1. ST CATHERINE’S HOSPICE The management of venous thromboembolism when the evidence is lacking M Johnson

2. ST CATHERINE’S HOSPICE Overview What evidence do we have? What are the gaps? Pragmatism

3. ST CATHERINE’S HOSPICE What evidence do we have? 4 randomised controlled trials All open label 3 - randomisation method and power calculation method clearly stated 2 – achieved power 1 – feasibility study

4. ST CATHERINE’S HOSPICE Meyer et al Arch Intern Med 2002 D – randomised, open labelled multicentre parallel group P – patients with cancer and VTE I – 1.5mg/kg enoxaparin C – 4 days enoxaparin/warfarin O – combined outcome major bleeding or recurrent VTE within 3 months  147 randomised patients (240 required for power)

5. ST CATHERINE’S HOSPICE Lee AYY et al NEJM 2003 D – randomised, open labelled multicentre parallel group P – patients with cancer and VTE 676 randomised patients. 85% power achieved. I – 200iu/kg dalteparin for1 month; 150iu/kg for 5 months od subcut C – 5-7 days dalteparin/coumarin O – cumulative incidence of objectively measured symptomatic, recurrent VTE within 6 months

6. ST CATHERINE’S HOSPICE Hull et al Am J Med 2006 D – randomised, open labelled multicentre parallel group P – patients with cancer and VTE o 200 randomised patients; power achieved I – 175iu/kg tinzaparine C – UFH 6days/warfarin O – objectively measured symptomatic, recurrent VTE or death at 3 months

7. ST CATHERINE’S HOSPICE Deitcher et al Clin and Applied Thrombosis /Haemostasis. 2006 D – randomised, open labelled parallel group P – patients with cancer and VTE 91 patients randomised between the three groups I – 1mg/kg enoxaparin bd 5 days – then od 175 days OR od 1.5mg/kg 175 days C – 1mg/kg enoxaparin bd 5 days/warfarin O – feasibility of recruitment and compliance with long term daily injections

8. ST CATHERINE’S HOSPICE Meta-analysis: Noble et al. Lancet Oncol 2008

9. ST CATHERINE’S HOSPICE Meta-analysis: Noble et al. Lancet Oncol 2008

10. ST CATHERINE’S HOSPICE What’s the difficulty? About half patients had metastatic disease (42 – 67%) but… All studies excluded patients with ECOG >2, or prognosis < 3 months Lee et al: 1/3 potentially eligible patients screened excluded due to poor performance status, weight <40kg, recent bleeds or high risk of bleeding, renal failure or thrombocytopenia.

11. ST CATHERINE’S HOSPICE Evidence that we should worry about the excluded Prandoni et al. studied 842 consecutive patients (181 with cancer) with confirmed VTE referred to a single thrombosis unit initial UFH or LMWH then warfarin for at least 3 months categorised as having extensive, moderately extensive and less extensive disease 12 months, cumulative incidence recurrent VTE higher in cancer vs non-cancer patients (21% vs. 7%; HR; 3.2) 12 months, cumulative incidence major bleeding (12% vs. 5%; hazard ratio 2.2)  Prandoni et al Blood 2002

12. ST CATHERINE’S HOSPICE The effect of advanced disease Recurrent VTE: o Extensive; HR 4.6 o moderately extensive; HR 5.3 o less extensive disease; HR 1.9 Bleeding: o Extensive; HR 4.8 o moderately extensive; HR 2.5 o less extensive disease; HR 0.5

13. ST CATHERINE’S HOSPICE 87 hospice in patients raised levels of o fibrinogen (66% patients), mean level 4.38 (SD1.5) g/dl {NR 1.7 –3.5g/dl} o factor VIII:C (43% patients), mean ; 195.1(SD 85) iu/dl {46 – 189 iu/dl} o fragment 1+2 (71% patients) median level 1.9 (95% CI 1.5-2.4) nmol/l {NR 0.5 – 1.31nmol/l} o TAT levels (89% patients). Median 10.3 (95% CI. 8.7- 11.5) microg/l. {NR 1- 4.1 microg/l) –Johnson et al Clinical and Laboratory Haematology. 1999:

