Anticoagulant Options for the Management of Acute Cancer-Associated Thrombosis - PowerPoint Presentation

Slide1

Anticoagulant Options for the Management of Acute Cancer-Associated Thrombosis

Presented by

Slide2

Faculty/Presenter DisclosureFaculty:Relationships with commercial interests:

Slide3

Disclosure of Commercial SupportThis program has received financial support from Sanofi Canada, in the form of an educational grant.Potential for conflict(s) of interest: All funding for this program was at arms-length and the content was developed by an independent committee of Thrombosis Canada members. The presentation does include reference to medications which the Sanofi markets in Canada.

Slide4

Mitigating Potential BiasThe content for this program was developed by a scientific steering committee from Thrombosis Canada. All faculty have been directed that any recommendations involving clinical medicine are to be based on evidence that is accepted within the profession; and all scientific research referred to, reported, or used in the CME/CPD activity in support or justification of patient care recommendations conforms to the generally accepted standards.

Slide5

Planning faculty

Marc Carrier,

MD, MSc, FRCPC (Program Chair)

Hematologist

Ottawa, Ontario

Normand

Blais

, MD, MSc, FRCPC

Hematologist, Medical Oncologist

Montreal, Quebec

Mary

DeCarolis

, MD, CFE, MCFP 

Oncologist, Hematologist

Ayr, Ontario

Eddy Lang

, MDCM, CCFP(MU), CSPQ

Emergency Physician

Calgary, Alberta

Agnes Lee

, MD, MSc, FRCPC

Hematologist

Vancouver, British Columbia

Laurie

Sardo

, RN,

MScN

, NP, MBA

Nurse Practitioner, Thrombosis

Hamilton, Ontario

Vicky

Tagalakis

, MD, MSc, FRCPC

Internal Medicine

Montreal, Quebec

Slide6

Learning objectives

After attending this program, participants will be better able to:

Understand the risk of venous thromboembolism (VTE) in the cancer population;

Discuss best treatment options for cancer associated thrombosis (CAT) recognizing cancer subgroups and bleeding risk;

Define when to consider hospitalization and how this impacts VTE risk;

Discuss risk factors associated with an increased risk of VTE and major bleeding episodes in patients with CAT;

Identify best risk reduction strategies for recurrence of CAT (i.e. patient education on adherence, signs and symptoms recurrence/bleeding, follow-up).

Slide7

Cancer-associated Thrombosis

Slide8

Defining the terms

Thrombosis:

local coagulation or blood clot within the circulatory system

Venous thromboembolism (VTE):

blood clot (thrombus) that can occur in:

Deep veins of the legs (DVT)

Blood vessels of the lungs (pulmonary embolism; PE)

Arms, especially if a catheter is in place for giving chemotherapy

or taking blood

Organs (e.g. kidney, brain, bowels)

Cancer-associated thrombosis (CAT):

blood clot(s) that occur in patients

living with cancer

Slide9

CAT: a frequent and important complication

Patients with cancer have a 4-7x higher risk of VTE

VTE and thrombotic complications are the 2

nd

most frequent cause of mortality in patients with

cancer

Fatal PE is 3x more common in cancer patients

than in patients without cancer

Connolly GC, Francis CW.

Hematology

2013(1):684–91.

Elyamany

G, et al.

Clin Med Insights Oncol 2014;8:129–137.

Slide10

Why does CAT occur?

Virchow’s triangle

:

Risk factors are cumulative

Venous stasis

Obesity

Immobility (bed rest)

Tumour compression

Blood hypercoagulability

Malignancy

Hereditary risk factors

Age >40

Vascular injury

Intravasation

of cancer cells

Surgery

Chemotherapy

Trauma

Central catheters

Khalil

J, et al.

World J

Surg

Oncol

2015;13:204-220

.

Slide11

When does CAT occur?

CAT most frequently occurs in the first

3-6 months after cancer diagnosis

but can occur anytime

C

hemotherapy can increase

the risk of VTE by 2-6 fold

Connolly GC, Francis CW.

Hematology

2013(1):684–691.

Heit

JA, et al.

Arch Intern Med

2000;160:809–815.

Slide12

Treating Cancer-associated Thrombosis

Slide13

Current guidelines on treatment of CAT

Current guidelines (ASCO, Thrombosis Canada, Canadian Consensus) recommend low molecular weight heparins (LMWHs) for the treatment of established DVT and PE as well as for long-term secondary prophylaxis for at least 6 months

Direct oral anticoagulants (DOACs) are now being studied and used in the treatment of CAT

Lyman GH, et al.

J

Clin

Oncol

2015;33(6):654-656.

Thrombosis Canada. Cancer and Thrombosis.

http://thrombosiscanada.ca/clinicalguides/#

.

Carrier M et al

.

Curr

Oncol 2015;22(1):49-59.

Slide14

Summary: current guideline recommendations on CATASCO, American Society of Clinical Oncology; ACCP, American College of Chest Physicians; ESMO, European Society of Medical Oncology; NCCN, National Comprehensives Cancer Network; LMWH, low molecular weight heparin; UFH,

unfractionated

heparin; VKA, vitamin K agonist; VTE, venous thromboembolism

Adapted in part from Khorana AA, et al.

J

Clin

Oncol

2009;27:4919-4926.

1. Lyman GH, et al.

J

Clin

Oncol

2015;33:654-656. 2. NCCN 2017. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf 3. Mandala M, et al. Ann Oncol 2011;20(Suppl 6):vi85-92.4. Kearon C, et al. Chest 2016;149(2):315-352. 5. Easaw JC, et al.

Curr Oncol 2015;22:144-155.

