Update on thrombosis 13/07/2017. To focus on

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1 Update on thrombosis Oxford Advanced Course 2017 Simon Noble Clinical Professor Palliative and Supportive Medicine Cardiff University Wales, UK To focus on Changing thrombogenicity of cancer What is the current evidence Where do DOACs fit? Patent Experience Treatment of incidental PE 3 1

2 The coagulation pathway Initiation X TF VIIa IX Propagation Xa IXa II Prothrombin Inactive factor Active factor Transformation Catalysis IIa Clot formation Fibrinogen Fibrin The coagulation pathway Initiation X TF VIIa IX Propagation Xa IXa II Prothrombin Inactive factor Active factor Transformation Catalysis Thrombin IIa Clot formation Fibrinogen Fibrin The coagulation pathway LIQUID Initiation X TF VIIa IX Propagation Xa IXa GEL POINT II Prothrombin Inactive factor Active factor Transformation Catalysis Thrombin IIa SOLID Clot formation Fibrinogen Fibrin 2

3 The New Biomarker Fractal Dimension, a measure of clot structure Collaborative work between the school of medicine and the school of engineering have been trying to solve this problem, by developing a global marker of haemostasis that quantifies clot structure This new marker is called fractal dimension Gel point and fractal dimension Applying numerous different Oscillating Forces at different frequencies. A frequency independent point is obtained highlighting the first point the blood becomes solid The Gel Point measurement provides the user with several important parameters: T GP gel time - the time it takes to form the clot D f fractal dimension a quantification of the microstructure of the clot G` - elasticity a measure of the elastic response of the clot as it forms G`` - viscosity (not shown) a measure of the viscous response of the material Fractal Dimension a New Biomarker Fractal dimension (df) provides a quantitative description of complex structures 3

4 Lung cancer Non-cancer Healthy vs Cancer fractal analysis (d f ) of incipient clot formation in vitro, predicts the ultimate structure of mature clot d f of the incipient blood clot acts as a template for the mature clot structure In healthy patients normal 1.74 (±0.07) Current work to evaluate change in d f with chemotherapy and radiologically assessed VTE 12 4

5 Hematological Lung Gastrointestinal Breast Distant metastases 0 to 3 months 3 to 12 months 1 to 3 years 5 to 10 years > 15 years Adjusted odds ratio 13/07/2017 Virchow s triad Circulatory stasis Endothelial injury Hypercoagulable state Inflammatory Cytokines (TNFα, IL-1) and VEGF EXTRINSIC FACTORS Therapies Chemotherapy Anti-angiogenic Hormonal CANCER THROMBOSIS Surgery Central access Procoagulant molecules Tissue factor and others PLATELETS Immobility Local stasis Effect of Malignancy on Risk of Venous Thromboembolism (VTE) Population-based case-control (MEGA) study N = 3220 consecutive patients with 1 st VTE vs. N = 2131 control subjects CA patients = 7x OR for VTE vs. non-ca patients Type of cancer Time since cancer diagnosis Silver In: The Hematologist - modified from Blom et al. JAMA 2005;293:

6 Incidence of symptomatic CAT according to the cancer type and stage Wun T, White RH. Best Pract Res Clin Haematol. 2009;22: Treatment impact on VTE Incidence In Various Tumors Oncology Setting Breast cancer (Stage I & II) w/o further treatment VTE Incidence 0.2% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma 3-5% Renal cell carcinoma 43% Solid tumors (anti-vegf + chemo) 47% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 Treatment impact on VTE Incidence In Various Tumors Oncology Setting Breast cancer (Stage I & II) w/o further treatment VTE Incidence 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma 3-5% Renal cell carcinoma 43% Solid tumors (anti-vegf + chemo) 47% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 6

7 Treatment impact on VTE Incidence In Various Tumors Oncology Setting Breast cancer (Stage I & II) w/o further treatment VTE Incidence 0.2% Breast cancer (Stage I & II) w/ chemo 2% Breast cancer (Stage IV) w/ chemo 8% Advanced cancer (1-year survival=12%) 9% High-grade glioma 26% Multiple myeloma 3-5% Multiple myeloma (thalidomide + chemo) 28% Renal cell carcinoma 43% Solid tumors (anti-vegf + chemo) 47% Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17 TREATMENT OF VTE 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):

