Cancer Associated Thrombosis

Vicky Tagalakis MD MSc

Associate Professor McGill University

Division of Internal Medicine

Center for Clinical Epidemiology

Jewish General Hospital

Objectives

• To review risk factors and epidemiology of cancer

associated thrombosis (CAT).

• To discuss primary and secondary treatment

approaches to cancer associated thrombosis.

• Optimization of anticoagulation in cancer patients

with VTE:

– Is there a role for the new direct oral inhibitors

(DOACs)?

Two-way Nature of Thrombosis and Cancer

CANCER VTE

1. Carrier M, et al. Ann Intern Med. 2008;149(5):323-333.

2. Prandoni P, Piccioli A. Curr Opin Hematol. 2006;13(5):362-365.

3. Boccaccio C, Comoglio PM. Cancer Res. 2005;65(19):8579-8582.

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

• Relationship documented >100 years ago1,2

• Common pathological finding of postmortem blood clots in patients dying of

cancer, and fibrin-like material noted in tumours3

• 2%-20% of cancer patients develop VTE4 (vs. 0.2% in general population)

• 10% of patients with idiopathic VTE are diagnosed with malignancy within

one year of VTE occurrence 1,2

VTE Risk Factors

Risk Factor Characteristics OR

Recent surgery w/ hospitalization 21.72

Trauma 12.69

Hospitalization without recent surgery 7.98

Malignancy with chemotherapy 6.53

Prior CVC or pacemaker 5.55

Prior superficial vein thrombosis 4.32

Malignancy without chemotherapy 4.05

Neurological disease w/ extremity paresis 3.04

Serious liver disease 0.10

OR: Odds ratio

CVC: Central venous catheter

Heit JA, et al. Arch Intern Med. 2000;160(6):809-815.

Virchow’s Triad:

Cancer Contributes Multiple Risk Factors

Venous Stasis Vascular compression

by tumor

Prolonged bed rest

Hypotension

Vascular Injury Direct invasion

Central catheters

Endothelial damage

Surgery

Chemotherapy

Hypercoagulability Tumor procoagulants

Cytokines

Impaired endothelial

cell defense

Cellular interactions

Rudolph Virchow

Adapted from Joist JH. Semin Thromb Hemost. 1990;16:151-157.

Factors That May Affect Risk for

Cancer-Associated VTE

Patient-related factors1,2

• Older age

• Female sex

• Black ethnicity

• Comorbid conditions

• Prior history of VTE

Treatment-related factors1,2

• Recent major surgery

• Hospitalization

• Chemotherapy

• Hormonal therapy

• Anti-angiogenic agents

• Erythropoiesis-stimulating agents

Cancer-related factors1,2

• Primary site of cancer and

histology

• Advanced stage

• Initial period after diagnosis

1. Khorana AA, et al. Thromb Res. 2007;120(Suppl 2):S41-50.

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

Type of Cancer and

Relative Risk of VTE

Stein PD, et al. Am J Med. 2006;119(1):60-68.

RR of VTE in cancer patients ranges from 1.02-4.34 vs. noncancer patients

Pancr

eas

Brain

Mye

lopr

olife

rativ

e

Stom

ach

Lym

phom

a

Ute

rus

Lung

Esoph

agus

Prost

ate

Rec

tal

Kidne

y

Col

on

Ova

ryLi

ver

Leuk

emia

Breas

t

Cer

vix

Bladd

er

RR

of

VT

E in

Ca

nce

r P

atien

ts

Type of Cancer

4.5

4

3.5

3

2.5

2

1.5

1

0.5

VTE: Venous thromboembolism

RR: Risk ratio

Patients with solid tumours who have metastatic disease have a

20-fold risk of VTE vs. those without metastases

Cancer Distant

Metastases

Adjusted OR

(95% CI)*

n=3050

Adjusted OR

(95% CI)**

n=2088

No No 1.0 -

Yes No 3.9

(2.5 – 6.0) 1.0

Yes Yes 58.0

(9.7 – 346.7)

19.8

(2.6 – 149.1)

Distant Metastases and VTE Risk

Blom JW, et al. JAMA. 2005;293(6):715-722.