ASCO

1

NCCN

2

ESMA

3

ACCP

4

Canadian Consensus

5

Initial treatment

LMWH

is the preferred option for initial 5-10 days

LMWH, UFH or

fondaparinux

according to patient profile and clinical situation

LMWH preferred option

LMWH

LMWH

over VKA,

dabigatran

,

rivaroxaban

,

apixaban

or

edoxaban

In patients with established VTE LMWH is the therapy of choice

Secondary prophylaxis

LMWH for at least 6 months

is preferred

;

> 6 months may be considered in select patients with active cancer (e.g. metastatic disease or receiving chemotherapy

LMWH for at least 6 months as

monotherapy

in patients with advanced or metastatic cancer

Patients with active cancer, under treatments or persistent risk factors indefinitely

LMWH for 6 months

Extended therapy

(> 3 months) is suggested

Patients with recurrent VTE

should receive extended

(>3 months) anticoagulation therapy

Slide15

CAT treatment: LMWH vs. VKA data*As per the follow-up period in each study. D =

dalteparin

;

E =

enoxaparin

; OAC – oral anticoagulant; T =

tinzaparin

1. Meyer G, et al.

Arch Intern Med

2002;162:1729-1735. 2. Lee AY, et al.

N Eng J Med

2003;3492:146-153. 3. Lee AY, et al.

JAMA

2015;314:677-686.

4. Hull RD, et al.

Am J Med 2006;119:1062-1072. 5. Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-296.

Study

Design

Length of Therapy (months)

N

Recurrent VTE (%)

Major Bleeding (%)

Deaths* (%)

CANTHANOX (Meyer, 2002)

E (1.5 mg/kg qd)

OAC

3

67

71

4

5

p

=NS

7

16

p

=0.09

11

23

p

=0.07

CLOT

(Lee, 2003)

D (150 IU/kg

qd

)

OAC

6

336

336

8

16

p

=0.002

6

4

p

=0.27

39

41

p

=0.53

LITE

(Hull, 2006)

T (175 IU/kg

qd

)

OAC

3

100

100

6

10

p

=NS

7

7

p

=NS

20

19

p

=NS

CATCH

(Lee, 2015)

T (175 IU/kg

qd

)

OAC

6

449

451

6.9

10.0

p

=NS

2.7

2.4

p

=NS

33.4

30.6

p

=NS

ONCENOX (Deitcher, 2006)

E (1.0 mg/kg

qd

)

E (1.5 mg/kg

qd

)

OAC

6

31

36

34

3

3

7

p

=NS

7

11

3

p

=NS

23

42

32

Slide16

CAT treatment: new data on DOACs

Recently, studies assessing the efficacy and safety of DOACs in prevention and treatment of CAT have been published

DOACs vs. VKA

DOACs vs. LMWH

Subgroup analyses of acute treatment trials comparing DOACs to VKA for the management of VTE suggest that DOACs seem to have similar efficacy and safety profiles compared to VKA among cancer patients.

However, very few cancer patients were included in these trials.

These patients seem to have been at low risk of recurrent VTE and major bleeding.

Pabinger

I,

Riedl

J.

Hematology Am Soc

Hematol

Educ

Program 2017;1:136-143.Smrke A, Gross PL.

Frontiers Med 2017;4:142.

Slide17

CAT treatment: Meta-analysis of DOACs to VKA in cancer patients with acute VTE

Vedovati

MC, et al.

Chest

2015;147(2):475-483.

CI, confidence interval;

df

, degrees of freedom; M–H, Mantel–

Haenszel

; DOAC, direct oral anticoagulant

Use of DOAC and VTE recurrence in patients with cancer

DOAC

Slide18

CAT treatment: Meta-analysis of DOACs to VKA in cancer patients with acute VTE

Vedovati

MC, et al.

Chest

2015;147(2):475-483.

CI, confidence interval;

df

, degrees of freedom; M–H, Mantel–

Haenszel

; DOAC, direct oral anticoagulant

Panel A:

Use of DOAC and major bleeding in patients with cancer

Panel B:

Use of DOAC and clinically relevant bleeding in patients with cancer

DOAC

DOAC

Slide19

CAT treatment: Meta-analysis of LMWHs and DOACs to VKA in cancer patients with acute VTE

Risk of recurrent VTE

Posch

F, et al.

Thromb Res

2015;136(3):582-589.

Slide20

CAT treatment: Meta-analysis of LMWHs and DOACs to VKA in cancer patients with acute VTE

Posch

F, et al.

Thromb Res

2015;136(3):582-589.

Risk of major bleeding

Slide21

Hokusai VTE cancer trial: oral edoxaban vs

dalteparin

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Study design

Open-label, noninferiority trial with 1046 patients with cancer who had acute symptomatic or incidental VTE

Treatment

Randomly assigned patients to receive any LMWH for at least 5 days followed by:

Edoxaban

group: oral

edoxaban

60 mg*

od

, or

Dalteparin

group: subcutaneous

dalteparin

200 IU/kg body weight

od

for 1 month followed by dalteparin 150 IU/kg body weight od

Treatment durationAt least 6 months and up to 12 monthsPrimary outcomeComposite of recurrent VTE or thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration

* Edoxaban 30 mg od was used in patients with CrCl 30 to 50 ml/min, or body weight of

<

60 kg or in those receiving concomitant treatment with potent P-glycoprotein inhibitors.

Slide22

Hokusai VTE cancer trial: study design

Treatment for up to 12 months (at least 6 months)

Efficacy and safety data collected during the entire 12-month study period

Independent blind adjudication of all suspected outcomes

Severity of major bleeding at presentation also adjudicated

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Slide23

Hokusai: baseline characteristics

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624.

