylactic Warfarin Does Not WARP: Prophylactic Warfarin Does Not Reduce Catheter-Associated Thrombosis in CAReduce Catheter-Associated Thrombosis in CA



Bleeding Bleeding and Raised and Raised

INRINR









Major Major bleeding and bleeding and no reported no reported raised INRraised INR

1 (<1%)1 (<1%) 3 (<1%)3 (<1%) -- 5 (1%)5 (1%) 7 (1%)7 (1%) --

Major Major bleeding and bleeding and raised INRraised INR

00 4 (<1%)4 (<1%) -- 2 (<1%)2 (<1%) 9 (2%)9 (2%) --

Total major Total major bleedingbleeding 1 (<1%)1 (<1%) 7 (2%)7 (2%) 6.93 6.93

(0.85-56.08, 0.07)(0.85-56.08, 0.07) 7 (1%)7 (1%) 16 (3%)16 (3%) 2.282.28(0.95-5.48, 0.09)(0.95-5.48, 0.09)

Moderate and Moderate and severe raised severe raised INR and no INR and no

major major bleedingbleeding

00 3 (<1%)3 (<1%) -- 1 (<1%)1 (<1%) 12 (3%)12 (3%) --

Minor Minor bleedingbleeding 1 (<1%)1 (<1%) 14 (3%)14 (3%) -- 21 (4%)21 (4%) 24 (5%)24 (5%) --



Combined Combined thrombosis thrombosis and major and major bleeding bleeding eventsevents









Total Total catheter-catheter-related related

thrombosis thrombosis and major and major bleeding bleeding eventsevents

25 (6%)25 (6%) 31 (8%)31 (8%) 1.231.23(0.83-1.52, 0.51)(0.83-1.52, 0.51) 41 (9%)41 (9%) 29 (6%)29 (6%) 0.840.84

(0.74-2.04, 0.17)(0.74-2.04, 0.17)

All thrombotic All thrombotic and major and major bleeding bleeding eventsevents

39 (10%)39 (10%) 37 (9%)37 (9%) 0.940.94(0.61-1.44, 0.87)(0.61-1.44, 0.87) 44 (9%)44 (9%) 42 (9%)42 (9%) 0.95 0.95

(0.64-1.42, 0.89)(0.64-1.42, 0.89)

Tolerability of Low-Dose WarfarinTolerability of Low-Dose Warfarin

► 95 cancer patients receiving FU-based infusion 95 cancer patients receiving FU-based infusion chemotherapy and 1 mg warfarin dailychemotherapy and 1 mg warfarin daily

► INR measured at baseline and four time pointsINR measured at baseline and four time points

► 10% of all recorded INRs >1.510% of all recorded INRs >1.5

► Patients with elevated INRPatients with elevated INR2.0–2.92.0–2.9 6% 6%

3.0–4.93.0–4.9 19%19%

>5.0>5.0 7% 7%

Central Venous Catheters: WarfarinCentral Venous Catheters: Warfarin

Masci et al. Masci et al. J Clin Oncol.J Clin Oncol. 2003;21:736-739 2003;21:736-739

In 10 studies involving more than 1250 cancer patients with In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls:CVADs vs CA controls:

The attributable risk of catheter associated thrombosis The attributable risk of catheter associated thrombosis conferred by:conferred by:

In 10 studies involving more than 1250 cancer patients with In 10 studies involving more than 1250 cancer patients with CVADs vs CA controls:CVADs vs CA controls:

The attributable risk of catheter associated thrombosis The attributable risk of catheter associated thrombosis conferred by:conferred by:

Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564Dentali F et al. JTH 2007; 5(Suppl 2):P-S-564

Influence of Thrombophilia on Thrombotic Influence of Thrombophilia on Thrombotic Complications of CVADs in CancerComplications of CVADs in Cancer

CA + FVL OR=5.18 (95% confidence interval: 3.0-8.8)

CA + G20210A OR=3.95 (95% confidence interval: 1.5-10.6)

FVL 13.5%

G20210A 3.6%

88thth ACCP Consensus Guidelines ACCP Consensus Guidelines

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)

Revised 2009 NCCN guidelines Revised 2009 NCCN guidelines diverge from this philosophy diverge from this philosophy

ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S

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.)

