1. Venous thromboembolism in the palliative care setting: what are the challenges? Dr Simon Noble Cardiff University and Royal Gwent Hospital

2. Evidence based medicine Where the evidence is lacking

3. To cover Is cancer associated VTE different? Can the evidence be applied to the palliative population? Heterogeneity of palliative population Attitudinal challenges Outcome measures How it fits into health policy Finding the answers

4. How does the thrombogenicity of cancer patients differ to from non cancer patients?

5. Virchow’s triad Circulatory stasis Endothelial Hypercoagulable injury state

6. Mechanism of tumour mediated hypercoaguable state Malignanttumour Tumour cell surface tissue factor Macrophage Tissue factor Other tumour-derived procoagulants Tumour mediated platelet activation and accumulation Tumour induced endothelial cell activation Expression of cell surface phospholipids that support coagulation activation

7. Relative risk for VTE by Cancer Type Type of Cancer VTE (n)Cancer (n)Relative Risk (95% CI) Breast 469186 273 0.44 (0.40-0.48) Oesophagus 6414 472 0.76 (0.58-0.97) Prostate 1230218 743 0.98(0.93-1.04) Hospitalised non- cancer patient 1.00 Lung 1504232 764 1.13 (1.07-1.19) Colon 1320168 832 1.36 (1.29-1.44) Pancreas 48841 551 2.05 (1.87-2.24) Ovary 32726 406 2.16 (1.93-2.41) Brain 18413 529 2.37 (2.04-2.74)

8. Prothrombotic state Therapeutic interventions -Chemotherapy -Surgery -Central venous access -Brachytherapy

9. Chemotherapy Pyrimidine analogues –Reduced protein C –Increased fibrinopeptide A –Endothelial damage Platinum based regimes –Increased TF expression on monocytes –Increased platelet activation –Endothelial damage

10. How does cancer associated thrombosis differ?

11. DVT/PE only Number of days Probability of readmission 0.05 0.00 0.10 0.15 0.20 0.25 4080120160 0 Nonmalignant disease Malignant disease DVT/PE and malignant disease Levitan et al (1999) The risk of recurrence of VTE is increased in cancer patients Probability of hospital readmission with DVT/PE within 183 days of initial hospital admission

12. DVT/PE only Nonmalignant disease Malignant disease DVT/PE and malignant disease Probability of death 0.20 0.00 0.40 0.60 0.80 1.00 Number of days 4080120160 0 Levitan et al (1999) Concurrent VTE and cancer increases the risk of death Probability of death within 183 days of initial hospital admission

13. Long term anticoagulation Cancer patients at high risk of recurrent thromboses Higher risk of bleeding (28% vs 8%) 1 Bleeding risk increases with disease progression 2 Poorer control of INR despite increased INR monitoring 3 1. Hutten et al (1997) 2. Noble et al (2008) 3. Bona et al (1997)

14. Incidence increases with advancing disease Incidence of symptomatic VTE in cancer patients VTE is 15 % VTE evident in 30-50% of cancer post mortems Asymptomatic DVT present in 50% of hospice inpatients.

15. What the evidence covers Metastatic disease Performance status 0-2 Estimated prognosis > 3 months Platelet count >75,000 mm 3 Weight > 40kg No active bleeding

17. THROMBOGENICITY PERFORMANCE STATUS BLEEDING RISK PROGNOSIS METASTATIC SPREAD THERAPEUTIC INTERVENTION CO-MORBIDITIES QUALITY OF LIFE

18. Attitudinal issues… We don’t see many DVTs or PEs! Hmmm.. A large PE is a nice way to go…

19. Attitudinal issues… We don’t see many DVTs or PEs!

20. Attitudinal issues… We don’t see many DVTs or PEs! At least not in all our breathless patients with swollen legs…

21. Post mortem study 92 patients where PE identified as cause of death 27 (30%) died within 10 minutes of symptoms 9 (10%) had no symptoms Havig (1977)

