Transcript Where's the evidence?

IST-3 collaborators
meeting
Professor Peter Sandercock
University of Edinburgh, UK
ISS conference, Capetown, October 2006
Outline
• What do we know? Analysis of existing trials of
thrombolysis for stroke
– Overall effects: risks and benefit
– Subgroups: effect of time & age
• Who is treated? Current use of rt-PA in Europe &
USA
• Do we need further randomised trials? YES
• Randomised trials of IV thrombolysis
• IST-3 protocol
• Progress with trial
• Imaging update
Background
ISIS-2: 17,000 patients with acute MI
Percent dead Diff. per
Placebo Treated
1000
Streptokinase
12.0%
9.2%
28
Aspirin
11.8%
9.8%
24
P < 0.00001 for both comparisons. NOTE: The 22%
reduction in the odds of death observed in ISIS-2 was
identical to the estimate of benefit from a meta-analysis of
all previous trials
Rapid change in clinical practice.
Thrombolysis for MI increased markedly after
publication of megatrials in ‘86 & ‘87
Ketley and Woods Lancet 1993: 342: 891-4
GISSI
ISIS-2
GISSI
AIMS
ISIS-2
ASSET
Trials in acute stroke have been
far too small
“It is still not sufficiently widely appreciated
just how large clinical trials need to be to
detect reliably the sort of moderate, but
important, differences in major outcomes that
might exist (especially if effects in different
subgroups are to be assessed reliably).”
Collins and MacMahon Lancet 2001; 357: 373-380
Randomised trials of thrombolysis vs
control in acute myocardial infarction
Total no. patients by 1994!
58,600
Randomised trials trials of thrombolysis vs
control in acute ischaemic stroke
Total (all agents)
5,675
rt-PA
2,700
rt-PA < 3hrs
rt-PA aged > 80 years
930
42
Previous trials of rt-PA
Review of trials of thrombolysis with rtPA for acute ischaemic stroke
• Risks
– Symptomatic cerebral haemorrhage
– Death
• Benefits
– Reduced ‘death or dependency’
– ?reduction in massive cerebral oedema?
• Subgroup analyses: effect of
–
–
–
–
Time to treatment
Age
Risk factors for intracerebral haemorrhage
Appearance of CT scan
rt-PA < 6 hrs RISK: symptomatic
intracerebral haemorrhage (SICH)
< 3 hours
3 – 6 hours
More with control
More with rt-PA
Cochrane Database of Systematic Reviews 2004
rt-PA < 6hrs RISK: effects on death
rt-PA saves lives
rt-PA kills
Non-significant 16% increase in deaths
(95% CI, 6% reduction to 44% increase)
POSSIBLE BENEFIT of rt-PA < 6hrs
? Reduction in symptomatic cerebral oedema
rt-PA <6 hours: BENEFIT = reduction in
‘death or dependency’, despite risk
20% reduction with rt-PA (95% CI 7-23%)
BUT the significant between- trial
heterogeneity (I2=62%) makes result unreliable
Areas of uncertainty
Review of trials of thrombolysis with rtPA for acute ischaemic stroke
• Risks
– Symptomatic cerebral haemorrhage
– Death
• Benefits
– Reduced ‘death or dependency’
– ?reduction in massive cerebral oedema?
• Subgroup analyses: effect of
–
–
–
–
–
Time to treatment
Age
Stroke severity
Risk factors for intracerebral haemorrhage
Appearance of CT scan
rt-PA trials meta-analysis. Benefit declines
with increasing time to treatment, but scope
for benefit up to 6h (Lancet 2004; 363: 768–74)
Benefit
Upper and lower 95% confidence limits
Harm
Line of no effect
3 hours
6 hours
Only a small, variable proportion of
patients are treated with rt-PA
Country
no.
hospitals
no. % treated
patients rt-PA (range)
USA
42
1,195
4.1% (0-12%)
USA
29
3,948
1.8% (0-10%)
USA
137
23,058
1.6%
Germany
104
13,440
3.0% (0-18%)
(0-5%)
Effect of hospital, age and race, and presence of
neurologist on likelihood of receiving
thrombolysis for acute ischaemic stroke among
23,058 acute stroke patients from 137 community
hospitals in USA
• In 35% of hospitals, no patients at all
given rt-PA.
• Strong trends to LESS rt-PA use:
– with increasing age of the patient,
– if no neurologist available.