8 LMWH vswarfarin meta analysis Florian Posch et at, Thrombosis Research 136 (2015) p. 022 Guideline recommendations Guideline recommendations: Long-term Guideline treatment Treatment duration Standard AOIMof treatment LMWHfor cancer-associated 3 to 6 months then LMWH thrombosis until cancer is resolution three to six months NCCN LMWH LMWH or VKA DVT: 3 to 6 months; PE: 6 to 12 months ASCO LMWH At least 6 months (Grade A) 3 to 6 months then VKA or LMWH until cancer INCa LMWH resolution In patients with ongoing active cancer, consideration should be 3 to 6 months then VKA or LWMH until cancer given to ACCP indefinite LMWH anticoagulation resolutionbut decision should be made on a case by case basis, taking into 3 to consideration 6 months and beyond bleeding 6 months risk if LMWH and ansm LMWH patient preference. well-tolerated 3 to 6 months then VKA or LMWH until cancer (Grade D) ISTH LMWH resolution DVT = deep vein thrombosis; LMWH = low molecular weight heparin; PE = pulmonary embolism; VKA = vitamin K antagonist 23 Noble et al BMJ Open

9 Scope of patients Urological Colorectal Upper GI Brain Breast Gynae Lung Other UKP 25 Patient spread 44% metastatic 60% during chemotherapy (majority palliative) 59% known to specialist palliative care services 26 Need for specialist input 334 CLOT regime 124 (27%) non CLOT o Bleeding/ risk of bleeding o Thrombus progression/ recurrence o Renal impairment (EGFR<25) o Intolerant injections o Extremes of bodyweight 27 9

10 Carrier M, Khorana AA, Zwicker JI, Noble S, Lee AYY Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. Journal Thromb and Haem 2013 September; 11(9) Understanding cancer associated thrombosis You never really understand a person until you consider things from his point of view... Until you climb inside of his skin and walk around in it.. To Kill a Mockingbird by Harper Lee Noble S, et al Patient Preference and Adherence. 2015;9:

11 [ ] but they don t tell you you re gonna get clots after chemo, that s the one thing they haven t, they never said but we, we just put it down to, it s just my breathing [ ] just that one item of information that we weren t aware of. [VCC07] [ ] but I didn t realize that that was what causing it like, obviously a clot like you know, I didn t have any pain or anything, I just thought I was getting short of breath anyway like, do you know what I mean, because of the chemo and everything. [VCC04] [ ] in the beginning, it s just in and out sort of thing innit, take this, take that, don t get a lot of information. [RG05] [ ] having the cancer and then the thrombosis on top of it, erm, not knowing how bad it was when I went in, I know I was in terrific pain with my chest and that erm, it was frightening to be honest. [VCC01]] Nobody really explained, [ ]So you don t feel as though erm, you know, I think if it was a little bit more relaxed er, they probably would ve got somebody you know, from a department to come and explain it more. [VCC05] [ ] it s only when you start reading up about it, you sort of realize just how serious erm, you know, sort of blood clots are [ ] I was very lucky that you know, it was a fatal, you know attack, so er which is a little bit erm, scary. [VCC05]] You want to try to recover and get back to some sort of um, you know, some sort of normality. [RG06] [ ] they give me the option of doing em myself, that s when I decided to do em myself. And now I do em myself, I do em, you know, it s to suit me. So I do em in the morning. And the day s my own then like, do you know what I mean like? [VCC05] Right we sit here and I say I ve got to have me jab. I go in the bedroom [ ] shut the door, coz I got to pull this up, pull that down. It s only a little thing like that. [VCC01] 11

12 International programme PELICANADA : data analysis PELICANOS: in write up LE PÉLICAN: data collection ongoing PELICANZ: data collection completed PELICAN SINGAPORE: data collection ongoing Can we use DOACs yet? DOAC Pharmacology Adapted from: Heidbuchel H et al. Europace 2013; U.S., Canadian Prescribing Information CrCl = creatinine clearance 36 12

13 Oral direct IIa and Xa inhibitors dabigatran rivaroxaban apixaban Target IIa Xa Xa t½ h 9 h 12 h Dose / frequency Renal clearance 150mg bd 110mg bd 20mg od 5mg bd 85% 33% 27% Peak 2 h 2-4 h 2-4 h Cancer patients in DOAC trials of VTE treatment RCT Total studied population Patients with cancer EINSTEIN Acute DVT Rivaroxaban = 1731 Rivaroxaban = 6.8% EINSTEIN DVT extension Enox/VKA= 1718 Rivaroxaban= 602 placebo= 594 Enox/VKA = 5.2% Rivaroxaban = 4.5% Placebo = 4.4% EINSTEIN-PE Rivaroxaban= 2419 Enox/VKA= 2413 RECOVER Dabigatran = 1274 VKA = 1265 Rivaroxaban = 4.7% Enox/VKA= 4.5% Dabigatran = 5% VKA = 4.5% 38 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 39 13

