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

ST CATHERINE’SHOSPICE

The management of venous thromboembolism

when the evidence is lackingM Johnson

http://www.stcatherineshospice-nyorks.org/History/Logo.JPG


Overview



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



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)



Lee AYY et al NEJM 2003


• 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



Hull et al Am J Med 2006


• P – patients with cancer and VTEo 200 randomised patients; power achieved

• I – 175iu/kg tinzaparine

• C – UFH 6days/warfarin

• O – objectively measured symptomatic, recurrent VTE or death at 3 months



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



Meta-analysis: Noble et al. Lancet Oncol 2008

Study name Statistics for each study Risk ratio and 95% CI

Risk Lower Upper ratio limit limit Z-Value p-Value

Meyer 2002 0.704 0.121 4.091 -0.391 0.696

Lee 2003 0.509 0.329 0.789 -3.018 0.003

Hull 2006 0.438 0.188 1.017 -1.920 0.055

Deitcher 2006 0.690 0.124 3.832 -0.425 0.671

0.509 0.351 0.737 -3.571 0.000

0.01 0.1 1 10 100

Risk of developing recurrent VTE with LMWH compared to warfarin

p 0.000 = < 0.0001, fixed effect model



Meta-analysis: Noble et al. Lancet Oncol 2008

Study name Statistics for each study Risk ratio and 95% CI

Risk Lower Upper ratio limit limit Z-Value p-Value

Meyer 2002 0.440 0.163 1.186 -1.622 0.105

Lee 2003 1.583 0.781 3.210 1.275 0.202

Hull 2006 1.125 0.700 1.809 0.486 0.627

Deitcher 2006 2.194 0.209 23.014 0.655 0.512

1.103 0.768 1.584 0.532 0.595

0.01 0.1 1 10 100

Risk of bleeding with LMWH compared to warfarin

p 0.000 = < 0.0001, fixed effect model



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.



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



The effect of advanced disease

•Recurrent VTE:o Extensive; HR 4.6 o moderately extensive; HR 5.3o less extensive disease; HR 1.9

•Bleeding:o Extensive; HR 4.8 o moderately extensive; HR 2.5o less extensive disease; HR 0.5



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:



Overview



The patient who…

•Continues to clot whilst on therapeutic doses of LMWH

• Is at risk of bleeding:o Thrombocytopeniao Brain metastasiso GI/GU tumourso Requires operative intervention

• Is poor performance status

• Is in renal failure



Overview



General principles 1

• In advanced disease avoid warfarino Poor control of INRo Variable oral absorptiono Poor nutritional stateo Multiple and variable medicationso Poor liver functiono Underlying pathophysiology of

compensated DIC, which worsens with worsening extent of disease



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



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

• Optionso Change to bd regimeo Increase the doseo Change to unfractionated heparin



Increase dose of LMWH

• Increase doseo 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



Continued clotting

• Insertion IVC filtero 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



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



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



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



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 x109/l, dose 5,000 IU; <10x 109/l, dose 2,500 IU}

• O: bleeding, recurrent VTE



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



Option of therapeutic dose?

• Anecdotal experience using therapeutic dose of LMWH in patients with counts > 50 x 109/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 109/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



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 dayo Weinkove and Hunt. VTE in Advanced Disease:

a clinical guide. OUP 2008



Other indications for UFH

• Occasionally patients may need short term UFHo 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



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



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



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



Best practice

•Possible outcomes of management:o Bleeding gets worseo Major bleedo Fatal bleedo Recurrent VTEo Fatal PEo Symptoms resolve

•“best practice” – trial LMWH



Best practice vs patient acceptable

•Possible outcomes of management:o Bleeding gets worseo Major bleedo Fatal bleedo Recurrent VTEo Fatal PEo Symptoms resolve

•“best practice” – trial LMWH

•Any increased bleeding risk unacceptable



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



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



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