Characteristic

Edoxaban

(N = 522)

Dalteparin

(N = 524)

Age; yrs

64.3

+

11.0

63.7

+

11.7

Male gender; no (%)

277 (53.1)

263 (50.2)

Mean weight; kg

Weight ≤60 kg; no (%)

78.8

+

17.9

83 (15.9)

79.1

+

18.1

78 (14.9)

Risk factors for bleeding; no (%) 0

1

2

3

92 (17.6)

148 (28.4)

174 (33.3)

108 (20.7)

92 (17.6)

151 (28.8)

159 (30.3)

122 (23.3)

Active cancer; no (%)

513 (98.3)

511 (97.5)

Metastatic disease; no (%)

274 (52.5)

280 (53.4)

Cancer treatment within previous 4 wks; no (%)

374 (71.6)

383 (73.1)

CrCl of 30-50 mL/min; no (%)

38 (7.3)

34 (6.5)

Platelets 50-100 x 10

9

/L; no (%)

32 (6.1)

23 (4.4)

Lower dose of

edoxaban

; no (%)

122 (23.4)

117 (22.3)

Slide24

Hokusai: types of chemotherapies used

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Note: Patients could receive more than one anticancer drug. Treatment does not include anticancer therapy initiated after randomization.

Chemotherapies; no (%)

Edoxaban

(N = 522)

Dalteparin

(N = 524)

Antimetabolites

124 (23.8)

118 (22.5)

Platinum-based chemotherapies

105 (20.1)

107 (20.4)

Monoclonal antibodies

42 (8.0)

54 (10.3)

Bevacizumab

13 (2.5)

17 (3.2)

Taxanes

40 (7.7)

47 (9.0)

Hormonal therapy

41 (7.9)

37 (7.1)

Topoisomerases

30 (5.7)

48 (9.2)

Alkylating agents

30 (5.7)

38 (7.3)

Anthracytes

22 (4.2)

25 (4.8)

Vinca alkaloids

16 (3.1)

18 (3.4)

Kinase inhibitors

18 (3.4)

18 (3.4)

Immunomodulating agents

16 (3.1)

9 (1.7)

Proteasome inhibitors

7 (3.1)

8 (1.5)

Antitumour antibiotics

5 (1.0)

5 (1.0)

Miscellaneous

14 (2.7)

14 (2.7)

Slide25

Hokusai: Kaplan–Meier cumulative event rates for the primary outcome

Primary outcome: composite of recurrent VTE or major bleeding

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Inset: same data on an enlarged y axis

HR 0.97 (0.7 – 1.36)

P=0.006

Slide26

Hokusai: results

Primary Edoxaban Dalteparin Hazard Ratio

Outcome (N = 522) (N = 524) (95% CI)

p

Value

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Recurrent VTE 67 (12.8) 71 (13.5) 0.97 (0.70–1.36) 0.006 for noninferiority;

or major bleeding 0.87 for superiority

no (%)

Conclusion:

Oral

edoxaban

was

noninferior

to subcutaneous

dalteparin

with respect to the composite outcome of recurrent venous thromboembolism or major bleeding.

Slide27

Hokusai: Kaplan–Meier cumulative event rates for secondary outcomes

Recurrent VTE

Major bleeding

Insets: same data on an enlarged y axis

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

HR 0.71 (0.48 – 1.06); p = 009

HR 1.77 (1.03 – 3.04); p= 0.04

Slide28

Hokusai: length of therapy between two groups

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

#1 reason for discontinuation: patient preference

Characteristic

Edoxaban

(N = 522)

Dalteparin

(N = 524)

p

value

Treatment duration (median)

211 days

184 days

0.01

Patients completed study treatment at 12 months; n

200

154

Slide29

Hokusai: Point estimates for recurrent or major bleeding

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Outcomes; no (%)

Edoxaban

(N = 522)

Dalteparin

(N = 524)

Hazard ratio (95% CI)

Recurrent VTE

41 (7.9)

59 (11.3)

0.71 (0.48, 1.06)

p

= 0.09

Recurrent DVT

19 (3.6)

35 (6.7)

0.56 (0.32, 0.97)

Recurrent PE

27 (5.2)

28 (5.3)

1.00 (0.59, 1.69)

Major Bleeding

36 (6.9)

21 (4.0)

1.77 (1.03, 3.04)

p

= 0.04

CRNMB

76 (14.6)

58 (11.1)

1.38 (0.98, 1.94)

MB + CRNMB

97 (18.6)

73 (13.9)

1.40 (1.03, 1.89)

Deaths

206 (39.5)

192 (36.6)

1.12 (0.92, 1.37)

VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; MB, major bleeding; CRNMB, clinically-relevant non-major bleeding

Slide30

Hokusai: incidence of GI bleed

GI cancer

Edoxaban

(N = 522)

Dalteparin

(N = 524)

p

value

Yes, n/N (5)

18/136 (13.2)

3/125 (2.4)

0.02

No, n/N (%)

4/386 (3.6)

13/399 (3.3)

Supplement to:

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

.

Note: Upper GI bleeding was predominant site in patient with GI cancers

Slide31

Hokusai: survival results

Overall 266 (25.5%) patients died

6 deaths in each group were related to VTE or bleeding

No objectively confirmed fatal PEs

Of patients with recurrent PE, 5 (1%) patients in the

edoxaban

group and 3 (0.6%) in the

dalteparin

group had unexplained death (PE could not be ruled out)

Edoxaban

Dalteparin

6-months survival, % (95% CI)

354 (67.8%) 360 (68.7%)

Supplement to:

Raskob

GE, et al.