14. ST CATHERINE’S HOSPICE Overview What evidence do we have? What are the gaps? Pragmatism

15. ST CATHERINE’S HOSPICE The patient who… Continues to clot whilst on therapeutic doses of LMWH Is at risk of bleeding: o Thrombocytopenia o Brain metastasis o GI/GU tumours o Requires operative intervention Is poor performance status Is in renal failure

16. ST CATHERINE’S HOSPICE Overview What evidence do we have? What are the gaps? Pragmatism

17. ST CATHERINE’S HOSPICE General principles 1 In advanced disease avoid warfarin o Poor control of INR o Variable oral absorption o Poor nutritional state o Multiple and variable medications o Poor liver function o Underlying pathophysiology of compensated DIC, which worsens with worsening extent of disease

18. ST CATHERINE’S HOSPICE General principles 2 If the cancer remains active, continue anticoagulation (may make the decision regarding full or reduced dose) Discuss management options with the patient and don’t make assumptions on their behalf

19. ST CATHERINE’S HOSPICE The patient who continues to clot Small case series – LMWH effective if continue to clot on warfarin Luk et al Am J Med 2001 No data if already on LMWH Options o Change to bd regime o Increase the dose o Change to unfractionated heparin

20. ST CATHERINE’S HOSPICE Increase dose of LMWH Increase dose o Increase dose by empiric 25%, reassess in 5 – 7 days and increase again if no improvement in symptoms o Monitor with anti-factor Xa levels 3 hours post injection at this point to guide further dose increase (some people need higher than weight adjusted dose to achieve therapeutic levels ? Greater non-scpefivic bdinign in those with aggressive disease if there are high levels of acute phase reactiants)  Lee AYY VTE in Advanced Disease: a clinical guide. OUP 2008

21. ST CATHERINE’S HOSPICE Continued clotting Insertion IVC filter o Indications, efficacy, and safety poorly studied  RCT with proximal DVT: with anticoagulation reduces PE compared with ac alone Decousus et al NEJM 1998  But 2 year FU – more DVT recurrence; 20.8% vs 11.6% in filter arm  Only retrospective studies or anecdotal experience in oncology patients No role if patients an tolerate anticoagulant therapy Fatal PE can occur from thrombus in the vena cava proximal to the filter

22. ST CATHERINE’S HOSPICE The patient who is bleeding No published evidence to guide management Usually a contraindication, but minor bleeding should not be an absolute contraindication because the converse risk is fatal PE or at least significant morbidity from VTE Try and stop bleeding If site is where will be easily seen and monitored and not likely to be life-threatening e.g epistaxis, give full dose LMWH and monitor closely

23. ST CATHERINE’S HOSPICE The patient who is bleeding If bleeding is from tumour-invaded mucosal surface more caution needed Start with prophylactic dose If bleeding severity does not worsen and Hb stable then cautiously increase dose If active bleed/dangerous site (upper GI/intracranial) – not for anticoagulation IVC filter if proximal DVT If bleeding is likely to be temporary, put in retrievable filter

24. ST CATHERINE’S HOSPICE Bleeding whilst on LMWH Assess extent and site of blood loss Reassurance and close monitoring whilst readjusting dose may be appropriate Arrange treatment to treat bleeding if possible e.g. radiotherapy Check weight adjusted dose is still correct – cachectic patients may need the dose readjusting according to new body weight Bleeding does not always require cessation of LMWH

25. ST CATHERINE’S HOSPICE What about thrombocytopenia? Monreal et al J Thromb Haemost. 2004 D: prospective observational cohort study P: 203 patients with metastatic cancer I: 200iu/kg 1 week followed by 10,000u dalteparin 3 months: {platelet count <50 x10 9 /l, dose 5,000 IU; <10x 10 9 /l, dose 2,500 IU} O: bleeding, recurrent VTE

