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Innovation ● Investigation ● Application. A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer Linking Science and Evidence to Clinical Practice— What Do Trials Teach?. Program Chairman Craig Kessler, MD MACP Director, Division of Coagulation

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slide1

Innovation ● Investigation ● Application

A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer

Linking Science and Evidence to Clinical Practice—

What Do Trials Teach?

Program Chairman

Craig Kessler, MD MACP

Director, Division of Coagulation

Lombardi Comprehensive Cancer Center

Georgetown University Medical Center

Washington, DC

vte and cancer epidemiology
Of all cases of VTE:

About 20% occur in cancer patients

Annual incidence of VTE in cancer patients ≈ 1/250

Of all cancer patients:

15% will have symptomatic VTE

As many as 50% have VTE at autopsy

Compared to patients without cancer:

Higher risk of first and recurrent VTE

Higher risk of bleeding on anticoagulants

Higher risk of dying

VTE and Cancer: Epidemiology

Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

dvt and pe in cancer facts findings and natural history
VTE is the second leading cause of death in hospitalized cancer patients1,2

The risk of VTE in cancer patients undergoing surgery is 3-to 5-fold higher than those without cancer2

Up to 50% of cancer patients may have evidence of asymptomatic DVT/PE3

Cancer patients with symptomatic DVT exhibit a high risk for recurrent DVT/PE that persists for many years4

DVT and PE in CancerFacts, Findings, and Natural History

Ambrus JL et al. J Med. 1975;6:61-64

Donati MB. Haemostasis. 1994;24:128-131

Johnson MJ et al. Clin Lab Haem. 1999;21:51-54

Prandoni P et al. Ann Intern Med. 1996;125:1-7

clinical features of vte in cancer
VTE has significant negative impact on quality of life

VTE may be the presenting sign of occult malignancy

10% with idiopathic VTE develop cancer within 2 years

20% have recurrent idiopathic VTE

25% have bilateral DVT

Clinical Features of VTE in Cancer

Buraet. al.,J ThrombHaemost 2004;2:445-51

thrombosis and survival likelihood of death after hospitalization

1.00

DVT/PE and Malignant Disease

0.80

0.60

Probability of Death

Malignant Disease

0.40

DVT/PE Only

0.20

Nonmalignant Disease

0.00

0 20 40 60 80 100 120 140 160 180

Number of Days

Thrombosis and SurvivalLikelihood of Death After Hospitalization

Levitan N, et al. Medicine 1999;78:285

slide6

Incidence of VTE and Colon Cancer Stage

7%

6%

5%

4%

3%

2%

1%

0%

Local Regional Remote

Incidence of VTE (%)

0 50 100 150 200 250 300 350 400

Days after Cancer Diagnosis

White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40

slide7

Symptomatic VTE in Cancer Reduces Survival Counterintuitively, Magnitude of Effect on Survival is Greatest with Local Stage Disease

* p<0.05; †p<0.01); ‡ p<0.001)

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

slide8

VTE Associated with Accelerated Death in Breast Cancer Does Symptomatic VTE Reflect Presence or Emergence of Metastatic, Aggressive Cancer?

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

recurrent ovarian cancer
Recurrent Ovarian Cancer

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

Fotopoulou C et al. Thromb Res 2009

hospital mortality with or without vte
Hospital Mortality With or Without VTE

Mortality (%)

N=66,016

N=20,591

N=17,360

Khorana, JCO, 2006

slide11

Thrombosis Risk In Cancer

Primary Prophylaxis

  • Medical Inpatients
  • Surgery
  • Radiotherapy
  • Central Venous Catheters
risk factors for cancer associated vte
Cancer

Type

Men: prostate, colon, brain, lung

Women: breast, ovary, lung

Stage

Treatments

Surgery

10-20% proximal DVT

4-10% clinically evident PE

0.2-5% fatal PE

Chemotherapy

Central venous catheters (~4% generate clinically relevant VTE)

Patient

Prior VTE

Comorbidities

Genetic background

Risk Factors for Cancer-Associated VTE
antithrombotic therapy choices
Antithrombotic Therapy: Choices

Pharmacologic

(Prophylaxis & Treatment)

Nonpharmacologic

(Prophylaxis)

Low Molecular Weight Heparin (LMWH)

Unfractionated

Heparin (UH)

Intermittent

Pneumatic

Compression

Elastic

Stockings

Inferior

Vena Cava

Filter

Oral

Anticoagulants

New Agents: e.g.

Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?

prophylaxis studies in medical patients
Prophylaxis Studies in Medical Patients

Relative risk reduction 47%

Relative risk reduction 63%

Rate of VTE (%)

Relative risk reduction 44%

Placebo Enoxaparin

MEDENOX Trial

Placebo Dalteparin

PREVENT

Placebo Fondaparinux

ARTEMIS

Francis, NEJM, 2007

asco guidelines
1. SHOULD HOSPITALIZED PATIENTS WITH

CANCER RECEIVE ANTICOAGULATION FOR

VTE PROPHYLAXIS?

Recommendation. Hospitalized patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation.

ASCO Guidelines

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

incidence of vte in surgical patients
Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis:Incidence of VTE in Surgical Patients

Kakkar AK, et al. ThrombHaemost 2001; 86 (suppl 1): OC1732

natural history of vte in cancer surgery the @ristos registry
Web-Based Registry of Cancer Surgery

Tracked 30-day incidence of VTE in 2373 patients

Type of surgery

• 52% General

• 29% Urological

• 19% Gynecologic

82% received in-hospital thromboprophylaxis

31% received post-discharge thromboprophylaxis

Findings

2.1% incidence of clinically overt VTE (0.8% fatal)

Most events occur after hospital discharge

Most common cause of 30-day post-op death

Natural History of VTE in Cancer Surgery: The @RISTOS Registry

Agnelli, Ann Surg 2006; 243: 89-95

prophylaxis in surgical patients
LMWH vs. UFH

Abdominal or pelvic surgery for cancer (mostly colorectal)

LMWH once daily vs. UFH tid for 7–10 days post-op

DVT on venography at day 7–10 and symptomatic VTE

Prophylaxis in Surgical Patients

1. ENOXACAN Study Group. Br J Surg 1997;84:1099–103

2. McLeod R, et al. Ann Surg 2001;233:438-444

prophylaxis in surgical patients21
Prophylaxis in Surgical Patients

Canadian Colorectal DVT Prophylaxis Trial

16.9%

P=0.052

13.9%

N=234

Incidence of Outcome Event

N=241

1.5% 2.7%

VTE Major Bleeding

(Cancer) (All)

McLeod R, et al. Ann Surg 2001;233:438-444

slide22

Extended Prophylaxis inSurgical Patients

12.0%

ENOXACAN II

P=0.02

Incidence of Outcome Event

N=167

5.1%

4.8%

N=165

3.6%

1.8%

NNT = 14

0% 0.4%

0.6%

VTE Prox Any Major

DVT Bleeding Bleeding

Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980

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

RESULTS: Cumulative incidence of VTE was reduced from 16.3% with short-term thromboprophylaxis (29/178 patients) to 7.3% after prolonged thromboprophylaxis (12/165) (relative risk reduction 55%; 95% confidence interval 15-76; P=0.012).

CONCLUSIONS:4-week administration of dalteparin, 5000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with 1 week of thromboprophylaxis.

Major Abdominal Surgery: FAME Investigators—Dalteparin Extended

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

asco guidelines vte prophylaxis
All patients undergoing major surgical intervention for malignant disease should be considered for prophylaxis.

Patients undergoing laparotomy, laparoscopy, or thoracotomy lasting > 30 min should receive pharmacologic prophylaxis.