*Adjusted for age and sex, control group is patients with no malignancy

**Adjusted for age and sex, control group is patients with malignancy, but without distant metastases

VTE: Venous thromboembolism

Cancer Treatment-Related

Risk Factors

Cancer Treatment VTE Incidence (%)

Chemotherapy1 9.6

Angiogenesis Inhibitorsa

Thalidomide-containing regimens2 3-22

Thalidomide alone2 3.4

Thalidomide + dexamethasone2 14.8

Thalidomide + chemotherapy2 22.0

Lenalidomide + high-dose dexamethasone3 26

Lenalidomide + low-dose dexamethasone3

Bevacizumab4b

12

11.9

Hormone Therapy5

Aromatase inhibitors 1.3-1.6

Tamoxifen 2.4-3.5

Erythropoietin6 7.5

a newly diagnosed patients only b meta-analysis VTE: Venous thromboembolism

1. Sousou T, Khorana A. J Clin Oncol. 2007 (ASCO meeting);25(18S):90-92. 2. Wu CM, et al. J Clin Oncol. 2007 (ASCO meeting);25(18S):9056.

3. Rajkmur SV, et al. Lancet Oncology. 2010;11(1):29-37. 4. Nalluri SR, et al. JAMA. 2008;300(19):2277-2285.

5. Lycette JL, et al. Breast Cancer Res Treat. 2006;99(3):249-255. 6. Bennett CL, et al. JAMA. 2008;299(8):914-924.

Important Clinical Questions

1. Should medical patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized?

2. Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis?

3. Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy?

4. What is the best method for treatment of patients with cancer with established VTE to prevent recurrence?

Prevention of VTE during medical hospitalization

Trials of anticoagulation for VTE prophylaxis in acutely ill hospitalized medical patients:

Cancer subpopulations

Reference Patients

(n)

Cancer

patients

n (%)

Whole pop

Placebo

arm events

n (%)

Whole pop

Treatment

arm events

(%)

RR 95% CI

MEDENOX1 579 72 (12) 43 (15) 16 (6) 0.37 0.22-0.63

PREVENT2 3706 190 (5) 73 (5) 42 (3) 0.55 0.38-0.8

ARTEMIS3 849 131 (15) 34 (11) 18 (6) 0.47 0.08-0.69

1. Samama et al., N Engl J Med. 1999;341(11):793-800

2. Leizorovicz et al., Circulation. 2004;110(7):874-879

3. Cohen et al., BMJ. 2006;332(7537):325-329

Recommendations for Prevention of

VTE in Hospitalized Cancer Patients

NCCN2 ESMO3 ACCP4

Prophylactic anticoagulation

for all hospitalized cancer

patients in the absence of

contraindication

Prophylactic

anticoagulation in

immobilized

hospitalized cancer

patients with acute

medical illness

Prophylactic anticoagulation

for at risk patients with acute

medical illness (Grade 1B)

If bleeding or high risk for

bleeding, use mechanical

prophylaxis with graduated

compression stockings (Grade

2C) or intermittent pneumatic

compression (Grade 2C)

Recommended Agents as per ASCO guidelines

• UFH (5000 U SC tid)

• LMWH (Dalteparin 5000 U SC qd; Enoxaparin 40 mg SC qd)

• Fondaparinux (2.5 mg SC qd)

2. National Comprehensive Cancer Network. 2011. Available at: www.nccn.org

3. Mandalà M, et al. Ann Oncol. 2011;20(Suppl 6):vi85-92..

4. Kahn SR, et al. Chest. 2012 ;141(2 Suppl):e195S-226S.

ASCO 2013: VTE Prophylaxis recommendations for hospitalized cancer patients

In the absence of bleeding or other contraindications, pharmacologic thromboprophylaxis:

Recommended for hospitalized patients with active malignancy and acute medical illness or reduced mobility

May be considered for hospitalized patients who have active malignancy without additional risk factors

Not recommended for routine use in patients admitted for minor procedures, short chemo infusion or stem-cell/bone marrow transplant

Lyman GH, et al. J Clin Oncol. 2013

For how long to prophylax

While in hospital?

While immobilized?

While acutely ill?

Prevention of VTE in the surgical setting

Degree of Thromboembolism Risk in Surgical Patients Without Prophylaxis

Risk Level Calf DVT Proximal

DVT

Clinical

PE

Fatal PE

Low risk

•Minor surgery in patients aged ˂ 40 y with no

additional risk factors

2% 0.4% 0.2% ˂0.01%

Moderate risk

•Minor surgery in patients with additional risk

factors

•Surgery in patients aged 40–60 y with no

additional risk factors

10-20%

2-4%

1-2%

0.1-0.4%

High risk

•Surgery in patients ˃ 60 y or with additional

risk factors (eg, prior VTE, cancer)

20-40%

4-8%

2-4%

0.4-1%

Highest risk

•Surgery in patients with multiple risk factors

(age ˃ 40 y, cancer, prior VTE)