N

Engl

J Med

2018;378:615-624

Slide32

SELECT-D pilot trial: oral rivaroxaban vs dalteparin

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

Study design

Prospective, randomised, open-label, multicentre pilot phase II

Participants

406 patients with active cancer with symptomatic DVT and/or any PE ECOG PS < 2

Treatment groups

Rivaroxaban

group: 15 mg bid for 21 days followed by 20 mg

od

Dalteparin

group: 200 IU/kg

od

for the first 30 days followed by 150 IU/kg

od

Treatment duration

6 months

Primary outcome

To assess VTE recurrence in cancer patients with a first VTE, treated with

rivaroxaban

or

dalteparin

To assess rates of major and clinically relevant non-major bleeding

Slide33

SELECT-D: study design

Second randomization was deemed not feasible

The study protocol did not specify central adjudication of suspected VTE events

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

Slide34

SELECT-D: baseline characteristics

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

Characteristic

Rivaroxaban

(N=203)

Dalteparin

(N=203)

Age, years – median (range)

67 (34-87)

67 (22-87)

Male gender; no (%)

97 (48)

109 (54)

BMI, median; kg/m

2

26.7

26.6

Metastatic cancer; no (%)

118 (58)

118 (58)

Currently

receiving cancer treatment; no (%)

140 (69)

142 (70)

ECOG performance status; no (%) 0

1

2

58 (29)

90 (47)

52 (26)

61 (30)

95 (47)

43 (21)

Qualifying VTE; no (%) Symptomatic

Incidental

97 (48)

106 (52)

93 (46)

110 (54)

Slide35

SELECT-D: Kaplan–Meier cumulative event rates for primary outcome

Primary outcome: time to recurrent VTE within 6 months

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

Slide36

SELECT-D: primary outcome results

Primary

Rivaroxaban

Dalteparin

Hazard Ratio

Outcome, n (%) (N = 203) (N = 203) (95% CI)

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

VTE recurrence within 6 months 8* 18**

DVT or PE*** 6 16

Other location 2 2

6 month VTE recurrent rate, % (95% CI) 4% (2-9%) 11% (7-16%) 0.43 (0.19–0.99)

* 2 patients experienced symptomatic PE and 1 experienced incidental PE

** 2 patients experienced symptomatic and 6 experienced incidental PE

***One fatal PE in each arm

Conclusion:

Rivaroxaban

was associated with relatively low rate of recurrent VTE

Slide37

SELECT-D: Kaplan–Meier cumulative event rates for the secondary outcomeTime to major bleeds within 6 months

Dalteparin

Rivaroxaban

(n= 203) (n=203)

Major* 6 (3%) 11 (5%)

CRNMB** 6 (3%) 25 (12%)

Total 12 (6%) 36 (17%)

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

*Most major bleeding events were GI; no CNS bleeds.

**Most CRNMBs were GI or urologic.

Rivaroxaban

was associated with a higher CRNMB compared with

dalteparin

.

Slide38

SELECT-D: survival results

Overall 104 (26%) patients died

92 (88%) died from progressive cancer

2 (2%) fatal PEs

Rivaroxaban

Dalteparin

6-months survival, % (95% CI) 75 (69-81%) 70% (63-76%)

Young AM, et al.

J

Clin

Oncol

2018;36(20):2017-2023.

Slide39

DOACs vs LMWH for treatment of CAT: systematic review and meta-analysis

DOACs (42/725) had a non-significant lower incidence of 6-month recurrent VTE compared to LMWHs

B.

DOACs (40/725) had a higher incidence of

6-month major bleeding compared to LMWHs

Li A, et al.

Thrombo

Res

2018;doi:10.1016/j.thromres.2018.02.144.

Slide40

When to hospitalize?

Estimating risk for adverse outcomes is key

Pulmonary Embolism Severity Index (PESI) and

its simplified version (

sPESI

) are widely validated

(see next slide)

Addition of biomarker data such as

cTnT

, BNP,

NT-

proBNP

, H-FABP as well as echocardiography

may help with risk assessment

There is a trend to outpatient management to reduce strain on inpatient resources

Elias A, et al. BMJ Open 2016;6(4):e010324.

cTnT

, cardiac

troponin

T; BNP, brain

natriuretic

peptide ; NT-

proBNP

, N-terminal

proBNP

; heart-type fatty acid-binding protein, H-FABP

Slide41

PESI and sPESI

Thrombosis Canada website.

http://thrombosiscanada.ca/tools/?calc=pesi

;

http://thrombosiscanada.ca/tools/?calc=simplifiedPesi

Slide42

Tailoring anticoagulation management in patients with acute CAT

Slide43

Summary / key learnings: LMWHs vs DOACs for treatment of CAT

Clinical

considerations

Avoid DOACs in certain GI cancers and potentially

urothelial

malignancies

Consider LMWHs in patients with renal dysfunction (

CrCL

< 30 mL/min)

Consider drug-drug interactions when choosing a DOAC

High risk of bleeding (e.g. previous major bleeding episodes, thrombocytopenia)

Current cancer treatment

Patient considerations

Preference

Insurance coverageExtremes of body weights

Noble S. Thromb Res. 2018;164(Suppl 1):S157-S161.

Slide44

Drug-drug interactions: Inducers and inhibitors of CYP3A4 and P-gp

Kinase

inhibitors

CYP3A4

P-

gp

Afatinib

↓

Alectinib

↓

Ceritinib

↓

Crizotinib

↓

Dasatinib

↓

Ibrutinib

↓

Idelalisib

↓

↓

Imatinib

↓

Lapatinib

↓

↓

Nilotinib

↓

↓

Osimertinib

↓

Vemurafenib

↑

↓

Lenvatinib

↑

↑

Chemotherapies

CYP3A4

P-

gp

Doxurubicin

↓

Topotecan

↓

Vinblastine

↓

Mitotane

↑

Venetoclax

↓

Supportive care

CYP3A4

P-

gp

Aprepitant

↓

Methylprednisolone

↓

Dexamethasone

↑

↑

CYP, cytochrome P450; P-

gp

, P-glycoprotein;

↓,

inhibitor;

↑

,induce

r

Inhibitors of CYP3A4 and/or P-gp may increase risk of bleeding on DOACs.