Reed et al. Stroke 2001: 32; 1832-44
Number of older patients with
acute stroke per year in UK
87,000 patients aged > 70 years
47,000 patients aged > 80 years
= A big problem for acute medical
services!
9 am. This 85 year old man suddenly cannot speak
and his right arm is weak. At 3hrs, CT confirms it is
an ischaemic stroke: should he be treated? does his
age affect his response to thrombolysis?
?
Effect of age on benefit from rt-PA
• Analysis of major randomised trials of rt-PA
for stroke
• Adjustment for age did not modify the
relation between benefit and time
• No subgroup analysis to answer the simple
questions:
– Does age alter the balance of risk and benefit?
– Should there be an upper age limit for
treatment?
Lancet 2004; 363: 768–74
Log (OR) good outcome
Effect of stroke severity (NIHSS) on
good outcome with rt-PA
10
2.6
1
1.2
1.9
2.5
2.1
2.1
0.1
0-5
6-10
11-15
16-20
> 20
All
Patients
Baseline NIHSS Score
Test for equal OR’s: Chi-square (4 DF) = 1.70; p = 0.79
No evidence of difference in treatment benefit of rt-PA
across the five NIHSS severity groups
Ingall et al Stroke. 2004;35:2418-2424.
Effect of age on risk? (NINDS
trial): factors which predict
intracerebral haemorrhage
• Baseline NIHSS > 20
• Age > 70 years
• Ischaemic changes present on
initial CT
• Glucose > 16.7 mmol/L
Ingall et al Stroke. 2004;35:2418-2424.
Outcome by no. of SICH risk factors,
adjusted for co-variates
Log (OR)
10
1.9
1
2.6
1.4
0.1
0
1
>=2
Number of SICH Risk Factors
Test for equal OR’s: Chi-square (2 DF) = 1.77; p = 0.41
= no evidence of a difference in risk of SICH in these three
groups
NINDS conclusions on SICH.
Subgroup analyses suggested that some clinical
characteristics were related to the occurrence of
SICH
However, after adjustment, the differences
between subgroups were not statistically
significant.
Cannot predict reliably who will develop SICH
Ingall et al Stroke. 2004;35:2418-2424.
Early ischaemia signs on CT
Hypodensity : loss of grey/white differentiation,
loss of the lentiform nucleus
Swelling
: effacement of sulci, compression of ventricle
4 hours
24 hours
‘Early ischaemia’ signs on CT: effect
on response to rt-PA
• Two randomised trials, 1,926 patients.
• No evidence that ‘early infarct sign’
significantly modifies effect of
thrombolysis
• But analysis has insufficient statistical
power – need larger trials
Wardlaw et al, Radiology 2005: 235: 444
What is known: summary
• Limited rt-PA trial data (2,100 patients)
• Very limited data of effects in older
people
• Effects on death unclear
• ‘Time is brain’; early treatment is best
• Clear ~3% risk of fatal brain
haemorrhage
• Despite risk, potential for net benefit for
selected patients up to 6hrs.
Current use of rt-PA in clinical
practice
Current rt-PA approval for use in
routine clinical practice
• Patient MUST be
– able to be treated within 3 hours
– aged under 80
– not have a history of prior stroke + Diabetes
– not have any of the standard exclusions
– NIHSS < 25
– No extensive infarction on CT
• There must be a discussion of risk/consent
Variation in use of rt-PA for acute ischaemic
stroke ‘within licence’ in Europe
rt-PA for stroke per million pop'n
60
Finland
Austria
Sweden
Norway
Belgium
Spain
Germany
Netherlands
Denmark
Italy
UK
Greece
France
Portugal
50
40
30
20
10
0
SITS register (2003-5) March 2005
We need further large trials to:
• Determine reliably:
– whether there are patients outside strict criteria of
current approval who benefit < 3hrs
– which type of patients benefit 3-6 hours
– Balance of risk and benefit in older patients
• Contribute further evidence to:
– persuade doubting clinicians to change practice
– reduce inequalities in patient access to treatment
– persuade health authorities to fund:
• cost of drug treatment
• a well-organised acute stroke service in every acute
hospital
Current small scale randomised trials of i.v.
thrombolysis
Trial
Thrombolytic
agent
Patient selection
trial size & time window
EPITHET
rt-PA
Clinical, CT (+ DWI/PWI MRI)
3-6 hours
100 patients
DIAS -2
Desmoteplase
DWI/PWI or CT perfusion
3-9 hours
186 patients
ECASS III
rt-PA
Clinical and CT
3-4 hours
800 patients
Third International Stroke Trial. A large
randomised trial to answer the question: can a
wider variety of patients be treated?