•Hip or knee arthroplasty, hip fracture surgery

40-80% 10-20% 4-10% 0.2-5%

Agnelli. Circulation 2014;110(suppl 4):4-12

Surgery in cancer patients

• Cancer patients have higher rates of postoperative VTE,

PE, fatal PE, and death compared to non-cancer

patients despite thromboprophylaxis

Short term thromboprophylaxis in Surgical Patients with Cancer: LMWH as effective as UFH

Studies examined:

• LMWH vs. UFH in abdominal or pelvic surgery for cancer (mostly colorectal)

• Treatment Regimens: LMWH qd vs. UFH tid for 7–10 days postoperatively

• Outcomes: DVT on venography at day 7–10 and/or VTE

1. ENOXACAN Study Group. Br J Surg. 1997;84(8):1099-1103.; 2. McLeod RS, et al. Ann Surg. 2001;233(3):438-444.; 3. Petrov M, et al. J Thromb Haemost. 2007;5(Suppl 1):Abstract P-T-668.; . 4. Fricker JP, et al. Eur J Clin Invest. 1988;18(6):561-567.

Study N Design Regimens Primary Outcome Major Bleeding

ENOXACAN 1 631* Double-blind Enoxaparin

vs. UFH

E: 14.7%

UFH: 18.2%

E: 4.1%

UFH: 2.9%

Canadian

Colorectal DVT

Prophylaxis 2

936 Double-blind Enoxaparin

vs. UFH

E: 13.9%

UFH: 16.9%

E: 2.7%

UFH: 1.5%

Petrov et al.3 256 Double-blind Enoxaparin

vs. UFH

VTE:

E: 3.1%

UFH: 4.0%

ND

Fricker et al.4 80 Open label Dalteparin

vs. UFH

Pulmonary Embolism

D: 0/40

UFH: 2/40

Severe bleed

D: 2/40

UFH: 1/40

*: Evaluable patients; UFH: Unfractionated heparin; NS: Non significant; tid: Three-times daily; qd: Once daily; DVT:

Deep-vein thrombosis; ND: No data; E: Enoxaparin; D: Dalteparin; VTE: Venous thromboembolism

P=NS P=NS

P=NS P=NS

P=NS

P=NS P=NS

Time Distribution of VTE Events

Following Cancer Surgery

Agnelli G et al. Ann Surg. 2006;243(1):89-95.

• N=2373, @RISTOS Registry: Prospective cohort study

40% of VTE events occurred >21 days after surgery

Num

ber

of

Patients

Days after Surgery

20

Extended prophylaxis in cancer patients undergoing surgery

• Abdominal or pelvic surgery for cancer

• LMWH for 7 days vs. ~28 days

• Endpoints: routine bilateral venography at ~28 days and

symptomatic VTE

N Design Regimens VTE P-value

ENOXACAN II1 332 Double

blind

Enoxaparin

vs. placebo

4.8% (E) vs.

12% (P)

0.02

FAME2

(subgroup)

198 Open label Dalteparin

vs. no

prophylaxis

8.8% (D)

vs. 19.6%

(P)

0.03

1. Bergqvist et al. N Engl J Med. 2002;346(13);975-980

2. Rasmussen et al. J Thromb Haemostat. 2006;4(11):2384-90

Other groups’ recommendations for

Prevention of VTE in Surgical Cancer Patients

NCCN2 ESMO3 ACCP4

Initial

prophylaxis

Prophylactic

anticoagulation is

recommended with

LMWH, UFH, or

fondaparinux

Prophylactic anticoagulation

with s.c. LMWH for patients

undergoing elective major

abdominal or pelvic surgery

LMWH, UFH for

moderate/high VTE-risk

patients who are not at

risk of major bleeding

Prolonged

prophylaxis

Out of hospital

primary VTE

prophylaxis is

recommended for up

to 4 wks post-

operatively

particularly for high

risk abdominal or

pelvic surgery

Consider continuing LMWH

up to 1 month after major

abdominal or pelvic surgery

Extended prophylaxis (4

wks) with LMWH is

recommended for high-

VTE-risk patients

undergoing abdominal or

pelvic surgery for cancer

who are not at high risk

for major bleeding (Grade

1B)

2. National Comprehensive Cancer Network. 2011. Av ailable at: www.nccn.org; 3. Mandalà M, et al. Ann Oncol. 2011;20(Suppl 6):vi85-92.; 4. Gould MK, et

al. Chest. 2012;141(2 Suppl):e227S-77S.