Slide45

Patient preference and coverage

Patient preference is important in the choice of any medication or treatment

Needs to take into consideration the balance of risks/benefits in their particular situation

Patients experiencing nausea, vomiting and/or anorexia may not be able to take oral medication

Some patients may have needle phobias or needle fatigue

Cost may be a factor

Slide46

Preventing Recurrence: Patient Education

Slide47

Risk reduction strategies: patient education

Risk of recurrence after a first episode of VTE is higher in cancer patients than in those without underlying malignancy.

Adherence to anticoagulant treatment plan is important in reducing risk.

Review reasons for anticoagulant (e.g. treat blood clot, prevent more from developing, prevent extension)

Target compliance (e.g. set phone alarm as reminder, use of

dossette

, family member)

Bring medication to medical appointments

Review appropriate LMWH injection technique (i.e. 90 degree angle, do not eject air bubble, inject 1" outside of bruised areas for best absorption)

Khorana AA, et al.

J Thromb Thrombolysis

2016;41:81–91.

Slide48

Patient education: signs and symptoms of recurrence

The signs and symptoms of recurrent VTE are usually the same as the first presentation

Signs and symptoms of DVT

Edema - most specific symptom

Leg pain - occurs in 50% of patients but

is nonspecific

Tenderness - occurs in 75% of patients

Warmth or

erythema

Clinical symptoms of PE as the primary manifestation

Dilated superficial veins

Signs and symptoms of PE

Dyspnea,

tachypnea

Pleuritic

chest pain, cough, or

hemoptysis

Tachycardia

Anxiety

Syncope/

presyncope

Slide49

Patient education: signs and symptoms of bleeding

Remind patients to seek medical attention if symptoms of bleeding occur

Signs and symptoms of bleeding

Unusual black or melena stool

Hematuria

Hematemesis

Slide50

Patient education

Patients need a reasonable level of understanding of risk factors and preventative measures

Allow patients to make informed decisions in partnership with healthcare providers

Address patients’ individual needs and preferences

Clear, consistent patient education materials are beneficial

Sadideen

H, et al.

J R Soc Med

Sh

Rep

2011;2:97.

Slide51

Patient education materials: Thrombosis Canada

http://thrombosiscanada.ca/resourcepage/patient-family-information/

Bilingual disease and drug information sheets

Videos for patients

Slide52

Questions?

Slide53

Case Studies

Slide54

Case Study:

Metastatic

Colorectal Cancer

Slide55

Mrs RS: Profile

54 year-old high school teacher

Married, mother of 2 adult children

Past medical history: significant for hypertension and hypercholesterolemia, both well controlled with appropriate medications

BMI 31 (height 1.52 m; weight 72 kg)

CBC, Lytes, Ur, Cr and LFTs are all within normal limits

Slide56

Mrs RS: Presentation

Metastatic colorectal cancer

Receiving palliative chemotherapy (FOLFIRI and

bevacizumab

) in a stop-and-go fashion for 2 years

Presents with painful, swollen and red lower left limb

Ultrasound confirms a proximal deep vein thrombosis of the left popliteal vein

Slide57

Mrs RS: What would you do?

How would you treat Ms RS, and why do you chose this option?

Treat with

dalteparin

only

Treat with

enoxaparin

only

Treat with

tinzaparin

only

Treat with LMWH for 5-7 days with transitioning to warfarin

Treat with LMWH for 5-7 days, then switch to

edoxaban

Treat with rivaroxaban

only

Slide58

Mrs RS: What if…?

What if her renal function is decreased with a CrCl 29 mL/min?

Treat with

dalteparin

only

Treat with

enoxaparin

only

Treat with

tinzaparin

only

Treat with LMWH for 5-7 days with transitioning to warfarin

Treat with LMWH for 5-7 days, then switch to

edoxaban

Treat with

rivaroxaban

only

Slide59

Anticoagulation and renal dysfunction

Renal function surveillance should be exercised in

patients with

CrCl

<50 mL/min

Therapeutic doses of LMWH should be avoided in

cases of severe renal disease (CrCl <30 mL/min)

unless monitored by anti–factor

Xa

heparin levels

LMWH should be used with extreme care in patients with end-stage renal disease requiring dialysis.

Carrier M, et al.

Curr

Oncol

2015; 22:49-59.

Slide60

LMWH in patients with CAT and RIVTE and bleeding outcomes

Variable

Treatment

Events

n/N

%

Hazard ratio

(95% CI)

p

– value

VTE (ITT)

(N

= 162)

Dalteparin

2/74

2.7

0.15

(0.03,

0.65)

0.01

VKA

15/88

17.0

Major bleeding

(N

= 161)

Dalteparin

7/749.51.29(0.43, 3.83)0.65VKA6/87

6.9

CI = confidence interval; CrCl = creatinine clearance; CRNMB = clinically-relevant non-major bleeding;

ITT = intent to treat; NS = not significant

Variable

Treatment

Events

n/N

%

Hazard ratio

(95% CI)

p

– value

VTE (ITT)

(N

= 131)

Tinzaparin

9/69

13.0

0.90

(0.38, 2.12)

NS

VKA

9/62

14.5

Major bleeding

(N

= 131)

Tinzaparin

3/69

4.3

0.54

(0.13, 2.16)

NS

VKA

5/62

8.1

CATCH patients with

CrCl

20–59 mL/min

2

CLOT patients with CrCl <60 mL/min

1

1. Woodruff S et al.

J Thromb Thrombolysis

2016;42(4):494–505; 2. Bauersachs R et al.

