The Strength of Evidence for Thrombolytic Therapy in

Report
Evidence based stroke
medicine. Evaluating
treatments for acute
ischaemic stroke -what
works and what doesn’t?
Professor Peter Sandercock
85% of strokes are ischaemic, and related to
blockage of an artery by a blood clot, so potential
treatments to improve the circulation might be:
• Thrombolytic (clot-dissolving): eg
Streptokinase, TPA. Breaks up clot by
splitting fibrin
• Anticoagulant (Clot preventing): prevents
formation of fibrin, prevents spreading of clot
& formation of new clot
• Antiplatelet (clot preventing): prevents
platelets sticking together prevents spreading
of clot & formation of new clot.
Does treatment X do more
good than harm?
• Benefits of the
treatment (eg
reduced
disability)?
• Risks (eg fatal
bleeding)?
?
What is the balance of RISK
and BENEFIT?
RISK
BENEFIT
Getting reliable evidence on new
treatments (in animals and patients)
• Minimise selection bias - RANDOM
ALLOCATION
• Minimise observer bias - BLIND
ASSESSMENT of outcome
• Minimise random error - LARGE
SAMPLE
• Choose appropriate measure of
outcome - use COMMON SENSE
OK, how to design appropriate
randomised trial?
• Large, simple
• What to use as primary measure of outcome?
–
–
–
–
–
–
–
vessel patency
volume of brain damaged on scan?
disability
handicap?
Quality of life
death?
what about side effects (eg bleeding?)
• Highly selected patients or a broad range?
Effects of treatment X on
death in a small trial
Experimental
(n=100)
Control
(n=100)
10/100
(10%)
12/100
(12%)
Difference = 2% or 20 deaths avoided per 1000 treated,
but not statistically significant. Would need a trial with over
10,000 subjects to confirm or refute a benefit of this size.
Thrombolysis in AMI: accumulating the evidence
Antman & Lau. JAMA 1992; 268: 240-8
By the 1980’s, what did we know about
thrombolysis for heart attacks (AMI)?
• 23 small randomised trials completed, including a
total of about 6000 patients, showing:
– It can unblock arteries after heart attacks, but bleeding
could be a side-effect (sometimes fatal)
– trials were too small reliably to answer the question ‘does
thrombolysis save lives in patients with heart attacks?’ ,
but suggested the benefit might be about 20 lives saved
per 1000 patients treated
• Doctors not convinced: treatment not used
• 2 Mega- trials, each with 20,000 patients then
completed (ISIS-2 and GISSI), showing thrombolysis
reduced risk of death after MI by about a fifth:
clotbusters save lives
Publication of large-scale MI trials followed
by increased use in UK Trent region
(Ketley and Woods Lancet 1993: 342: 891-4)
What is the best sort of
evidence?
BEST
• Up-to date systematic review of all
relevant randomised trials
• Narrative review article
• Textbook
WORST
What is a systematic
review?
• Defined aim
• Defined methods
– defined search strategy
– criteria to include studies
• type of study (eg strictly randomised)
• type of patient
• type of outcome
• Estimate of overall treatment effect
Where can you find
systematic reviews and
RCT’s?
• MEDLINE: but only about 50% of
relevant RCT’s can be found here
• Cochrane Library: in many hospital
libraries on CD ROM, or Internet
(Abstracts at: http://www.updatesoftware.com/ccweb/cochrane/revabstr/
abidx.htm)
Cochrane systematic review of the evidence
for thrombolytic therapy in acute ischaemic
stroke
Joanna Wardlaw
abstract available free at:
www.dcn.ed.ac.uk/csrg
or on CDROM
The Cochrane Library
Fatal intracerebral haemorrhage (ICH)
with thrombolysis for ischaemic stroke
ICH after thrombolysis for ischaemic
stroke
• Fatal ICH increased from 1% to 5%.
– five fold increase (p<0.00001)
– 50 extra fatal ICH per 1000 treated
• Fatal or non-fatal symptomatic ICH
increased from 3% to 10%.
– three fold increase (p<0.00001)
– 70 extra haemorrhages per 1000 treated
• Similar proportional increase in ICH with
different thrombolytic agents
Thrombolysis for ischaemic stroke: dead or dependent
Overall, thrombolytic treatment within 6
hours of onset of acute ischaemic stroke
significantly improved long-term outcome
• At final follow-up, patients treated with
thrombolysis had a highly significant 24%
reduction in the relative odds of a bad outcome
(2p <0.0001) (= 10% relative risk reduction).
• For every 1000 patients treated < 6hrs, 65
avoided ‘death or dependence’.
• Need to treat 16 to prevent one poor outcome
Implications for research. A large
randomised trial of thrombolysis with
rt-PA in acute ischaemic stroke would
help answer:
• how wide is the time window beyond
3hours (6,9, 12 hours?)