UFH: Unfractionaled heparin; LMWH: Low molecular weight heparin; s.c.: Subcutaneous; VTE: Venous thromboembolism;

wks: Weeks

ASCO 2013: VTE Prophylaxis and Treatment Recommendations for Perioperative Cancer Patients

All patients with malignant disease undergoing major surgical intervention should be considered for pharmacologic thromboprophylaxis with either UFH or LMWH unless contraindicated because of active bleeding or high bleeding risk Should be continued for at least 7–10 days

Extended prophylaxis with LMWH for up to 4 weeks should be considered for patients with high-risk features such as restricted mobility, obesity, history of VTE, or other risk factors

Mechanical methods may be added to pharmacologic ppx (eg high risk patients) but should not be used alone, unless pharmacologic ppx contraindicated due to bleeding

Lyman GH, et al. J Clin Oncol. 2013

Summary: Recommendations for VTE prophylaxis in hospitalized medical and surgical cancer patients Most hospitalized medical and surgical cancer patients

should receive thromboprophylaxis

Prophylaxis for patients undergoing major cancer surgery should continue for min. 7–10 days

Consider extending postoperative prophylaxis up to 4 weeks in high-risk patients

Patients should be educated about the signs and symptoms of VTE

Low threshold to investigate for DVT and/or PE

Prophylaxis in ambulatory cancer patients undergoing chemotherapy

Prevention of VTE in patients treated

with thalidomide-based regimens

Cumulative risk of recurrent VTE in patients who

received MPT, MPT and Enoxaparin or MPL and ASA

Palumbo A, et al. J Thromb Haemost. 2006;4(8):1842-1845.

0 5 10 15 20 25

20%

10%

0%

Cum

ula

tive P

erc

enta

ge (

%)

Months

MPT (n=65)

MPT and Enoxaparin (n=78)

VTE: Venous thromboembolism

ASA: Acetylsalicylic acid

MPT: Melphalan and prednisone plus thalidomide

MPL: Melphalan and prednisone plus lenalidomide

• Retrospective analysis

MPL and ASA (n=50)

• Dose: Enoxaparin 40 mg qd or ASA 100 mg qd

Prevention of chemotherapy-associated VTE in breast and lung cancer

TOPIC 1 trial: Metastatic breast cancer (n=353)

TOPIC 2 Trial: Stage 3 or 4 NSCLC (n=547)

• Primary prevention of chemotherapy-associated VTE

• LMWH certoparin (3000 anti Factor Xa units daily) vs. placebo for 6

months

• DUS screen every 4 weeks

TOPIC 1: VTE rate: 4% (LMWH) vs. 4% (placebo)

Bleeding rate: 1.7% (LMWH) vs. 0% (placebo)

TOPIC 2: VTE rate: 4.5% (LMWH) vs. 8.3% (placebo) (p=0.07)

Bleeding rate: 3.7% (LMWH) vs. 2.2% (placebo) (p=0.03)

Prevention of Chemotherapy-Associated VTE

in Lung Cancer: Topic 2

Haas SK, et al. Clin Appl Thromb Hemost. 2012;18(2):159-165.

*Thrombosis = symptomatic and asymptomatic

• Double-blind, randomized, controlled study (N=547)

• Duration of therapy: 6 months

Rate

s (

%)

P=NS

P=NS

P=0.032

VTE: Venous thromboembolism

Primary Thromboprophylaxis in Patients

Receiving Chemotherapy: PROTECHT Trial

P=0.02

Cumulative Hazard of Thromboembolic Events by Treatment

• 5/769 (0.7%) patients in the nadroparin group and 0/381 patients in the placebo group had a major bleeding

event (P=0.18)

• The incidence of minor bleeding was 7.4% (57/769) with Nadroparin and 7.9% (30/381) with placebo

Agnelli G, et al. Lancet Oncol. 2009;10(10):943-949.

• Double-blind, randomized study; metastatic or locally advanced lung, GI, pancreatic,

breast, ovarian, or heard and neck

• Duration of therapy: Length of chemotherapy (maximum 4 months)

• Primary outcome: Composite of symptomatic venous and arterial thrombotic events

Rate

s (

%)

Rate of Thromboembolic Events

Prevention of chemotherapy associated VTE

in pancreatic cancer (CONKO 004 Trial)

1. Riess H, et al. J Clin Oncol. 2009;27(188):LBA4506.

2. Riess H, et al. J Clin Oncol. 2010:28(suppl):abstr 4033.

RRR=70%

Rate

s (

%)

• Open, prospective, randomized, multicentre study in pancreatic cancer patients undergoing

palliative chemotherapy

• Dosing: Enoxaparin daily (1 mg/kg SC qd for 12 weeks, then changed to 40 mg SC qd)

• Endpoint: reduction of symptomatic VTE

• After a median follow-up of 45.44 months, overall survival was not significantly different between the two arms

