Cancer associated thrombosis

Transcription

1 Cancer associated thrombosis Simon Noble Marie Curie Professor of Supportive and Palliative Medicine Marie Curie Palliative Care Research Centre Cardiff University

2 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

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5 Schematic of the optical analyzer system by American Society of Hematology Valerie Tutwiler et al. Blood 2016;127:

6 Schematic of the optical analyzer system by American Society of Hematology Valerie Tutwiler et al. Blood 2016;127:

7 Schematic of the phase dynamics of blood clot contraction by American Society of Hematology Valerie Tutwiler et al. Blood 2016;127:

8 Schematic of the phase dynamics of blood clot contraction by American Society of Hematology Valerie Tutwiler et al. Blood 2016;127:

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10 Electron microscopy 10 Healthy blood Blood from patient with stage IV lung cancer

11 Clot stabilization and resorption 1. Initial stabilization: 5 days 2. Stable clot: 6 weeks 3. Resorption 4-12 weeks 11

12 Clot presentation DVT: 7-14 days PE: 21 days 12

13 13 DOACs

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

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16 The CLOT Trial Primary outcome: VTE recurrence Risk reduction = 52% HR 0.48 (95% CI 0.30, 0.77) log-rank p = NNT = 13 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):

17 LMWH vs warfarin meta analysis Florian Posch et at, Thrombosis Research 136 (2015) p. 017

18 Guideline recommendations Guideline recommendations: Guideline Long-term treatment LMWH or VKA ASCO LMWH At least 6 months ansm ISTH LMWH LMWH Treatment duration Standard 3 to 6 months then LMWH until cancer AOIMof treatment LMWHfor cancer-associated thrombosis is three to resolution six months LMWH DVT: 3 to 6 months; PE: 6 to 12 months NCCN (Grade A) In patients with ongoing active 3 to cancer, 6 months consideration then VKA or LMWH should until be INCa LMWH given to indefinite anticoagulation cancer resolution but decision should be made on a case by case basis, taking into 3 to consideration 6 months then VKA bleeding or LWMH risk until and ACCP LMWH patient preference. cancer resolution (Grade D) 3 to 6 months and beyond 6 months if LMWH well-tolerated 3 to 6 months then VKA or LMWH until cancer resolution DVT = deep vein thrombosis; LMWH = low molecular weight heparin; PE = pulmonary embolism; VKA = vitamin K antagonist 18

19 DOACs in the treatment of CAT Recurrent VTE Pooled incidence rates: 4.1% ( ) for DOACs 6.1% ( ) for VKAs [RR 0.66 ( )] Major bleeding or CR-NMB Recurrent VTE warfarin Lee A et al. 2003: 16% Meyer G et al % van der Hulle T et al. J Thromb Haemost CRNMB = clinically-relevant non-major bleeding 19

20 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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23 23 Primary end point

24 24 Recurrent VTE

25 25 Bleeding

26 26 Appendix: page 16/32

27 Appendix: page 16/32 GI cancers: 13.1% major bleeding Urothelial cancers 8% major bleeding 27

28 (VTE) recurrence within 6 months.

29 Select-D 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 29

30 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, DOI: /JCO Copyright 2018 American Society of Clinical Oncology

31 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, DOI: /JCO Copyright 2018 American Society of Clinical Oncology

32 Drug interations Interaction effect* Increases DOAC plasma levels Reduces DOAC plasma levels Dabigatran Rivaroxaban Apixaban Edoxaban P-glycoprotein P-glycoprotein P-glycoprotein CYP3A4 CYP3A4 P-glycoprotein 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 Dexamethasone Dexamethasone Dexamethasone Dexamethasone Doxorubicin Doxorubicin Doxorubicin Doxorubicin Vinblastine Vinblastine Vinblastine Vinblastine *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. CYP3A4 = cytochrome P450 3A4; DOAC = direct oral anticoagulant Lee, AY, Peterson EA. Blood

33 ISTH SSC DOACS 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. 33 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 Jun 29. doi: /jth.14219

34 Special circumstances LMWH DOACs Extremes of body weight Chemotherapy Commonly used Few drug-drug interactions (Not recommended) 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) 34

35 LMWH DOACs Heparin induced thrombocytopenia Contraindicated Not contraindicated Upper GI/ urothelial cancers Commonly used Increased bleeding risk: avoid Needle phobia Not advised Acceptable Notes: further details here (or delete) Source: details here (or delete) 35 Liver disease Used with caution Used with caution

36 Renal impairment Apixaban Edoxaban Dabigatran Rivaroxaban Renal Clearance 27% 50% 80% 35% CrCL <30ml/m in Notes: further details here (or delete) Source: details here (or delete) Use with caution Dose reduction Do not use Do not use 36

37 37 Tranexamic acid

38 TRANEXAMIC ACID Synthetic analogue of lysine Antifibrinolytic Binds to plasmin preventing binding to and breaking down of fibrin 38

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41 Pulmonary embolism 72 (0.7%) 71 (0.7%) Deep vein thrombosis 40 (0.4%) 41 (0.4%) 41

42 Anticoagulants and Hospices 42

43 RHESO study 22 SPCUs, 1199 patients CRB 9.8% (95% CI ) Clinically relevant bleeding = Major Bleeding + Clinically Relevant Non Major Bleeding 43 Tardy B, et al J Thromb Haemost Mar;15(3):

44 44 Characteristics of patients

45 45 Risk factors for bleeding

46 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

47 Cancer diagnoses: n= /09/ Urological Colorectal Upper GI Brain Breast Gynae Lung Other UKP

48 Patient spread at initial review 44% metastatic 60% during chemotherapy (majority palliative) 59% known to specialist palliative care services. 48 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

49 Place of death Community Hospital 2% Acute Hospital 25% Home 46% Hospice 27% 49

50 When anticoagulation stopped Over 1 month 1-4 weeks 7 days Until death

51 When anticoagulation stopped % Over 1 month 1-4 weeks 7 days Until death

52 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 52 Secondary outcomes Attributable symptoms Incidence of VTE and symptoms Associated variables Survival White C et al 2018 (under review)

53 Thromboprophylaxis: Hospice Inpatient DVT Detection Study (HIDDEN 1390 screened 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 Declined participation 206 (30% of those eligible) Recruited 343 (70% of those eligible)

54 Demographics Average AKPS =49 Mean survival = 44 days White C et al 2018 (under review) 54

55 Results: 273 evaluable scans 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 difference White C et al 2018 (under review) 55

56 No association with Serum albumin (p =0 430), Thromboprophylaxis (p = 0 173) and No impact on survival (p = 0 473) 56

57 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

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