Risk Factors for VTE inRisk Factors for VTE inMedical Oncology PatientsMedical Oncology Patients

► Tumor typeTumor type● Ovary, brain, pancreas, lung, colonOvary, brain, pancreas, lung, colon

► 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,

anti-VEGF, radiationanti-VEGF, radiation

► Miscellaneous VTE risk factorsMiscellaneous VTE risk factors● Previous VTE, Previous VTE, hospitalization, immobility, hospitalization, immobility,

infection, thrombophiliainfection, thrombophilia

Independent Risk Factors for DVT/PEIndependent Risk Factors for DVT/PE

Risk Factor/CharacteristicRisk Factor/Characteristic O.R.O.R.

Recent surgery with institutionalizationRecent surgery with institutionalization 21.7221.72

TraumaTrauma 12.6912.69

Institutionalization without recent surgeryInstitutionalization without recent surgery 7.987.98

Malignancy with chemotherapyMalignancy with chemotherapy 6.536.53

Prior CVAD or pacemakerPrior CVAD or pacemaker 5.555.55

Prior superficial vein thrombosisPrior superficial vein thrombosis 4.324.32

Malignancy without chemotherapyMalignancy without chemotherapy 4.054.05

Neurologic disease w/ extremity paresisNeurologic disease w/ extremity paresis 3.043.04

Serious liver diseaseSerious liver disease 0.100.10

Heit JA et al. Heit JA et al. Thromb HaemostThromb Haemost. 2001;86:452-463. 2001;86:452-463

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

Oncology SettingOncology Setting VTE VTE IncidenceIncidence

Breast cancer (Stage I & II) w/o further treatmentBreast cancer (Stage I & II) w/o further treatment 0.2%0.2%

Breast cancer (Stage I & II) w/ chemoBreast cancer (Stage I & II) w/ chemo 2%2%

Breast cancer (Stage IV) w/ chemoBreast cancer (Stage IV) w/ chemo 8%8%

Non-Hodgkin’s lymphomas w/ chemoNon-Hodgkin’s lymphomas w/ chemo 3%3%

Hodgkin’s disease w/ chemoHodgkin’s disease w/ chemo 6%6%

Advanced cancer (1-year survival=12%)Advanced cancer (1-year survival=12%) 9%9%

High-grade gliomaHigh-grade glioma 26%26%

Multiple myeloma (thalidomide + chemo)Multiple myeloma (thalidomide + chemo) 28%28%

Renal cell carcinoma Renal cell carcinoma 43%43%

Solid tumors (anti-VEGF + chemo)Solid tumors (anti-VEGF + chemo) 47%47%

Wilms tumor (cavoatrial extension) Wilms tumor (cavoatrial extension) 4%4%

PrimaryPrimary VTE Prophylaxis VTE Prophylaxis

► 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

Naluri SR et al. JAMA. 2008;300:2277Naluri 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 MyelomaApproaches Risk of Antiangiogenesis in Myeloma

All-Grade Venous All-Grade Venous Thromboembolism, Thromboembolism,

No./Total No.No./Total No.

Tumor TypeTumor Type No. of No. of StudiesStudies BevacizumabBevacizumab ControlControl Incidence Incidence

(95% CI), %(95% CI), %RR (95% RR (95%

CI)CI)

OverallOverall 66 155/1196155/1196 107/1083107/1083 11.9 11.9 (6.8-19.9)(6.8-19.9)

1.29 1.29 (1.03-1.63)(1.03-1.63)

Colorectal Colorectal cancercancer 33 108/564108/564 85/53285/532 19.1 19.1

(16.1-22.6)(16.1-22.6)1.19 1.19

(0.92-1.55)(0.92-1.55)

NSCLCNSCLC 11 10/6610/66 3/323/32 14.9 14.9 (8.2-25.5)(8.2-25.5)

1.59 1.59 (0.47-5.37)(0.47-5.37)