1

2 2

SC: Subcutaneous; QD: once daily; VTE: Venous thromboembolism

Recommendations for Prevention of

VTE in High Risk Ambulatory Cancer Patients

ASCO1 NCCN2 ESMO3 ACCP4

LMWH or adjusted-

dose warfarin for

patients with

multiple myeloma

receiving

thalidomide or

lenalidomide plus

chemotherapy

or dexamethasone

Prophylaxis with

LMWH or warfarin is

recommended for

patients receiving

highly thrombotic

angiogenic therapy or

myeloma patients

with 2 myeloma risk

factors

LMWH, aspirin or

adjusted-dose

warfarin should be

considered in

myeloma patients

receiving thalidomide

plus dexamethasone

or thalidomide plus

chemotherapy

Prophylactic dose LMWH or UFH is

recommended in outpatients with solid tumors

who have additional risk factors for VTE:

previous venous thrombosis, immobilization,

hormonal therapy, angiogenesis inhibitors,

thalidomide, and lenalidomide and who are at low

risk of bleeding,

Currently guidelines do not recommend routine prophylaxis In outpatients with cancer and indwelling central

venous catheters.

LMWH: Low-molecular-weight heparin

SC: Subcutaneous

tid: 3 times daily

UFH: Unfractionated heparin

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

2. National Comprehensive Cancer Network. 2011. Available at: www.nccn.org

3. Mandalà M, et al. Ann Oncol. 2011;20(Suppl 6):vi85-92..

4. Kahn SR, et al. Chest. 2012 ;141(2 Suppl):e195S-226S.

VTE Risk Assessment Scores in Patients with Cancer

Thaler et al., J Thrombo Haemostat. 2012; 108(4):1-7

Comparison of the Khorana VTE Risk Score Applied in Four Observational Studies

Thaler et al., J Thrombo Haemostat. 2012; 108(4):1-7

Treatment of

Cancer-Associated Thrombosis

Limitations of Warfarin

• Warfarin is problematic in cancer patients

– unpredictable anticoagulant response1

– dosing changes confusing1

– need reliable venous access and frequent monitoring1

– impairs quality of life1

– High risk of recurrent VTE and bleeding despite

therapeutic INR levels1

– difficult to rapidly reverse2

1. Zacharski et al. The Oncologist 2005;10:72-79

2. Warkentin et al. Can J Anaesth. 2002;49(6):S11-S25

Study Design

Length of

Therapy

(Months)

N

Recurrent

VTE

(%)

Major

Bleeding

(%)

Deaths*

(%)

CANTHENOX

(Meyer, 2002)

E (1.5 mg/kg qd)

OAC 3

67

71

3

4

7

16

11

23

CLOT

(Lee, 2003)

D (150 IU/kg qd)

OAC 6

336

336

8

16

6

4

39

41

LITE

(Hull, 2006)

T (175 IU/kg qd)

OAC 3

100

100

6

10

7

7

20

19

ONCENOX (Deitcher, 2006)

E (1.0 mg/kg qd)

E (1.5 mg/kg qd)

OAC

6

31

36

34

3

3

7

7

11

3

23

42

32

P=0.07

P=NS P=NS

P=NS

P=0.09 P=NS

P=NS

P=NS

P=NS

P=0.002 P=0.53 P=0.27

1. Meyer G, et al. Arch Intern Med. 2002;162(15):1729-1735.

2. Lee AY, et al. N Engl J Med. 2003;3492):146-153.

3. Hull RD, et al. Am J Med. 2006;119(12):1062-1072.

4. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006;12(4):389-396.

OAC: Oral anticoagulant

T: Tinzaparin

E: Enoxaparin

D: Dalteparin

Treatment of Cancer-Associated VTE

31

*as per the follow up period in each study

CLOT Trial: Reduction in Recurrent VTE

Lee AY, et al. N Engl J Med, 2003;349(2):146-153.

P=0.002

0%

5%

10%

15%

20%

25%

Days Post Randomization

0 30 60 90 120 150 180 210

Recurr

ent

VT

E P

robabili

ty (

%)

Dalteparin

OAC

15.8%

8.0%

VTE: Venous thromboembolism

OAC: Oral anticoagulant

CLOT Trial: No. of patients by Site of Solid Tumours

Lee et al. NEJM. 2003;349(2):146-153

CLOT Trial:

Bleeding Events and Survival* Data

Bleeding1 Dalteparin

(N=338)

OAC

(N=335) P**

Major bleed 6% 4% 0.27

Any bleed 14% 19% 0.09

1. Lee AY, et al. N Engl J Med. 2003;349(2):146-153.

2. Lee AY, et al. J Clin Oncol. 2005; 23(10):2123-2129.

OAC: Oral anticoagulant

Probability of

Death*2 Dalteparin OAC P

Patients with

Metastases 72% 69% 0.46

Patients without

Metastases 20% 36% 0.03

*Posthoc analysis

** Fisher’s exact test

34

0.50 (0.35 – 0.72) 0.80 (0.61 – 1.05)