Thromb

Haemost

2018;118(5):914-921. 

Slide61

Mrs RS: What if…?

What if she was receiving adjuvant FOLFOX chemotherapy and her platelets were chronically in the 75-80 range?

Treat with

dalteparin

only

Treat with

enoxaparin

only

Treat with

tinzaparin

only

Treat with LMWH for 5-7 days with transitioning to warfarin

Treat with LMWH for 5-7 days, then switch to

edoxaban

Treat with

rivaroxaban

only

Slide62

Anticoagulation and thrombocytopenia

Heparin-induced thrombocytopenia must be excluded in patients developing thrombocytopenia during heparin therapy

The risk-benefit balance of anticoagulation should be reassessed in the presence of thrombocytopenia

The risk of VTE recurrence is particularly high in the first 3 months after thrombosis; safe administration of anticoagulant therapy is recommended

Full anticoagulation (DOACs or LMWH)

does not pose excessive risk when platelet count remains above 50 x 10

9

/L

Watson HG, et al. Br

J

Haematol

2015;170(5):640-648.

Slide63

Platelets < 50 X 10

9

/L

Able to maintain platelets

with transfusion (≥ 50)

Therapeutic doses

Unable to maintain

platelets

20-50

50% dose

LMWH

< 20

Hold LMWH

Samuelson

Bannow

BT, et al.

J

Thromb

Haemost

2018;16(6):1246-1249

.

Thrombocytopenia in patients with acute VTE

(< 1 month)

Slide64

Thrombocytopenia in patients with acute VTE (≥ 1 month)

ISTH SSC suggest reducing the dose of LMWH to 50% of the therapeutic dose or using a prophylactic dose of LMWH in patients with a platelet count of 20–50 X 10

9

/L

ISTH SSC suggest discontinuing anticoagulation in patients with a platelet count of < 20 X 10

9

/L

Samuelson

Bannow

BT ,et al.

J

Thromb

Haemost

2018;16(6):1246-1249.

Slide65

Mrs RS: What if…?

What if she is visually impaired such that she cannot safely self-administer LMWH?

What if she has a needle phobia and will not agree to LMWH injections for any length of treatment?

What if her disease is stable for several months such that her chemotherapy is held. Would you consider switching her to a DOAC? If you did, would you switch her back to LMWH when you need to restart IV chemotherapy?

Slide66

Case Study:

Recurrent Thrombosis In Aggressive Colorectal Cancer

Slide67

Mr NN: Profile

39-year-old accountant

Married, three children

Non-smoker, non-drinker

Past medical-surgical history

Abdominal hernia repair and vasectomy

Family history:

Maternal grandmother: colorectal cancer

Paternal grandmother: breast cancer 


BMI 23 (height 1.84 m; weight 78 kg)




Slide68

Mr NN: Presentation

March 10: presents in the ER

1 week progressive shortness of breath and cough, non-responding to oral antibiotic (Levaquin) 


Normal CBC, LFTs and electrolytes:

HGB 155 (140-175), WBC 9.2 ANC 4.5,

PLT 189

,

PT 13.7

(9.4–12.9),

INR 1.2

, creatinine 88,

eGFR >60

, CEA 4.8 (0–3.0)

CT scan of chest

: enlarged mediastinal LNs, right hilar lymph nodes, retroperitoneal LNs, and right middle lobe

bronchovesicular thickening Refer to ENT for diagnosis and biopsy

Slide69

Mr NN

March 13: returns to ER

Progressive right upper extremity swelling and pain for 2 days

Right doppler US of the right upper extremity: acute DVT in axillary, subclavian and internal jugular vein

 

Slide70

Mr NN: What would you do?

How would you treat Mr NN, and why do you chose this option?

Hospitalize with LMWH

Outpatient treatment with

dalteparin

only

Outpatient treatment with

enoxaparin

only

Outpatient treatment with

tinzaparin

only

Outpatient treatment with LMWH for 5-7 days with transitioning to warfarin

Outpatient treatment with LMWH for 5-7 days, then switch to

edoxaban

Outpatient treatment with rivaroxaban only

Slide71

Mr NN

Treated with therapeutic dose of LMWH

March 22

FNAB right neck LN: metastatic adenocarcinoma consistent with colorectal origin

C-scope: semi-circumferential indented mass in proximal transverse colon

Low-grade colorectal adenocarcinoma, KRAS WT, NRAS WT, MSS, V600 BRAF mutated

Slide72

Mr NN

April 20

New right upper extremity symptoms (worsening of swelling)

Doppler confirmed extension of the previously described thrombus

Confirm patient compliance of LMWH and heparin induced thrombocytopenia was excluded

LMWH increased by 25% (up to 125% of weight-base)

Slide73

Recurrent VTE

Subtherapeutic doses

Therapeutic doses

Switch to full doses

↑ doses by 20-25%

Reassess in 5 to 7 days

Same

Better

?

Another dose

Escalation?

Yes

No

Recurrent VTE despite LMWH

Carrier M, Khorana AA,

Zwicker

JI, et al.

J

Thromb

Haemost

2013;11(9):1760-1765.