Prophylaxis should be continued at least 7 – 10 days post-op. Prolonged prophylaxis for up to 4 weeks may be considered in patients undergoing major surgery for cancer with high-risk features.

ASCO Guidelines: VTE Prophylaxis

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

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

Fibrin sheath formation

Superficial phlebitis

Ball-valve clot

Deep vein thrombosis (DVT)

Central Venous Catheters

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

prophylaxis for venous catheters
Placebo-Controlled TrialsProphylaxis for Venous Catheters

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

slide27

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

Young AM et al. Lancet 2009;373:567

slide28

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

Young AM et al. Lancet 2009;373:567

slide29

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

Young AM et al. Lancet 2009;373:567

central venous catheters warfarin
Tolerability of Low-Dose Warfarin

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

INR measured at baseline and four time points

10% of all recorded INRs >1.5

Patients with elevated INR

2.0–2.9 6%

3.0–4.9 19%

>5.0 7%

Central Venous Catheters: Warfarin

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

slide31

Influence of Thrombophilia on Thrombotic Complications of CVADs in Cancer

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

The attributable risk of catheter associated thrombosis conferred by:

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%

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

8 th accp consensus guidelines
8th ACCP Consensus Guidelines

No routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH (2B) and fixed-dose warfarin (1B)

Revised 2009 NCCN guidelines diverge from this philosophy

Chest Jun 2008: 454S–545S

primary prophylaxis in cancer radiotherapy the ambulatory patient
No recommendations from ACCP

No data from randomized trials (RCTs)

Weak data from observational studies in high risk tumors (e.g. brain tumors; mucin-secreting adenocarcinomas: Colorectal, pancreatic, lung, renal cell, ovarian)

Recommendations extrapolated from other groups of patients if additional risk factors present (e.g., hemiparesis in brain tumors, etc.)

Primary Prophylaxis in Cancer Radiotherapy The Ambulatory Patient
risk factors for vte in medical oncology patients
Tumor type

Ovary, brain, pancreas, lung, colon

Stage, grade, and extent of cancer

Metastatic disease, venous stasis due to bulky disease

Type of antineoplastic treatment

Multiagent regimens, hormones,anti-VEGF, radiation

Miscellaneous VTE risk factors

Previous VTE, hospitalization, immobility, infection, thrombophilia

Risk Factors for VTE inMedical Oncology Patients
independent risk factors for dvt pe
Independent Risk Factors for DVT/PE

Heit JA et al. ThrombHaemost. 2001;86:452-463

vte incidence in various tumors
VTE Incidence In Various Tumors

Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

primary vte prophylaxis
Recommended for hospitalized cancer patients

Not universally recommended for outpatients, but there are exceptions

New data for certain agents

Heterogeneous population

Primary VTE Prophylaxis

Need for risk stratification

slide38

VTE Risk with Bevacizumab in Colorectal Cancer

Approaches Risk of Antiangiogenesis in Myeloma

Naluri SR et al. JAMA. 2008;300:2277

slide39

Bevacizumab Increases Risk of

Symptomatic VTE by 33% vs Controls

Naluri SR et al. JAMA. 2008;300:2277

slide40

Incidence of VTE: USA and Canada Greater than Israel, Australia, and Europe

  • rEPO used more in USA and Canada
  • L+Dex: 23% VTE with EPO vs 5% w/o EPO
  • Placebo + Dex: 7% VTE with EPO vs 1% without EPO

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

Treatment Odds Ratio P Value

(95% CI)

Lenalidomide plus 3.51 (1.77-6.97) <0.001

High-dose dexamethasone

Concomitant erythropoietin 3.21 (1.72-6.01) <0.001

Knight: N Engl J Med.2006,354:2079

oral anticoagulant therapy in cancer patients problematic
Warfarin therapy is complicated by:

Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc.

Frequent interruptions for thrombocytopenia and procedures

Difficulty in venous access for monitoring

Increased risk of both recurrence and bleeding

Is it reasonable to substitute long-term LMWH for warfarin ? When? How? Why?