Target: 6000 patients from 300 centres in
36 Countries
Main features of IST - 3
• International, multi-centre, Prospective,
Randomised, Open, Blinded Endpoints study
of i.v. rt-PA vs control. Independent.
Investigator-led
• Primary outcome: the proportion of patients
alive and independent at six months
(Modified Rankin 0,1 or 2)
• Randomisation by telephone or internet with
on-line minimisation to balance key
prognostic factors.
• Blinded central review of all scans
May 2007
Nov 2006
May 2006
Nov 2005
May 2005
Nov 2004
May 2004
Nov 2003
May 2003
Nov 2002
May 2002
Nov 2001
May 2001
Nov 2000
May 2000
Number of patients
.
700
Recruitment
600
500
400
300
200
100
0
Recruitment at 28.10.06:
648 patients from 65 centres in 9 countries.
Recruitment by country
Country
No. centres
Pts.
%
UK
22
252
38%
Poland
4
128
21%
Norway
9
94
15%
Italy
12
56
10%
Belgium
2
45
8%
Australia
9
36
5%
Sweden
9
24
3%
Austria
Canada
1
1
5
4
1%
1%
Countries in process of
joining/seeking to join trial
In process
• Czech Republic
• Hungary
• India
• Mexico
• Portugal
Seeking to join
• Argentina
• Belarus
• Brazil
• Chile
• South Africa
• Switzerland
• Taiwan
• Thailand
• Ukraine
Age at randomisation
Number of patients
192
200 patients aged > 80 = increased world evidence base 5 x!
180
160
140
120
100
80
60
40
20
0
120 patients aged over 80
50 or
under
51-60
61-70
71-80
81-90
91-100
Age in years at randomisation
Over
100
Number of patients
Delay between stroke onset and randomisation
180
160
Median = 4.1 hours
140
120
100
80
60
40
20
0
1 or less
1 to 2
2 to 3
3 to 4
4 to 5
5 to 6
Hours between stroke onset and randomisation
Report of the IST 3 Data
Monitoring Committee
The Data Monitoring Committee for the IST-3
trial reviewed the interim outcome data on 26
September 2006, and had no safety
concerns. We would encourage all
collaborators to support this important trial
and the study organisers to explore all
appropriate ways to achieve the required rate
of recruitment as rapidly as possible.
Professor Rory Collins, Chairman
Summary
• IST-3 is obtaining very important data about
thrombolysis, outside the current licence
• It has already increased the world randomised
evidence base on the effect of rt-PA in patients
aged > 80, by 5 times!
• It is encouraging new centres to use
thrombolysis in a randomised trial
– Closely monitored
– Adds to the randomised evidence
• It will provide uniquely useful data on the impact
of clinical and CT findings on response to rt-PA
Persisting hyperdense artery sign, ASPECTS
score and risk of developing mass effect: an
analysis based on the first 389 patients from the
IST-3 Trial.
Kobayashi A,1,2 Skowronska M1,2, Bembenek J3,
Sandercock P4, Kane I4, Czlonkowska A1,2, Lewis S4,
Wardlaw J4, for the IST-3 Collaborative Group
1 Medical
Univerity of Warsaw, Poland, 2 Institute of Psychiatry and Neurology,
Warsaw, Poland, 3 Wolski Hospital, Warsaw, Poland, 4 University of Edinburgh,
United Kingdom
Background
• In patients with acute ischaemic stroke, the
hyperdense artery sign is a marker of fresh
thrombus occluding the vessel
• The hyperdense artery sign
– is associated with greater stroke severity
– can disappear with reperfusion,
– can persist if the artery remains occluded
– If persistent, may predict infarct swelling
• No evidence that hyperdense artery on
baseline CT influenced response to rt-PA in
NINDS trial
Hyperdense artery
Aims of this analysis
• In patients randomised in IST3, to
assess how often the hyperdense
artery sign:
– is seen on baseline CT scan
– disappears by the time of second scan
– is associated with ‘early ischaemic
change’ and mass effect on baseline and
follow-up CT
• Assess associations with a persistent
hyperdense artery
IST-3 image assessment protocol
• Design:
– randomised controlled trial of rt-PA vs control in 6000 patients with
acute ischaemic stroke < 6 hrs of onset
• Eligibility for the trial
– No clear indication for, or contraindication to, thrombolysis with iv rt-PA.