Breast Breast cancercancer 11 17/22917/229 12/21512/215 7.3 7.3

(4.6-11.5)(4.6-11.5)1.30 1.30

(0.64-2.67)(0.64-2.67)

Renal cell Renal cell carcinomacarcinoma 11 20/33720/337 6/3046/304 3.0 3.0

(1.6-5.5)(1.6-5.5)3.00 3.00

(1.23-7.33)(1.23-7.33)

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

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 Multivariate Analysis of the Risk of Thrombosis Associated with Lenalidomide plus High-Dose Dexamethasone and with Lenalidomide plus High-Dose Dexamethasone and Concomitant Erythropoietin for the Treatment of Multiple Concomitant Erythropoietin for the Treatment of Multiple Myeloma 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

Concomitant erythropoietin Concomitant erythropoietin 3.21 (1.72-6.01)3.21 (1.72-6.01) <0.001<0.001

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?

CLOT: Landmark Cancer/VTE TrialCLOT: Landmark Cancer/VTE Trial

[N = 677] [N = 677]

► Primary Endpoints:Primary Endpoints: Recurrent VTE and Bleeding Recurrent VTE and Bleeding► Secondary EndpointSecondary Endpoint:: Survival Survival

Lee, Levine, Kakkar, Rickles et.al. Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, N Engl J Med, 2003;349:1462003;349:146

Dalteparin Dalteparin

Dalteparin Oral Anticoagulant

CANCER PATIENTS WITH

ACUTE DVT or PERandomization

Landmark CLOT Cancer TrialLandmark CLOT Cancer TrialReduction in Recurrent VTEReduction in Recurrent VTE

00

55

1010

1515

2020

2525

Days Post RandomizationDays Post Randomization

00 3030 6060 9090 120120 150150 180180 210210

Pro

bab

ility

of R

ecu

rre

nt V

TE

, %P

roba

bili

ty o

f Re

curr

en

t VT

E, % Risk reduction = 52%Risk reduction = 52%

pp-value = 0.0017-value = 0.0017

DalteparinDalteparin

OACOAC

Recurrent VTERecurrent VTE


DalteparinDalteparin N=338N=338

OACOACN=335N=335

P-value*P-value*

Major bleedMajor bleed 19 ( 5.6%) 19 ( 5.6%) 12 ( 3.6%)12 ( 3.6%) 0.270.27

Any bleedAny bleed 46 (13.6%)46 (13.6%) 62 (18.5%)62 (18.5%) 0.0930.093

* Fisher’s exact test* Fisher’s exact test

Bleeding Events in CLOTBleeding Events in CLOT


Treatment of Cancer-Associated VTETreatment of Cancer-Associated VTE

StudyStudy DesignDesignLength of Length of TherapyTherapy(Months)(Months)

NNRecurrent Recurrent

VTE VTE (%)(%)

Major Major BleedingBleeding

(%)(%)

DeathDeath(%)(%)

CLOT TrialCLOT Trial(Lee 2003)(Lee 2003)

DalteparinDalteparinOACOAC

6 6 336336336336

991717

6644

39394141

CANTHENOXCANTHENOX(Meyer 2002)(Meyer 2002)

EnoxaparinEnoxaparinOACOAC

3367677171

11112121

771616

11112323

LITELITE(Hull ISTH 2003)(Hull ISTH 2003)

TinzaparinTinzaparinOACOAC

3380808787

661111

6688

23232222

ONCENOXONCENOX(Deitcher ISTH (Deitcher ISTH 2003)2003)

Enox (Low)Enox (Low)Enox (High)Enox (High)OACOAC

66323236363434

3.43.43.13.16.76.7

NS

NS0.03

NS

NS0.002

NS

NS

NR

0.09 0.030.09

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 months (Grade 1A minimum of 3-6 months (Grade 1A recommendation—ACCP) recommendation—ACCP)

► NOTE: Dalteparin is only LMWH approved (May, NOTE: Dalteparin is only LMWH approved (May, 2007) for both the 2007) for both the treatment and secondary preventiontreatment and secondary prevention of VTE in cancer (NCCN preferred agent)of VTE in cancer (NCCN preferred agent)