Oral Anticoagulant Therapyin Cancer Patients: Problematic
clot landmark cancer vte trial
CLOT: Landmark Cancer/VTE Trial

Dalteparin

Dalteparin

CANCER PATIENTS WITH

ACUTE DVT or PE

Randomization

Dalteparin

Oral Anticoagulant

[N = 677]

  • Primary Endpoints: Recurrent VTE and Bleeding
  • Secondary Endpoint: Survival

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

slide43

Risk reduction = 52%

p-value = 0.0017

25

20

OAC

Probability of Recurrent VTE, %

15

10

Dalteparin

5

0

0

30

60

90

120

150

180

210

Days Post Randomization

Landmark CLOT Cancer Trial

Reduction in Recurrent VTE

Recurrent VTE

  • Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
slide44

Bleeding Events in CLOT

* Fisher’s exact test

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

treatment of cancer associated vte
Treatment of Cancer-Associated VTE

NS

NS

0.002

0.09

0.09

0.03

NS

0.03

NS

NR

NS

NS

treatment and 2 prevention of vte in cancer bottom line
New standard of care is LMWH at therapeutic doses for a minimum of 3-6 months (Grade 1A recommendation—ACCP)

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

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

Treatment and 2° Prevention of VTE in Cancer – Bottom Line

New Development

Chest Jun 2008: 454S–545S

slide47

CLOT 12-month Mortality

All Patients

100

90

80

70

60

50

Dalteparin

40

OAC

30

Probability of Survival, %

20

10

0

HR 0.94 P-value = 0.40

0

30

60

90

120

180

240

300

360

Days Post Randomization

Lee AY et al. J ClinOncol. 2005; 23:2123-9.

slide48

100

90

80

70

60

50

40

30

20

10

0

Anti-Tumor Effects of LMWH

CLOT 12-month Mortality

Patients Without Metastases (N=150)

Dalteparin

OAC

Probability of Survival, %

HR = 0.50 P-value = 0.03

0

30

60

90

120

150

180

240

300

360

Days Post Randomization

Lee AY et al. J ClinOncol. 2005; 23:2123-9.

lmwh influences survival of patients with advanced solid tumor malignancies
LMWH Influences Survival of Patients with Advanced Solid Tumor Malignancies

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

>6 mos anticipated survival

<6 mos anticipated survival

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

lmwh for small cell lung cancer turkish study
84 patients randomized: Chemo +/- LMWH (18 weeks)

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

LMWH for Small Cell Lung CancerTurkish Study

CEV = cyclophosphamide, epirubicin, vincristine;

LMWH = Dalteparin, 5000 units daily

Altinbas et al. J ThrombHaemost 2004;2:1266.

vte prophylaxis is underused in patients with cancer
VTE Prophylaxis Is Underused in Patients With Cancer

Cancer:

FRONTLINE Survey1— 3891 Clinician Respondents

Major Surgery2

Cancer: Surgical

Major AbdominothoracicSurgery (Elderly)3

Confirmed DVT (Inpatients)5

Rate of Appropriate Prophylaxis, %

Medical Inpatients4

Cancer: Medical

1. Kakkar AK et al. Oncologist. 2003;8:381-388

2. Stratton MA et al. Arch Intern Med. 2000;160:334-340

3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912

4. Rahim SA et al. Thromb Res. 2003;111:215-219

5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

slide52

Conclusions and Summary

  • Risk factors for VTE in the setting of cancer have been well characterized: solid tumors, chemotherapy, surgery, thrombocytopenia
  • Long-term secondary prevention with LMWH has been shown to produce better outcomes than warfarin
  • Guidelines and landmark trials support administration of LMWH in at risk patients
  • Cancer patients are under-prophylaxed for VTE
  • Health system pharmacists can play a pivotal role in improving clinical outcomes in this patient population
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