Recurrent VTE Bleeding

Study Patient

population LMWH

regimen LMWH Vit. K antag

RR (95%, CI)

Weight (%) LMWH

Vit. K antag

RR (95%, CI)

Weight (%)

Meyer 2002

VTE cancer

T* 2/71 3/75 0.70

(0.12 – 4.09) 3.8 5/71 12/75

0.44 (0.16 – 1.19)

11.8

Deitcher 2003

VTE cancer

T & M † T 2/28 1/31

3/29

0.49 (0.11 – 2.29)

5.3

Lee 2003

VTE cancer

T & M † 27/336 53/336 0.51

(0.33 – 0.79) 69.8 47/336 63/336

0.75 (0.53 – 1.05)

63.8

Hull 2007

Proximal vein

thrombosis broad-

spectrum

T* ‡

§ 6/100 7/100

10/100 16/100

0.44 (0.19 – 1.02)

21.1

27/100

24/100

1.12 (0.70 – 1.81)

24.3

Long-Term LMWH vs VKA in VTE and Cancer

Hull R, et al. Am J Med. 2006;119:1062-1072.

* Treatment duration 3 months † Treatment duration 6 months

Follow-up: ‡ 3 months; § 12 months

T = treatment dose; P = prophylactic dose; M = reduced maintenance dose

Results favour Results favour Results favour Results favour

LMWH Vit. K antagonists LMWH Vit. K antagonists

0.1 1 10.0 0.1 1 10.0

Recommendations for

Treatment of VTE in Cancer Patients

ASCO1 NCCN2 ESMO3 ACCP4*

LMWH for at least 6 months is

preferred; VKAs are acceptable

when LMWH is contraindicated or

not available ; Indefinite treatment

in patients with active cancer,

receiving chemo or metastases;

IVCF only if contraindication to A/C

or recVTE despite LMWH;

Use of NOACs not recommended

at this time;

Rx incidental DVT/PE same as

symptomatic VTE

LMWH preferred;

Patients with DVT at

least 3-6 months

Patients with PE at

least 6-12 months

Patients with active

cancer and

persistent risk factors

indefinitely

LMWH for at

least 6 months

Extended

therapy (>3

months) is

suggested.

LMWH is

preferred over

VKA

ASCO: American Society of Clinical Oncology; NCCN: National Comprehensive Cancer Network; ESMO: European Society of Medical Oncology

ACCP: American College of Chest Physicians; TIGC: Thrombosis Interest Group of Canada

VTE: Venous thromboembolism; LMWH: Low molecular weight heparin; UFH: Unfractionated heparin; VKA: Vitamin K antagonist;

PE; Pulmonary embolism

1. Lyman GH, et al. J Clin Oncol. 2007;25(34):5490-5505.; 2. National Comprehensive Cancer Network. 2011. Available at: www.nccn.org;

3. Mandalà M, et al. Ann Oncol. 2011;20(Suppl 6):vi85-92.; 4. Kearon C, et al. Chest. 2012 Feb;141(2 Suppl):e419S-94S. 5. The Thrombosis Interest

Group of Canada. 2007. Available at: www.tigc.org.

2013 updated ASCO recommendations

Treatment of CAT

• LMWH is the drug of choice

• Treatment duration is 6 months

• Beyond 6 months is uncertain

• Many MDs keep their patients on full dose

LMWH “indefinitely”

• We don’t know if this is necessary or safe

– VTE recurrence prediction rule to guide

management beyond 6 months?

Summary

• LMWHs are currently considered the standard of care for

thromboprophylaxis and treatment of VTE in cancer patients

• Thromboprophylaxis should be considered for most cancer patients

hospitalized for medical or surgical indications.

• Thromboprophylaxis of ambulatory cancer patients undergoing

chemotherapy should be considered only for high risk populations.

• Identification of several predictive VTE risk factors and biomarkers

has led to the development of VTE risk scoring systems which may

help identify cancer patients who might benefit from primary

thromboprophylaxis in the ambulatory setting.

• VTE in cancer patients should be treated for at least 6 months with

LMWH.

Case scenarios Optimizing management of CAT

• Can I use a DOAC to treat CAT?

• What if my patient has a recurrent thrombosis on

LMWH?

• My patient has a catheter-related DVT? How do

I treat? Do I remove the catheter?

44

Case Scenario 1

• 72 year old

• Man

• Non-small cell lung cancer

– Stage III

– Tx ?