22. 60% of patients: “gradual deterioration dominated by dyspnoea, tachycardia and fever” Correct diagnosis of PE in 10% of cases Approximately 2 hours to die Treated with diuretics, digoxin, antibiotics

23. Evidence not appropriate in our patient group Does the efficacy of LMWH in general medical/ healthier cancer patients transfer to palliative patients? Evidence base of –Analgesic ladder –EAPC constipation guidelines –APM BcP recommendations

24. Outcome measures not applicable Radiologically apparent VTE Major bleeding –Death –Critical site –Requiring transfusion –Requiring hospitalisation Minor bleeding –All other bleeds

25. Outcome measures not applicable Radiological apparent VTE Major bleeding –Death –Critical site –Requiring transfusion –Requiring hospitalisation Minor bleeding –All other bleeds Symptomatic VTE Quality of life Clinically relevant bleeding events –Haemoptysis –Epistaxis –Bruising

26. DoH. Letter from the CMO, 24 March 2010. Available at: www.dh.gov.uk NICE clinical guideline 92. Venous thromboembolism, 2010. Available at: www.nice.org.uk DoH. Using the CQUIN payment framework – an addendum to the 2008 policy guidance for 2010/11. Available at: www.dh.gov.uk Patient safety alert 18. Actions that can make anticoagulant therapy safer. 2007

27. NICE Guidelines 2010 Chapter 28: Palliative Care Consider thromboprophylaxis for people admitted with potentially reversible pathology Do not offer thromboprophylaxis to those admitted for terminal care or on ICP Regularly review decisions

28. Heterogeneity of our hospice population 52% discharge rate Earlier involvement in patient journey Not solely terminal care Reversible causes of deterioration

29. (NICE 2010)

30. Medical thromboprophylaxis

31. (Aslett M Pan Birmingham Guidelines 2008) Available www.palliativedrugs.com

32. Majority of palliative care patients admitted through medical take Will be receiving thromboprophylaxis by default

33. Research needed If we don’t find the answers, the majority of our patient group will receive thromboprophylaxis by default. Need to have the answer one way or another

34. What needs doing True prevalence and natural history of VTE in the palliative patient. Symptom burden of VTE and impact on quality of life A development of outcome measures that may be meaningful to the hospice setting –VTE measures –Symptoms –Complications Consensus of what clinical/ symptomatic outcome difference would be required to change thromboprophylaxis.

35. What needs doing True prevalence and natural history of VTE in the palliative patient. Symptom burden of VTE and impact on quality of life A development of outcome measures that may be meaningful to the hospice setting –VTE measures –Symptoms –Complications Consensus of what clinical/ symptomatic outcome difference would be required to change thromboprophylaxis.

36. What needs doing True prevalence and natural history of VTE in the hospice patient. Symptom burden of VTE and impact on quality of life A development of outcome measures that may be meaningful to the hospice setting –VTE measures –Symptoms –Complications Consensus of what clinical/ symptomatic outcome difference would be required to change thromboprophylaxis.

37. What needs doing True prevalence and natural history of VTE in the hospice patient. Symptom burden of VTE and impact on quality of life A development of outcome measures that may be meaningful to the hospice setting –VTE measures –Symptoms –Complications Consensus of what clinical/ symptomatic outcome difference would be required to change thromboprophylaxis.

38. Prophylactic anti-coagulation in cancer palliative care: a prospective randomised study 20 patients 1:1 randomisation Nandroparin vs nil Insufficient recruitment to conclude Weber C (2008)

39. That’s where you come in… www.tradalliance.org

40. What is needed Network of palliative care teams willing to recruit to studies 1-2 patients per year Increase knowledge base Experience of research Improve patient care

41. What are we asking of you? Be part of the alliance Europe wide strategy Register an interest so you can share your experiences and contribute to the work

42. TRAD ALLIANCE www.tradalliance.org

43. Thank you