14 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% Drug-Drug Interactions with DOACs Chemotherapeutic agents and immunosuppressants Interaction effect* Increases DOAC plasma levels Reduces DOAC plasma levels Dabigatran Rivaroxaban Apixaban P-glycoprotein P-glycoprotein CYP3A4 P-glycoprotein CYP3A4 Cyclosporine Cyclosporine Cyclosporine Tacrolimus Tacrolimus Tacrolimus Tamoxifen Tamoxifen Tamoxifen Lapatinib Lapatinib Lapatinib Nilotinib Nilotinib Nilotinib Sunitinib Sunitinib Sunitinib Imatinib Imatinib Dexamethasone Dexamethasone Dexamethasone Doxorubicin Doxorubicin Doxorubicin 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 Around one third of patients are currently treated with oral medication for their VTE Administration of medication (%) Base: all respondents Multiple answers Total n = 100 n = 50 n = 50 Tablet Injection under the skin * Other * Significant difference to Germany Noble S, et al Haematologica 2015 Aug 20. pii: haematol

15 Interference with cancer treatment is the most important attribute to patients, followed by efficacy of VTE therapy Relative importance of attributes* - Total 1% 2% 24% Efficacy Risk of minor bleeding 39% 2% Risk of major bleeding Administration form 13% 19% Interference with cancer treatment Frequency of administration Monitoring through blood test n = 100 * Impact / weight of each attribute on the overall preference / choice behavior Noble S, et al Haematologica 2015 Aug 20. pii: haematol When asked directly, patients allocate almost the same importance to efficacy and interference with cancer treatment Direct importance of characteristics for treatment decision (means) Base: all respondents Multiple answers Total n = 100 n = 50 n = 50 Please distribute 100 points in total to the features according to their importance 32 38* 27 Efficacy Risk of minor bleeding Risk of major bleeding Administration form Interference with cancer treatment Frequency of administration Monitoring through blood tests 5 7* * Significant difference to UK / Germany * 6* 6* Noble S, et al Haematologica 2015 Aug 20. pii: haematol What may the future hold for choosing anticoagulation for cancer-associated thrombosis? Current guidelines recommend LMWH for the treatment of patients with cancer and VTE. There are four active phase III trials of direct Xa inhibitors vs. LMWH that should be completed in the next 2 3 years. Drug Comparator Study design elements 1 Endpoint Edoxaban 1,2 Dalteparin Outcomes measured after both 6 months and 12 months of therapy Rivaroxaban 3 Dalteparin After randomization of active therapy for 6 months, patients are randomized to rivaroxaban vs. placebo for a further 6 months Composite of recurrent VTE and major bleeding Recurrent VTE Rivaroxaban 4 Any LMWH Randomized for 3 months Patient-reported treatment satisfaction Apixaban 5 Dalteparin Randomized for 6 months Safety 1. Clinical.trials.gov NCT ; 2. van Es N et al. Thromb Haemost 2015; 3. IRCTN Registry ISRCTN ; 4. Clinicaltrials.gov NCT ; 5. Clinicaltrials.gov NCT LMWH = low molecular weight heparin; VTE venous thromboembolism

16 What may the future hold for choosing anticoagulation for cancer-associated thrombosis? Current guidelines recommend LMWH for the treatment of patients with cancer and VTE. There are four active phase III trials of direct Xa inhibitors vs. LMWH that should be completed in the next 2 3 years. Drug Comparator Study design elements 1 Endpoint Edoxaban 1,2 Dalteparin Outcomes measured after both 6 months and 12 months of therapy Rivaroxaban 3 Dalteparin After randomization of active therapy for 6 months, patients are randomized to rivaroxaban vs. placebo for a further 6 months Composite of recurrent VTE and major bleeding Recurrent VTE Rivaroxaban 4 Any LMWH Randomized for 3 months Patient-reported treatment satisfaction Apixaban 5 Dalteparin Randomized for 6 months Safety 1. Clinical.trials.gov NCT ; 2. van Es N et al. Thromb Haemost 2015; 3. IRCTN Registry ISRCTN ; 4. Clinicaltrials.gov NCT ; 5. Clinicaltrials.gov NCT LMWH = low molecular weight heparin; VTE venous thromboembolism. 46 Incidental/ Unsuspected PE Unsuspected PE and survival in cancer patients O'Connell et al. J Thromb Haemost 2011; 9:

17 . Saddle PE Saddle PE Multiple PE 17

18 Saddle PE Multiple PE Isolated segmental PE Unsuspected PE and survival in cancer patients O'Connell et al. J Thromb Haemost 2011; 9: Unsuspected PE and survival in cancer patients O'Connell et al. J Thromb Haemost 2011; 9:

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