• Other comorbidities

– Diabetes II on metformin

– Hypertension on

monopril

• Pulmonary embolism

– Segmental right upper lobe

– Diagnosed on chest CT

angiogram

– Dalteparin 200units/kg sc

daily prescribed for 6

months

Patient in month 2 of treatment

and refusing daily injections. He

has heard of a new oral

anticoagulant and wants to

switch to this.

What would you

do next?

Case Scenario 1

• You ask why he is refusing the injections.

• He explains that he is fed up with the injections; they are

too painful

DOACs and LMWHs Advantages and disadvantages

LMWH DOAC

Advantages •Rapid onset vs. VKAs •Few drug interactions •Reliable measurement of activity •Monitoring not routinely needed

•Oral •Rapid onset vs. VKAs •Laboratory monitoring not needed •Few drug interactions vs. VKA

Disadvantages •Parenteral •Activity only partially reversible •Caution advised in renal insufficiency

•Inhibitors of P-glycoprotein and CYP 3A4 •Current lack of a reversal agent •No validated laboratory testing for anticoagulant effect •Caution advised in patient with renal insufficiency •Absorption may be affected by vomiting

DOACs General studies in the treatment of VTE vs. VKAs

DOAC Population No. of patients (n, % cancer patients)

Primary efficacy endpoint:* Symptomatic VTE

DOAC vs. VKA

Primary safety endpoint: Major and CRB DOAC vs. VKA

Dabigatran1 DVT or PE n = 2539 (121, 4.8%) Non-inferior DOAC superior

Rivaroxaban2 DVT n = 3449 (207, 6.0%) Non-inferior (Trend to superiority)

Not different

Rivaroxaban3 PE n = 4832 (223, 4.6%) Non-inferior Not different

Apixaban4 DVT or PE n = 5395 (143, 2.7%) Non-inferior DOAC superior

Edoxaban5 DVT or PE n = 8240 (208, 2.5%) Non-inferior DOAC superior

1. RE-COVER, Schulman S et al. N Engl J Med 2009; 2. EINSTEIN-DVT, EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN-PE, EINSTEIN-PE Investigators. N Engl J Med 2012; 4. AMPLIFY, Agnelli G et al. N Engl J Med 2013; 5. Hokusai-VTE, Hokusai-VTE Investigators. N Engl J Med 2013. *non-inferiority Abbreviations: CRB, clinically-relevant bleeding; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonists. Borrowed from Dr. Marc Carrier

DOACs in Cancer Patients Analysis of subsets from pivotal treatment trials

• There appears to be a reduction in recurrent VTE in patients with cancer that has warranted further investigation.

DOAC Population No. of cancer patients n/N (%)

Recurrent VTE DOAC vs. VKA

Major and CRB DOAC vs. VKA

Dabigatran1 DVT or PE 121/2539 (4.8) 3.1% vs. 5.3% n/a

Dabigatran2 VTE 335/5107 (6.6) 5.8% vs. 7.4% 14.5% vs. 13.2%

Rivaroxaban3 DVT 207/3449 (6.0) 3.4% vs. 5.6% 14.4% vs. 15.9%

Rivaroxaban4 PE 223/4832 (4.6) 1.8% vs. 2.8% 12.3% vs. 9.3%

Apixaban5 DVT or PE 143/5395 (2.7) n/a n/a

Edoxaban6 DVT or PE 208/8240 (2.5) 3.7% vs. 7.1% 18.3% vs. 25.3%

Adapted from: Wharin C, Tagalakis V. Blood Rev 2014; Schulman et al. Blood 2013. 1. RE-COVER, Schulman S et al. N Engl J Med 2009; 2. RECOVER & RECOVER II combined analysis. Schulman S et al. Blood 2013; 3. EINSTEIN-DVT, EINSTEIN Investigators. N Engl J Med 2010; 4. EINSTEIN-PE, EINSTEIN-PE Investigators. N Engl J Med 2012; 5. AMPLIFY, Agnelli G et al., N Engl J Med 2013; 6. Hokusai-VTE, Hokusai-VTE Investigators. N Engl J Med 2013. Abbreviations: CRB, clinically-relevant bleeding; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonists Borrowed from Dr. Marc Carrier

CYP 3A4* P-gp†

Inducers (may reduce DOAC plasma levels)

• Chemotherapy: paclitaxel •Targeted therapies: vemurafenib •Hormonal therapies: enzalutamide •Immune modulators: dexamethasone, prednisone

•Chemotherapy: vinblastine, doxorubicin •Immunomodulators: dexamethasone

Inhibitors (may increase DOAC plasma effect)

