Cancer associated thrombosis

Simon Noble

Marie Curie Professor of Supportive and Palliative Medicine

Marie Curie Palliative Care Research Centre

Cardiff University

Take home messages

1. Clots are cool

2. DOACS if

• Low bleeding risk (beware GI/GU)

• No DDIs (CYP3A4/ pGP)

• Kidneys/liver OK

3. Consider stopping anticoagulants as death approaches

4. Tranexamic does not increase thrombotic risk

5. Do not give thromboprophylaxis if

• Poor performance status (KPS<50)

• Short prognosis

2

)

3

4

Schematic of the optical analyzer system.

Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology

Schematic of the optical analyzer system.

Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology

Schematic of the phase dynamics of blood clot contraction.

Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology

Schematic of the phase dynamics of blood clot contraction.

Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology

9

Electron microscopy

Healthy blood Blood from patient with stage IV lung cancer10

Clot stabilization and resorption

1. Initial stabilization: 5 days

2. Stable clot: 6 weeks

3. Resorption 4- 12 weeks

11

Clot presentation

• DVT: 7-14 days

• PE: 21 days

12

DOACs

13

DOAC Pharmacology

14Adapted from: Heidbuchel H et al. Europace 2013; U.S., Canadian Prescribing Information CrCl = creatinine clearance

15

The CLOT TrialPrimary outcome: VTE recurrence

16

HR = hazard ratio; NNT = number needed to treat; VKA = vitamin K antagonist; VTE = venous thromboembolism

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

Risk reduction = 52%HR 0.48 (95% CI 0.30, 0.77)

log-rank p = 0.002

NNT = 13

LMWH vs warfarin meta analysis

p. 017

Florian Posch et at, Thrombosis Research 136 (2015) 582–589

GuidelineLong-term

treatmentTreatment duration

AOIM LMWH3 to 6 months then LMWH until cancer

resolution

NCCNLMWH or

VKA

DVT: 3 to 6 months; PE: 6 to 12 months

ASCO LMWH At least 6 months

INCa LMWH3 to 6 months then VKA or LMWH until

cancer resolution

ACCP LMWH3 to 6 months then VKA or LWMH until

cancer resolution

ansm LMWH3 to 6 months and beyond 6 months if LMWH

well-tolerated

ISTH LMWH3 to 6 months then VKA or LMWH until

cancer resolution

Guideline recommendations

Guideline recommendations:

Standard of treatment for cancer-associated thrombosis is three to six months LMWH

(Grade A)

In patients with ongoing active cancer, consideration should be given to indefinite anticoagulation but decision should be made on a case by case basis, taking into consideration bleeding risk and patient preference.

(Grade D)

DVT = deep vein thrombosis; LMWH = low molecular weight heparin; PE = pulmonary embolism; VKA =

vitamin K antagonist

18

van der Hulle T et al. J Thromb Haemost 2014. CRNMB = clinically-relevant non-major bleeding

Recurrent VTE

Major bleeding or CR-NMB

Recurrent VTE warfarin

Lee A et al. 2003: 16%

Meyer G et al. 2002 17%

Pooled incidence rates: 4.1% (2.6–6.0) for DOACs

6.1% (4.1–8.5) for VKAs [RR 0.66 (0.38–1.2)]

DOACs in the treatment of CAT

19

Proportion of metastatic patients

STUDY LMWH WARFARIN RIVAROXABAN

CLOT 66% 69%

LITE 47% 36%

CATCH 55% 54%

ONCENOX 54% 52%

EINSTEIN

DVT/PE

26% 19%

21

22

Primary end point

23

Recurrent VTE

24

Bleeding

25

Appendix: page 16/32

26

Appendix: page 16/32

27

GI cancers: 13.1% major bleeding

Urothelial cancers 8% major bleeding

(VTE) recurrence within 6 months.

Rivaroxaban vs dalteparin

400 patients: 90% metastatic disease, 83% chemo

4% vs 11% (95% CI 7-17%) recurrent VTE

4% vs 3% major bleeds

11% vs 2% CRNMB

Select-D

29

Fig 2. Time to venous thromboembolism (VTE) recurrence within 6 months.

Published in: Annie M. Young; Andrea Marshall; Jenny Thirlwall; Oliver Chapman; Anand Lokare; Catherine Hill; Danielle Hale; Janet A. Dunn; Gary H. Lyman; Charles Hutchinson; Peter

MacCallum; Ajay Kakkar; F.D. Richard Hobbs; Stavros Petrou; Jeremy Dale; Christopher J. Poole; Anthony Maraveyas; Mark Levine; Journal of Clinical Oncology 2018, 36, 2017-2023.

DOI: 10.1200/JCO.2018.78.8034

Copyright © 2018 American Society of Clinical Oncology

Fig 3. Time to major bleed within 6 months.

Published in: Annie M. Young; Andrea Marshall; Jenny Thirlwall; Oliver Chapman; Anand Lokare; Catherine Hill; Danielle Hale; Janet A. Dunn; Gary H. Lyman; Charles Hutchinson; Peter

MacCallum; Ajay Kakkar; F.D. Richard Hobbs; Stavros Petrou; Jeremy Dale; Christopher J. Poole; Anthony Maraveyas; Mark Levine; Journal of Clinical Oncology 2018, 36, 2017-2023.

DOI: 10.1200/JCO.2018.78.8034

Copyright © 2018 American Society of Clinical Oncology

Lee, AY, Peterson EA. Blood 2013.

*Clinicians should consult pharmacist; †Drugs that inhibit P-GP or CYP3A4 can

increase DOAC levels; ‡Drugs that induce P-GP or CYP3A4 can lower DOAC levels.

Dabigatran Rivaroxaban Apixaban Edoxaban

Interaction

effect*P-glycoprotein

P-glycoprotein

CYP3A4

P-glycoprotein

CYP3A4P-glycoprotein

Increases

DOAC

plasma

levels†

Cyclosporine Cyclosporine Cyclosporine Cyclosporine

Tacrolimus Tacrolimus Tacrolimus Tacrolimus

Tamoxifen Tamoxifen Tamoxifen Tamoxifen

Lapatinib Lapatinib Lapatinib Lapatinib

Nilotinib Nilotinib Nilotinib Nilotinib

Sunitinib Sunitinib Sunitinib Sunitinib

Imatinib Imatinib

Reduces

DOAC

plasma

levels‡

Dexamethasone Dexamethasone Dexamethasone Dexamethasone

Doxorubicin Doxorubicin Doxorubicin Doxorubicin

Vinblastine Vinblastine Vinblastine Vinblastine

Drug interations

32

CYP3A4 = cytochrome P450 3A4; DOAC = direct oral anticoagulant

ISTH SSC DOACS

Khorana AA, Noble S, Lee AYY, Soff G, Meyer G, O'Connell C, Carrier M. Role of direct oral

anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the

SSC of the ISTH. J Thromb Haemost. 2018 Jun 29. doi: 10.1111/jth.1421933

1. We recommend individualized treatment regimens after shared

decision‐making with patients.

2. We suggest the use of specific DOACs for cancer patients with an

acute diagnosis of VTE, a low risk of bleeding, and no drug–drug

interactions with current systemic therapy. LMWHs constitute an

acceptable alternative.

3. We suggest the use of LMWHs for cancer patients with an acute

diagnosis of VTE and a high risk of bleeding, including patients

with luminal gastrointestinal cancers with an intact primary, patients

with cancers at risk of bleeding from the genitourinary tract, bladder,

or nephrostomy tubes, or patients with active gastrointestinal

mucosal abnormalities such as duodenal ulcers, gastritis,

esophagitis, or colitis.

Special circumstances

Notes: further details here (or delete)

Source: details here (or delete)

34

LMWH DOACs

Extremes of body weight

Commonly used (Not recommended)

ChemotherapyFew drug-drug interactions

Avoid in strong inducers/ inhibitors of p-GP or CYP3A4

Renal impairment Dose adjustment Dose adjustment

Thrombocytopenia Dose adjustment Dose adjustment

Notes: further details here (or delete)

Source: details here (or delete)

35

LMWH DOACs

Heparin induced thrombocytopenia

Contraindicated Not contraindicated

Upper GI/ urothelial cancers

Commonly used Increased bleeding risk: avoid

Needle phobia Not advised Acceptable

Liver disease Used with caution Used with caution

Renal impairment

Notes: further details here (or delete)

Source: details here (or delete)

36

Apixaban Edoxaban DabigatranRivaroxaban

Renal Clearance

27% 50% 80% 35%

CrCL <30ml/min

Use with caution

Dose reduction

Do not use Do not use

Tranexamic acid

37

TRANEXAMIC ACID

• Synthetic analogue of lysine

• Antifibrinolytic

• Binds to plasmin preventing binding to and breaking down of fibrin

38

39

40

41

Pulmonary

embolism

72 (0.7%) 71 (0.7%)

Deep vein

thrombosis

40 (0.4%) 41 (0.4%)

Anticoagulants and

Hospices

42

RHESO study

Tardy B, et al J Thromb Haemost. 2017 Mar;15(3):420-428

43

• 22 SPCUs, 1199 patients

• CRB 9.8% (95% CI 8.3-11.6)

Clinically relevant bleeding = Major Bleeding

+

Clinically Relevant Non Major Bleeding

44

Characteristics of patients

45

Risk factors for bleeding

Study to identify current practice in patients

with cancer associated thrombosis at the end

of life

• Setting: Patients attending a regional cancer associated

thrombosis clinic

• Follow up over two years

• Notes review of patients at end of life

• Demographics, when anticoagulation stopped, bleeding/

thrombotic complications,

• Place of death

.46 Noble S, Banerjee S, Pease N. Anticoagulation for Cancer Associated Thrombosis at the End of Life:

Review of a Case Series of 214 Patients. Palliative Medicine 32(1S) 47-48

Cancer diagnoses: n=450

27/09/2018

47

0

20

40

60

80

100

120

UrologicalColorectal

Upper GIBrain

BreastGynae

LungOther

UKP

• 44% metastatic

• 60% during chemotherapy (majority palliative)

• 59% known to specialist palliative care services

.

48

Patient spread at initial review

Noble S, Banerjee S, Pease N. Anticoagulation for Cancer Associated Thrombosis at the End of Life:

Review of a Case Series of 214 Patients. Palliative Medicine 32(1S) 47-48

Place of death

49

Home46%

Hospice27%

Acute Hospital25%

Community Hospital2%

When anticoagulation stopped

50

40

2923

108

0

20

40

60

80

100

120

Over 1 month 1 -4 weeks 7 days Until death

When anticoagulation stopped

51

40

2923

108

0

20

40

60

80

100

120

Over 1 month 1 -4 weeks 7 days Until death

7%

Thromboprophylaxis: Hospice Inpatient DVT

Detection Study (HIDDEN

• Setting: Patients admitted to UK hospice/ SPCU

• Compression ultrasonography on admission and weekly

• Screened for symptoms attributable to VTE

• Primary outcome

• Prevalence of radiological apparent DVT

• Secondary outcomes

• Attributable symptoms

• Incidence of VTE and symptoms

• Associated variables

• Survival

White C et al 2018 (under review)

.

52

Thromboprophylaxis: Hospice Inpatient DVT

Detection Study (HIDDEN

53

1390 screened

Declined participation 206

(30% of those eligible)

Recruited 343

(70% of those eligible)

841 (60.5%) ineligible

Likely to die within 5 days 397

Physical limitations to perform ultrasonography 85

Lacking capacity to consent/ no proxy 48

Consultee or patient too distressed 22

insufficient English/ Welsh 8

Outside of consent timeframe 245

Non-cancer 44

Demographics

White C et al 2018 (under review)

54

• Average AKPS =49

• Mean survival = 44 days

Results: 273 evaluable scans

)

55

• 92/273 (34%, CI 28% to 40%) showed DVT.

• Excluding early scans, 64/232 (28%, 22% to 34%)

• Associated with

• Previous thromboembolism,

• bedbound ≤12 weeks for any reason (p=0·003)

• lower limb oedema (p=0.009)

No significant attributable symptom burden differenceWhite C et al 2018 (under review)

No association with

56

• Serum albumin (p =0·430),

• Thromboprophylaxis (p = 0·173) and

No impact on survival (p = 0·473)

Take home messages

1. Clots are cool

2. DOACS if

• Low bleeding risk (beware GI/GU)

• No DDIs (CYP3A4/ PgP)

• Kidneys/liver OK

3. Consider stopping anticoagulants as death approaches

4. Tranexamic does not increase thrombotic risk

5. Do not give thromboprophylaxis if

• Poor performance status (KPS<50)

• Short prognosis

57