Transcript Miriam johnson

The management of venous
thromboembolism
when the evidence is lacking
M Johnson
ST CATHERINE’S
HOSPICE
Overview
What
evidence do
we have?
ST CATHERINE’S
HOSPICE
What are
the gaps?
Pragmatism
What evidence do we have?
• 4 randomised controlled trials
• All open label
• 3 - randomisation method and power
•
•
ST CATHERINE’S
HOSPICE
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)
ST CATHERINE’S
HOSPICE
Lee AYY et al NEJM 2003
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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
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
•
•
•
ST CATHERINE’S
HOSPICE
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
•
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
•
•
ST CATHERINE’S
HOSPICE
• 91 patients randomised between the three groups
Meta-analysis: Noble et al. Lancet
Oncol 2008
Risk of developing recurrent VTE with LMWH compared to warfarin
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
Lee 2003
0.509
Hull 2006
0.438
Deitcher 2006 0.690
0.509
0.121
0.329
0.188
0.124
0.351
4.091
0.789
1.017
3.832
0.737
-0.391
-3.018
-1.920
-0.425
-3.571
0.696
0.003
0.055
0.671
0.000
0.01
p 0.000 = < 0.0001, fixed effect model
ST CATHERINE’S
HOSPICE
0.1
1
10
100
Meta-analysis: Noble et al. Lancet
Oncol 2008
Risk of bleeding with LMWH compared to warfarin
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
Lee 2003
1.583
Hull 2006
1.125
Deitcher 2006 2.194
1.103
0.163 1.186
0.781 3.210
0.700 1.809
0.209 23.014
0.768 1.584
-1.622
1.275
0.486
0.655
0.532
0.105
0.202
0.627
0.512
0.595
0.01
p 0.000 = < 0.0001, fixed effect model
ST CATHERINE’S
HOSPICE
0.1
1
10
100
What’s the difficulty?
•
•
•
ST CATHERINE’S
HOSPICE
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
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
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. 8.711.5) microg/l. {NR 1- 4.1 microg/l)
– Johnson et al Clinical and Laboratory Haematology. 1999:
ST CATHERINE’S
HOSPICE
Overview
What
evidence do
we have?
ST CATHERINE’S
HOSPICE
What are
the gaps?
Pragmatism
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
ST CATHERINE’S
HOSPICE
Overview
What
evidence do
we have?
ST CATHERINE’S
HOSPICE
What are
the gaps?
Pragmatism
General principles 1
• In advanced disease avoid warfarin
o
o
o
o
o
o
ST CATHERINE’S
HOSPICE
Poor control of INR
Variable oral absorption
Poor nutritional state
Multiple and variable medications
Poor liver function
Underlying pathophysiology of compensated
DIC, which worsens with worsening extent of
disease
General principles 2
• If the cancer remains active, continue
•
ST CATHERINE’S
HOSPICE
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
Options
o Change to bd regime
o Increase the dose
o Change to unfractionated heparin
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
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
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
•
ST CATHERINE’S
HOSPICE
18 (9%) patients developed recurrent VTE, which
included eight PE, fatal in two.
11(5%) patients experienced a major bleed (gastrointestinal (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?
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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 day
o Weinkove and Hunt. VTE in Advanced Disease: a
clinical guide. OUP 2008
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
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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
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
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
ST CATHERINE’S
HOSPICE
outcome
•
•
•
•
ST CATHERINE’S
HOSPICE
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
•
•
•
•
•
•
ST CATHERINE’S
HOSPICE
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
www.tradalliance.org
www.tradalliance.org
ST CATHERINE’S
HOSPICE