•Chemotherapies: Several anti-mitotic agents, etoposide, doxorubicin, idarubicin, cyclophosphamide, ifosphamide, lomustine •Targeted therapies: imatinib, crizotinib and other tyrosine kinase inhibitors •Hormonal therapies: tamoxifen, anastrozole, bicalutamide, abiraterone •Immunomodulators: cyclosporine, sirolimus, temsirolimus & tacrolimus •Supportive care: aprepitant, fosaprepitant, fentanyl, methadone, acetaminophen

•Targeted therapies: imatinib, nilotinib, lapatinib, sunitinib, crizotinib, vandetanib •Hormonal therapies: tamoxifen, enzalutamide, abiraterone •Immunomodulators: cyclosporine, temsirolimus, tacrolimus

Potential Drug Interactions in Patients with Cancer

*Moderate or strong interaction is indicated by red text. †Interaction with P-gp has been documented

Source: adapted from: Short NJ, Connors JM. The Oncologist 2014; Lee AYY et al. Blood 2013.

Borrowed from Dr. Marc Carrier

DOACs in Cancer Patients

Bottom line:

• DOACs have not been studied against the standard of therapy for CAT (i.e LMWH)

• And so, we do not know if they are as effective as LMWH for the treatment of CAT.

Case Scenario 1

Course of action:

• Re-assure patient that LMWH is widely considered the standard of care for PE.

• Explain that although the DOACs are effective and safe for treatment of PE in the general population, they have not been tested specifically in patients with cancer and PE.

• Moreover, there is little data to guide the use of DOACs in cancer patients with acute PE, especially advanced stage cancer patients receiving chemotherapy

• There may be interactions between DOACs and chemotherapy medications which may be undesirable

Results:

• After also reviewing some techniques to help with the local discomfort associated with the LMWH injections (eg. application of ice cube to the skin prior to injecting), the patient agrees to continue with the injections.

Clinical Scenario 2

• 42 year old man 90kg

• Non small cell lung

cancer IIIb

– cisplantin and

radiotherapy

• Diagnosed with acute

segmental PE

• Started on dalteparin 200

IU/kg (18,000 IU SC) for

3 weeks then 150 IU/kg

(15,000 IU sc)

• Two weeks after reducing

the dalteparin dose, he

presents with a massively

swollen and painful right leg

• Adequate limb perfusion

• Doppler ultrasound confirms

extensive DVT of right

popliteal and femoral veins

• Hg 112; plts 160 (baseline);

coags normal

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Clinical Scenario 2

• Review weight and

medication compliance

• Patient’s dose was

increased to 18,000 IU sc

daily (wt=90kg)

• Leg symptoms improved

• What if recurrence

occurred on full

therapeutic dose LMWH

(i.e. dalteparin 200

IU/kg)?

54

Clinical Scenario 2

• Recommend increasing the dose by 20-25% for

at least 4 weeks and likely indefinite

• Consider twice daily dosing and not capping

dose when using prefilled syringes

• Do not switch to warfarin, fondaparinux, or

DOACs

•

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Clinical Scenario 3

• 70 year old woman with DLBCL stage 3b with no prior

comorbidities

• Undergoes 2 cycles of R-CHOP. No complications

• Left arm PICC line inserted due to difficult venous

access

• After 4th cycle of R-CHOP, left arm swollen and painful

• Hemodynamically stable

• PICC line site OK

• Sent for doppler ultrasound which confirms left

subclavian DVT

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Central venous catheter associated upper extremity DVT

• http://www.anesthesiology.uci.edu/UI/ima

ges/cline.jpg

• 75% of all upper extremity

thromboses

– Asymptomatic CRT (15%)

– Symptomatic CRT (5%)

• CRT is associated with

significant morbidity in

cancer patients

– PE (detected in ~15% of

patients with symptomatic

CRT)

– Infection (both a risk factor

and consequence of CRT)

– Post thrombotic syndrome

– Early removal of CVC

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Clinical Scenario 3

• Do you treat?

• If yes, which anticoagulant regimen?

• Do you remove the catheter?

58

Clinical Scenario 3

• Treat with LMWH alone

– No direct evidence to support LMWH alone

– Indirect evidence from the CLOT trial

• If the PICC line is functioning, is needed, and symptoms

improving, then no need to remove the catheter.

• ACCP Guideline (Chest 2012)

• Do not recommend removal of an indwelling catheter if the

device is functioning and there is an ongoing need for the

catheter (Grade 2C)

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Clinical Scenario 3

• Duration of treatment?

– At least 3 months, even if catheter removed before

the completion of therapy (ACCP Grade 2C)

– Many MDs will treat beyond 3 months if catheter

remains in place.

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