• which patients benefit most?
• which patients most likely to be
harmed?
• is the risk of death reduced or not?
IST-3 trial design:
• Randomised controlled trial of rT-PA
versus placebo in 6,000 patients.
• < 6 hours symptom onset with CT
scan
• Eligibility based on ‘the uncertainty
principle’.
– Clear indication to treat: TREAT
– Clear contraindication: DON’T TREAT
– Uncertain: RANDOMISE
• Careful characterisation at baseline
Cochrane systematic review of the
randomised trials of anticoagulants in acute
ischaemic stroke (Gubitz et al CDSR 2002)
Anticoagulant
Trials Patients Deaths
Unfractionated heparin sc
6
20 048
4349
Heparinoid iv/sc
3
1413
98
LMW heparin
6
1321
292
Thrombin Inhibitor
2
294
10
Unfractionated heparin iv
2
270
27
Oral anticoagulant
2
81
28
21
23 427*
4804
TOTAL
* of whom 95% had CT head scans
Recurrent ischaemic stroke or intracranial
haemorrhage during treatment period
5%
4.1%
4.1%
2.7%
3.6%
p<0.0001
1.4%
0.5%
p<0.001
Anticoagulant
Control
NS
4%
3%
2%
1%
0%
Recurrent Ischaemic Stroke
Symptomatic Intracranial Haemorrhage
Outcome at end of follow-up
70%
NS
60%
50%
40%
30%
NS
59.7% 60.1%
20%
10%
21.4% 20.6%
0%
Dead
Anticoagulant
Dead or dependent
Control
Summary of effects of anticoagulants
(mainly heparin) in acute ischaemic stroke
• No net short- or long-term benefit.
• No subgroup of patient or anticoagulant
regimen associated with clear net benefit.
• Significant bleeding risk: 9 extra symptomatic
intracranial and 9 major extracranial
haemorrhages per 1000 patients treated.
• Bleeding risk dose-related: High > Low > Nil
• It gives no overall benefit, causes bleeds, is a
pain in the leg/arm/abdomen for the patient,
costs money (and nurses time); why use it?
Indications for early aspirin use in
acute ischaemic stroke: a combined
analysis of over 40,000 randomised
patients from CAST and IST
Sandercock PAG, Chen ZM, on behalf
of IST and CAST collaborative groups
Stroke 2000; 31:1240-49.
Design features of CAST & IST
• Randomised
• Acute ischaemic stroke <48 hours
• CT before entry where possible, or soon
after
• Aspirin dose (scheduled treatment period):
– IST: 300mg daily vs open control (2 weeks)
– CAST: 160mg daily vs placebo control (4
weeks)
Patients included in the trials
CAST
IST
20,655
19,435
- Before entry
87%
68%
- Total
97%
96%
0
50%
No. randomised
CT scan
Heparin allocation
Recurrent ischaemic stroke or intracranial
haemorrhage during treatment period
5
%
3.5%
4.0%
2p < 0.0001
4
3
2
1
2.5%
3.2%
2p < 0.0001
1%
0.8%
2p = 0.07
0
Aspirin
Control
Intracranial haemorrhage
Recurrent ischaemic stroke
Summary of aspirin benefit
• For every 1000 patients started < 48 hrs of onset:
– < 14 days, 7 avoid recurrent ischaemic stroke
– at 6 months, 12 avoid death or dependency, &
an extra 10 make a complete recovery
• The risk of cerebral haemorrhage is low (1-2 per
1000) and is completely outweighed by the
benefits
• Early aspirin is of net benefit for a wide range of
patients, so prompt treatment should be
considered for almost all patients presenting with
suspected acute ischaemic stroke.
Worldwide benefit each year of a
policy of 'give aspirin without delay' in
acute stroke
• 8 million patients with acute stroke
• 5 million with acute ischaemic stroke
• 1 million reach medical attention and
get aspirin
• 10,000 avoid a poor outcome, extra
10,000 make a complete recovery
• Lesson: a small benefit in a large
number of people adds up to a
worthwhile benefit to mankind
What have we learned about thrombolysis,
anticoagulants and aspirin?
• Thrombolysis: promising, but applicable to 1% of all
ischaemic strokes? Need much larger-scale trials.
• Anticoagulants/heparin: benefits balanced by bleeding
risk. No net benefit.
• Aspirin. Modest benefits, but applicable to almost all
patients. Like thrombolysis for AMI, It needed 40,000
randomised patients to prove it and persuade
clinicians to change
• Effort and audit needed to ensure ALL patients with
acute ischaemic stroke get aspirin
– CT has excluded haemorrhage?
– patient able to swallow safely? -> oral aspirin
– not able to swallow? -> rectally or via NG tube

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