• CT scan
– Before randomisation (MR permitted)
– Repeat CT at 24-48 hrs after randomisation
• All scans read centrally
– blinded to clinical details, treatment allocation, and later events
• Detailed assessment of
–
–
–
–
site, size, location of early ischaemic change & swelling
ASPECTS score
presence of of hyperdense artery
haemorrhage, non stroke lesions etc.
Scale to assess swelling and mass effect
Wardlaw AJNR 1994
ASPECTS Score
Each of 10 MCA territory regions scored normal/ abnormal for
hypodensity , and total no. abnormal areas subtracted from
10, so most extensive visible MCA ischaemia score = 0
(worst), no visible ischaemic change = 10 (best)
Material and methods
• We included in this analysis data from all
patients randomised, for whom we had on
15.12.05:
– Digitised copies of baseline and follow-up CT *
(we excluded patients with MR as baseline scan,
or who had no follow-up CT)
– The (blinded) assessment by the expert central
reader of both scans entered in database
• Analyses presented are based on the 389
patients who met these criteria
Frequency of hyperdense artery on
baseline and follow-up CT
Present on baseline scan
152 (39%)
Present on follow-up scan
102 (26%)
Persisted (seen on 1st & 2nd scan)
88 (23%)
Present on baseline,
disappeared by 2nd scan
64 (16%)
Baseline CT: hyperdense artery and early
ischaemic changes & swelling
Hyperdense
artery present
n (%)
Hyperdense
artery absent
n (%)
Loss of grey/white matter definition
128 (84%)
101 (43%)
<0.001
Loss of basal ganglia outline
98 (64%)
56 (24%)
<0.001
Hypodensity
27 (18%)
19 (8%)
0.004
Any mass effect
96 (63%)
58 (24%)
<0.001
5.0
6.3
<0.001
ASPECTS score, mean
p
Follow-up CT: ischaemic change and swelling in
patients with and without persisting hyperdense
artery
Hyperdense
artery
persisted
n (%)
Hyperdense
artery
disappeared
n (%)
p
Loss of grey/white definition
81 (92%)
50 (82%)
0.06
Loss of basal ganglia outline
71 (81%)
42 (69%)
0.2
Hypodensity
81 (92%)
53 (87%)
0.3
Any sign of mass effect
80 (91%)
51 (84%)
0.2
ASPECTS score (mean)
3.4
4.9
0.002
Summary
• In IST-3, the hyperdense artery was seen on
baseline CT in 152/389 patients (39%)
• In 64/152 (42%) the hyperdense artery was no
longer visible on the follow-up CT
• Compared with patients without hyperdense artery
sign (HAS), patients with persisting HAS showed
more extensive ischaemic change on both the
baseline and follow-up CT
• IST-3 will therefore have substantial data to assess
the influence of the hyperdense artery sign and
early ischemic change on the response to i.v. rt-PA
www.ist3.com
Lots of new features on the website!
Study protocol
Hypothesis #1
Intravenous thrombolysis with rt-PA
administered to a wide range of
patients with acute ischaemic
stroke within six hours of symptom
onset will increase the proportion of
patients alive and independent at
six months.
Hypothesis #2
The balance of risks and benefits of
thrombolysis may be modified by
clinically important variables,
including:
–age
–delay in treatment,
–stroke severity,
–initial brain scan appearances.
Main features of the IST - 3
• International, multi-centre, prospective,
randomised open treatment blinded end-point
design (PROBE) study.
• Large and pragmatic - 6000 patients.
• Eligibility criteria simple
• Blinded assessment of outcome at 6 months.
• Intention to treat analysis.
• Pharmaceutical industry not involved in trial
development, operation or data management.
Exclusion Criteria (1)
Contraindications to thrombolysis:
• Major surgery, trauma or gastrointestinal or urinary
tract haemorrhage within the previous 21 days.
• Arterial puncture at a non-compressible site within
the previous 7 days.
• Currently on oral anticoagulant or intravenous
heparin therapy with abnormal coagulation (APPT
and/or INR).
• Known defect of clotting or platelet function.
• Women of childbearing potential (unless pregnancy
impossible) or known to be breastfeeding.
Exclusion Criteria (2)
Not specified but might include:
• Prognosis very poor regardless of
therapy; likely to be dead within months.