► Oral anticoagulant therapy to follow for as long as Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation—ACCP)cancer is active (Grade 1C recommendation—ACCP)

ChestChest Jun 2008: 454S–545S Jun 2008: 454S–545S

New DevelopmentNew Development

CLOT 12-month MortalityCLOT 12-month MortalityAll PatientsAll Patients

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

00 3030 6060 9090 120120 180180 240240 300300 360360


OACOAC

HR 0.94 P-value = 0.40HR 0.94 P-value = 0.40

Days Post RandomizationDays Post Randomization

Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

Days Post RandomizationDays Post Randomization00 3030 6060 9090 120120 150150 180180 240240 300300 360360

Pro

bab

ility

of S

urv

iva

l, %

Pro

bab

ility

of S

urv

iva

l, %

OACOAC


HR = 0.50 P-value = 0.03HR = 0.50 P-value = 0.03

Anti-Tumor Effects of LMWHAnti-Tumor Effects of LMWHCLOT 12-month MortalityCLOT 12-month Mortality

Patients Without Metastases (N=150)Patients Without Metastases (N=150)

Lee AY et al. Lee AY et al. J Clin Oncol. J Clin Oncol. 2005; 23:2123-9.2005; 23:2123-9.

LMWH Influences Survival of Patients with LMWH Influences Survival of Patients with Advanced Solid Tumor MalignanciesAdvanced Solid Tumor Malignancies

<6 mos anticipated survival<6 mos anticipated survival >6 mos anticipated survival>6 mos anticipated survival

6 wks LMWH immediately post diagnosis of CA-no initial chemo 6 wks LMWH immediately post diagnosis of CA-no initial chemo 6 wks LMWH immediately post diagnosis of CA-no initial chemo 6 wks LMWH immediately post diagnosis of CA-no initial chemo

Klerk, C. P.W. et al. J Clin Oncol; 23:2130-2135 2005Klerk, C. P.W. et al. J Clin Oncol; 23:2130-2135 2005Klerk, C. P.W. et al. J Clin Oncol; 23:2130-2135 2005Klerk, C. P.W. et al. J Clin Oncol; 23:2130-2135 2005

► 84 patients randomized: Chemo +/- LMWH (18 weeks)84 patients randomized: Chemo +/- LMWH (18 weeks)

► Patients balanced for age, gender, stage, smoking Patients balanced for age, gender, stage, smoking history, ECOG performance statushistory, ECOG performance status

LMWH for Small Cell Lung CancerLMWH for Small Cell Lung CancerTurkish StudyTurkish Study

Altinbas et al. J Thromb Haemost 2004;2:1266.Altinbas et al. J Thromb Haemost 2004;2:1266.

ChemotherapyChemotherapyplus Dalteparinplus Dalteparin Chemo aloneChemo alone P-valueP-value

1-y overall survival, %1-y overall survival, % 51.351.3 29.529.5 0.010.01

2-y overall survival, %2-y overall survival, % 17.217.2 0.00.0 0.010.01

Median survival, mMedian survival, m 13.013.0 8.08.0 0.010.01

CEV = cyclophosphamide, epirubicin, vincristine; CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units dailyLMWH = Dalteparin, 5000 units daily

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

Cancer:Cancer:FRONTLINE SurveyFRONTLINE Survey11— — 3891 Clinician 3891 Clinician RespondentsRespondents

Rat

e of

App

ropr

iate

Pro

phyl

axis

, %R

ate

of A

ppro

pria

te P

roph

ylax

is, %

Major Major SurgerySurgery22

Major Major Abdominothoracic Abdominothoracic Surgery (Elderly)Surgery (Elderly)33 Medical Medical

InpatientsInpatients44

Confirmed DVT Confirmed DVT (Inpatients)(Inpatients)55

Cancer: Cancer: SurgicalSurgical

Cancer: Cancer: MedicalMedical

4.Rahim SA et al. Thromb Res. 2003;111:215-2195.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

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

A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer

Documents

Transcript of A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer