cancer associated thrombosis - guildford advanced courses · 2020. 7. 28. · isth ssc doacs...
TRANSCRIPT
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Cancer associated thrombosis
Simon Noble
Marie Curie Professor of Supportive and Palliative Medicine
Marie Curie Palliative Care Research Centre
Cardiff University
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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
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)
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Schematic of the optical analyzer system.
Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology
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Schematic of the optical analyzer system.
Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology
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Schematic of the phase dynamics of blood clot contraction.
Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology
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Schematic of the phase dynamics of blood clot contraction.
Valerie Tutwiler et al. Blood 2016;127:149-159©2016 by American Society of Hematology
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Electron microscopy
Healthy blood Blood from patient with stage IV lung cancer10
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Clot stabilization and resorption
1. Initial stabilization: 5 days
2. Stable clot: 6 weeks
3. Resorption 4- 12 weeks
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Clot presentation
• DVT: 7-14 days
• PE: 21 days
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DOACs
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DOAC Pharmacology
14Adapted from: Heidbuchel H et al. Europace 2013; U.S., Canadian Prescribing Information CrCl = creatinine clearance
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The CLOT TrialPrimary outcome: VTE recurrence
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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
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LMWH vs warfarin meta analysis
p. 017
Florian Posch et at, Thrombosis Research 136 (2015) 582–589
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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
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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
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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%
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Primary end point
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Recurrent VTE
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Bleeding
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Appendix: page 16/32
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Appendix: page 16/32
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GI cancers: 13.1% major bleeding
Urothelial cancers 8% major bleeding
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(VTE) recurrence within 6 months.
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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
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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
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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
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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
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CYP3A4 = cytochrome P450 3A4; DOAC = direct oral anticoagulant
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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.
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Special circumstances
Notes: further details here (or delete)
Source: details here (or delete)
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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
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Notes: further details here (or delete)
Source: details here (or delete)
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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
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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
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Tranexamic acid
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TRANEXAMIC ACID
• Synthetic analogue of lysine
• Antifibrinolytic
• Binds to plasmin preventing binding to and breaking down of fibrin
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Pulmonary
embolism
72 (0.7%) 71 (0.7%)
Deep vein
thrombosis
40 (0.4%) 41 (0.4%)
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Anticoagulants and
Hospices
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RHESO study
Tardy B, et al J Thromb Haemost. 2017 Mar;15(3):420-428
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• 22 SPCUs, 1199 patients
• CRB 9.8% (95% CI 8.3-11.6)
Clinically relevant bleeding = Major Bleeding
+
Clinically Relevant Non Major Bleeding
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Characteristics of patients
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Risk factors for bleeding
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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
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Cancer diagnoses: n=450
27/09/2018
47
0
20
40
60
80
100
120
UrologicalColorectal
Upper GIBrain
BreastGynae
LungOther
UKP
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• 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
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Place of death
49
Home46%
Hospice27%
Acute Hospital25%
Community Hospital2%
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When anticoagulation stopped
50
40
2923
108
0
20
40
60
80
100
120
Over 1 month 1 -4 weeks 7 days Until death
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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%
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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)
.
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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
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Demographics
White C et al 2018 (under review)
54
• Average AKPS =49
• Mean survival = 44 days
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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)
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No association with
56
• Serum albumin (p =0·430),
• Thromboprophylaxis (p = 0·173) and
No impact on survival (p = 0·473)
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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
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