Slide74

Case Study:

Lung Cancer-

associated

Venous

Thromboembolism

Slide75

Mr JD: Profile

56-year-old theater producer

Divorced, 2 teenaged children

Active

50 pack year smoker; occasional THC;

no alcohol

Reports reduced exercise tolerance lately limited by dyspnea

No previous medical history

No current medication

BMI 26 (height 1.70 m; weight 75 kg)

Slide76

Mr JD: Presentation

Presents to the ED with right-sided pleuritic chest pain

VS: HR = 90; BP 140/80; RR 20/min / Sat 93%

EKG – sinus with RV strain

CXR shows hyperinflation and possible RUL mass

hsTnT marginally +ve at 20 nmol/L / d-Dimer > 5.0 (n < 0.5)

CTPA show bilateral segmental emboli (RML and LLL)

Presence of a right apical mass, possible mediastinal invasion

Neutrophilia on CBC

Normal renal and liver function

Well-established lung mass follow-up outpatient program

Patient feels well after analgesia – big play tomorrow night – wants to go home

Slide77

PESI and sPESI

Thrombosis Canada website.

http://thrombosiscanada.ca/tools/?calc=pesi

;

http://thrombosiscanada.ca/tools/?calc=simplifiedPesi

Slide78

Mr JD: PESI Score

Class IV = 4-11% 30d mortality

Slide79

Mr JD: What would you do?

How would you treat Mr JD, and why do you chose this option?

Admit with IV UFH

Admit with LMWH

Discharge with

dalteparin

only

Discharge with

enoxaparin

only

Discharge with

tinzaparin

only

Discharge with LMWH for 5-7 days, then switch to warfarin

Discharge with LMWH for 5-7 days, then switch to edoxaban

Discharge with rivaroxaban only

Slide80

Mr JD: Investigations

Mild COPD on PFTs

PET scan confirms findings

Thoracic MRI confirms mediastinal contact, apical invasion but no brachial plexus involvement

Endobronchial ultrasound (EBUS) is scheduled

What is your

peri

-procedural anticoagulation recommendation?

EBUS turns out negative

Slide81

Mr JD: Investigations

Transthoracic needle biopsy (TTMB) is scheduled

What is your peri-procedural anticoagulation recommendation?

TTNB confirms squamous cell lung carcinoma (PD-L1 negative)

Staging concludes T4N0M0 SC-NSCLC

How do you approach anticoagulation at this point (post-discharge)?

Slide82

Mr JD: Oncology treatment plan

Pre-operative chemotherapy and radiation

Cisplatin-etoposide days 1-5 and day 8 every 3 weeks x 2 cycles

Chest radiation 45

Gy

(25 fractions of 1.8

Gy

)

Surgery planned on week 10-12

Post-operative cisplatin-etoposide x 2 cycles

What is your peri-operative anticoagulation recommendation?

Slide83

Mr JD: Progression

At 3 months post-end of chemotherapy:

Seizure

Brain CT shows necrotic left frontal-parietal brain metastasis (slightly hyper dense material – mild bleeding?)

CT thorax-abdomen-pelvis: no sign of recurrence

Would you change the type of anticoagulants (DOACs or LMWH) and why?

Confirmed single brain metastasis – operable

What are your peri-operative anticoagulation recommendations?

Slide84

Primary or metastatic brain tumours and anticoagulation

Primary or metastatic brain tumours confer an

increased risk of developing venous thromboses.

Potential benefit of anticoagulation must be weighed

against the potential complication of intracranial

hemorrhage.

For most primary and treated metastatic brain

tumours, the risk of spontaneous bleeding is

acceptable and not further increased by careful anticoagulation with LMWH or DOACs, although thrombocytopenia (platelet count <50,000/

μL

) and other coagulopathies are relative contraindications.

Lin RJ, et al.

Oncologist

2018;23(4):468-473.

Slide85

Metastatic brain disease on anticoagulation

Risk of intracranial bleeding episode: OR = 1.07 (95% CI: 0.61–1.88;

p

= 0.81; I

2

= 0%)

CI = confidence interval; OR = odds ratio

Zwicker

JI ,et al,

J

Thromb

Haemost

2016;14:1736–1740

.

Slide86

Primary brain tumour/gliomas on anticoagulation

Risk of intracranial bleeding episode: OR = 3.53 (95% CI: 1.34–9.02;

p

= 0.81; I

2

= 28.2%)

CI = confidence interval; OR = odds ratio

Zwicker

JI, et al,

J

Thromb

Haemost

2016;14:1736–1740.

Slide87

Mr JD: Further progression

At 9 months follow-up after brain surgery

In-field recurrence in the brain

Has developed progressive left lower limb palsy

Still on anticoagulation (DOACs vs. LMWH)

Receives further stereotactic brain radiation

Condition worsens after 2 more months –

radionecrosis

vs progressive disease

Mr JD requests transfer to hospice

What is your recommendation in regards to anticoagulation?

Slide88

Anticoagulation: continuation beyond 6 months

Beyond 6 months is the preferred option in patients with active advanced cancer in the absence of a contraindication to anticoagulation.

A reasonable option in patients with advanced cancer in complete remission for whom the short-term risk of cancer recurrence is high, or in the presence of other ongoing major risk factors for thrombosis.

Required in most circumstances if an indication for anticoagulation was present before the incident cancer (e.g. AF, VTE not related to malignancy). Chosen therapy should be adapted to the situation.

Carrier M, et al.

Curr

Oncol

2015; 22:49-59.

Slide89

Anticoagulation: discontinuation beyond 6 months

Anticoagulation

can be terminated after a minimum of 6 months of anticoagulant therapy if the underlying cancer has been treated with curative intent and any ongoing therapy is associated with a low risk of thrombosis.

Carrier M, et al.

Curr

Oncol

2015; 22:49-59.