26. ST CATHERINE’S HOSPICE Results 18 (9%) patients developed recurrent VTE, which included eight PE, fatal in two. 11(5%) patients experienced a major bleed (gastro- intestinal (5), haematuria (2), haematoma (2), brain (1) and wound (1)). 6 fatal bleeds; 3 patients were in the dying phase and 2 had serum creatinine levels three x upper limit NR. 16 (8%) patients minor bleeding (haematuria (7), epistaxis (5), other (4)). Bleeding or recurrent VTE rates were not higher in patients with liver or brain metastases

27. ST CATHERINE’S HOSPICE Option of therapeutic dose? Anecdotal experience using therapeutic dose of LMWH in patients with counts > 50 x 10 9 /l without incidence of serious bleeding Shouldn’t bleed even if lower counts unless source of bleed – so weigh up risk However below 20 x 10 9 /l most clinicians would not recommend without platelet transfusion first! In this case suggest platelet support to allow full dose LMWH for a month, then reduce dose of LMWH as per Monreal regime Such low dose has been used for prophylaxis in patients undergoing allogeneic BMT

28. ST CATHERINE’S HOSPICE Renal failure Either avoid LMWH or monitor anti-factor Xa activity in end stage renal failure as it will accumulate. Unfractionated heparin should be used If IV route is difficult, 12 hourly subcutaneous injections with APPT-R checked 4 – 6 hours post dose and titrated till target range achieved Platelet counts every other day o Weinkove and Hunt. VTE in Advanced Disease: a clinical guide. OUP 2008

29. ST CATHERINE’S HOSPICE Other indications for UFH Occasionally patients may need short term UFH o very high risk of clotting going for surgical procedure and don’t want to risk a long time without anticoagulation VTE resistant to LMWH because of tumour driven direct thrombin activation which will bypass factor Xa inhibiting activity Possible role here for newer oral thrombin inhibitors? Concern about an increased risk of bleeding

30. ST CATHERINE’S HOSPICE Brain metastases Evidence suggests that carefully monitored anticoagulation is safe Monreal’s study with fixed reduced dose appeared safe But small studies None specifically looked at renal or melanoma Common sense says avoid anticoagulation in vascular tumour types Prandoni’s principle that in general risk of bleeding increases with extent of disease

31. ST CATHERINE’S HOSPICE Poor performance status Palliation of symptoms is primary goal Withholding anticoagulation may be the optimal approach Never make assumptions, even in the most sick patient, they may have a goal that makes another week very important However no evidence a/c improves survival at this stage High risk of bleeding, high risk of clotting – whatever you do

32. ST CATHERINE’S HOSPICE Miss B 68 year old single lady with advanced endometrial carcinoma Mild but continuous bleeding PV 3 month worsening, progressive breathlessness V/Q scan – multiple pulmonary emboli Choices: LWMH/warfarin/filter or supportive care only

33. ST CATHERINE’S HOSPICE Best practice Possible outcomes of management: o Bleeding gets worse o Major bleed o Fatal bleed o Recurrent VTE o Fatal PE o Symptoms resolve “best practice” – trial LMWH

34. ST CATHERINE’S HOSPICE Best practice vs patient acceptable Possible outcomes of management: o Bleeding gets worse o Major bleed o Fatal bleed o Recurrent VTE o Fatal PE o Symptoms resolve “best practice” – trial LMWH Any increased bleeding risk unacceptable

35. ST CATHERINE’S HOSPICE outcome IVC filter inserted Breathlessness resolved over next couple of months Miss B lived for a further 8 months Grossly swollen lower limbs in end stage

36. ST CATHERINE’S HOSPICE Summary There is RCT evidence Applying this to people with advanced cancer can be difficult as they are often those excluded from the trials General principles can be applied Common sense can be applied Many patients appreciate becoming partners in joint decision making in uncertainty Balance the risks and monitor carefully

37. ST CATHERINE’S HOSPICE www.tradalliance.org www.tradalliance.org