Slide90

Summary / key learnings: LMWHs vs DOACs for treatment of CAT

Clinical

considerations

Avoid DOACs in certain GI cancers and potentially

urothelial

malignancies

Consider LMWHs in patients with renal dysfunction (

CrCL

< 30 mL/min)

Consider drug-drug interactions when choosing a DOAC

High risk of bleeding (e.g. previous major bleeding episodes, thrombocytopenia)

Current cancer treatment

Patient considerations

Preference

Insurance coverageExtremes of body weights

Noble S. Thromb Res. 2018;164(Suppl 1):S157-S161.

Slide91

Supplementary Slides

Slide92

Risk Factors for CAT

Slide93

Risk factors for VTE in cancer

Elyamany

G, et al.

Clin

Med Insights

Oncol

2014;8:129–137.

Blom

JW, et al.

JAMA

2005;9;293(6):715–722.

Increased risk varies from 1 – 30% depending on:

Patient characteristics

Cancer-related factors

Treatment-related

factors

Female gender

Older age

Race (black ethnicity)

Previous VTE

Common comorbidities,

e.g. diabetes, obesity,

inflammation, pulmonary disease, renal disease,

others

Genetic mutations

Site of tumour(s)

Tumour histologyStage and gradeInitial period after diagnosisDuration of cancerMajor surgeryHospitalizationImmobilizationChemotherapyRadiation therapyErythropoiesis-stimulating agentsAntiangiogenic

agents

Indwelling central catheters

Slide94

VTE risk: predictive model for CAT

Khorana AA, et al.

Blood

2008;111(10):4902–4906.

Khorana AA, et al.

Thromb Res

2018;164 (Suppl 1):S70-S76..

Slide95

VTE risk: post-surgical

VTE is a common complication of cancer surgery

@RISTOS study:

A prospective observational study that assessed

the incidence of VTE in 2372 patients undergoing

cancer surgery

A total of 50 patients (2.1%) experienced VTE

40% of the events occurred later than 21 days from surgery.

Overall death rate was 1.72%; 46.3% of these were caused by VTE

Agnelli

G, et al.

Ann

Surg

2006;243(1):89–95.

Slide96

Risk factors: post-surgical VTE

Agnelli

G, et al.

Ann

Surg

2006;243(1):89–95.

Risk Factors for VTE

Odds Ratio (95% CI)

Previous history of VTE

6.0 (2.1 – 16.8)

Anesthesia lasting

>

2 hours

4.5 (1.1 – 19.0)

Bed rest post-op

>

4 days

4.4 (2.5 – 7.8)

Advanced

tumour

2.7 (1.4 – 5.2)

Age

>

60

2.6 (1.2 – 5.7)

Results from @RISTOS

Slide97

VTE risk: hospitalization and immobilization

The risk of VTE due to vessel stasis increases with length of hospitalization/immobilization in patients with cancer who have and who have not had surgery

Increased risk of VTE

Khalil J, et al.

World J Surg Oncol

2015;13:204-220.

Slide98

VTE risk: cancer treatment

Mandala

M, et al.

Annals

Oncol

2011;22(

Suppl

6):vi85–vi92.

Chemotherapy increases the risk of VTE by at least four mechanisms:

acute damage to vessel walls

non-acute damage of the endothelium

a decrease in natural coagulation inhibitors (reduced level

of C, protein S or

antithrombin

III)platelet activationAntiangiogenic agents such as bevacizumab, thalidomide and lenalidomide contribute to thrombosis, through endothelial cell and platelet activation and damage to the vascular endothelium

Slide99

VTE risk: cancer treatment examples

Khalil

J, et al.

World J

Surg

Oncol

2015;13:204-220

. ;

Palumbo A, et al.

J

Clin

Oncol

2011;29:986–993.Carrier M, et al. J Thromb Haemost 2011;9:653–663.; Lyman GH, et al. The Oncologist 2013;18(12):1321–1329. Mandala M, et al. Annals Oncol 2011;22(Suppl 6):vi85–vi92.

Examples:Bevacizumab administered concomitantly with chemotherapy is associated with a 33% relative increase of VTE. The overall incidence of any-grade and high-grade VTE in patients receiving bevacizumab was 11.9 and 6.3%, respectively.

In patients with multiple myeloma, the incidence of thromboembolic events is 14% to 26% in patients receiving thalidomide plus dexamethasone and 10% to 20% in patients receiving thalidomide plus melphalan

Slide100

VTE risk with chemotherapy: a retrospective analysis

Lyman GH, et al.

The Oncologist

2013;18(12):1321–1329.;

Blom

JW, et al.

J Thromb

Haemost

2004;2:1760-1765.

VTE incidence (%)

*Adenocarcinomas are associated with higher risks of VTE than squamous cell carcinomas

Slide101

VTE risk: cancer site

Lyman GH, et al.

The Oncologist

2013;18(12):1321–1329

.

Risk of VTE in Cancer Patients Receiving Chemotherapy

Slide102

VTE risk: hematologic cancers

Patients with a hematological cancer have a six-fold increased risk of developing VTE compared to the matched controls with no hematological cancer.

Highest to lowest risk of developing VTE:

aggressive non-Hodgkin lymphoma

multiple myeloma

acute leukemia (myeloid and lymphoblastic)

chronic

myeloproliferative

neoplasms

and

myelodysplastic

syndrome

chronic lymphocytic leukemia

Hodgkin lymphoma

Gade IL, et al.

Blood

 2015;126:628.

Slide103

VTE risk: tumour stage

Cancer

Distant Metastases

Adjusted OR

(95% CI)

Adjusted OR

(95% CI)

No

No

1.0

Yes

No

3.9

(2.5 – 6.0)

1.0

Yes

58.0

(9.7 – 346.7)

19.8

(2.6 – 149.1)

Patients with metastatic disease have 20-fold risk of VTE compared with those without

Blom

JW, et al.

JAMA

2005;9;293(6):715–722.