• Unlikely to be available for follow-up (eg,
no fixed home address, visitor from
overseas).
Eligibility Criteria (1)
General Indications:
• Patients older than 16 years of age.
• Symptoms and signs of clinically definite
acute stroke (mild, moderate or severe).
• A clearly established time of stroke onset
that will allow thrombolysis to be given
within six hours.
• CT or MR brain scanning has excluded
intracranial haemorrhage.
Eligibility Criteria (2)
If your patient:
• Has a clear indication for thrombolysis:
Treat with rt-PA.
• Has a clear contraindication to thrombolysis:
DO NOT treat with rt-PA.
• Thrombolysis is ‘promising but unproven,’
consider RANDOMISING the patient in IST3.
Trial procedure: Brain imaging
• Mandatory initial scan (CT or MRI)
before randomisation to rule out
haemorrhage and stroke mimics.
• Patients eligible even if early ischaemic
changes visible.
• Repeat CT at 24-48 hrs after
randomisation.
Trial procedure: Ethics and Consent
• Each participating centre must obtain
approval from the appropriate Ethics
Committee / IRB
• Before randomisation, consent must be
obtained from the patient or their relatives
(or legal representative).
Randomisation (1)
• 24 hour computerised randomisation
service: telephone or via ist3 website
(www.ist3.com)
• Enter key demographic items and baseline
data
• Computer checks data for consistency.
• Treatment allocated immediately.
Patients allocated thrombolysis
• Admit patient to acute stroke unit
• Drug: recombinant tissue-type plasminogen
activator (rt-PA, Alteplase - Boehringer Ingelheim).
• Dose: total dose of 0.9mg per kg of body weight up
to a maximum of 90mg.
• Regimen: 10% of the total dose given as an
intravenous bolus delivered over one minute, with
the remainder infused over the next 60 minutes.
• Avoid aspirin and heparin for 24 hours
• All other standard treatments as usual
• Clinical monitoring according to IST-3 protocol
Patients allocated control
•
•
•
•
•
Admit patient to acute stroke unit
Patient must NOT be given rt-PA.
Aspirin can be started immediately
All other standard treatments as usual
Clinical monitoring according to IST-3
protocol
Monitoring vital signs and neurological
status after randomisation
• Every 15 minutes for 2 hours (use
manual not automated method for BP)
• Every 30 minutes for the next 6 hours
• Hourly for a further 6 hours
• 4 hourly for the next 36 hours
• If there is any cause for concern,
review, report, document and increase
observation frequency accordingly
Trial procedure:
Haemorrhages during
thrombolysis
• Stop infusion immediately if significant
bleeding (intra- or extracranial) occurs.
• Monitor blood pressure, maintain
circulating blood volume, transfuse
blood as appropriate for patients with
major extracranial bleeding.
• +/- neurosurgical opinion for intracranial
haemorrhages.
Data collection at 7 days
•
•
•
•
Demographic data.
Treatments given in hospital
Major clinical events within 7 days
Contact details of patient to permit
follow-up at 6 months (family doctor,
address of relatives etc.).
• Send pre-randomisation and follow-up
CT scans to Edinburgh (you can send
via email, web, or post)
Data collection at six months
• Is the patient alive and
independent?
• Modified Rankin, quality of life
• Assessed blind with a validated
postal or telephone questionnaire.
Events within 7 days
• Deaths from any cause.
• Symptomatic intracranial haemorrhage
(fatal and non-fatal).
• Asymptomatic intracranial haemorrhage
(repeat brain imaging data).
• Major extracranial haemorrhage (fatal,
or requiring transfusion or operation).
• Recurrent ischaemic stroke.
Data analyses: ‘intention to treat’
Subsidiary analyses, subdivided by:
•
•
•
•
•
•
•
•
•
Clinical stroke syndrome (OCSP)
Presence or absence of atrial fibrillation
Pre-randomisation scan appearances
Pre-randomisation antiplatelet use
Baseline risk
Blood pressure at randomisation
Antihypertensive use following randomisation
Age
Sex
Sample size: 6,000 patients
• Assuming a power of 80%, an alpha level of 5%, with
6000 patients, mostly treated between 3 & 6 hours of
onset, the trial could detect a 3% absolute difference
in the primary outcome (the proportion of patients
dead or dependent at 6 months).
• This absolute difference is clinically worthwhile, is
consistent with the effect size observed among
patients randomised between 3 & 6 hours of stroke
onset in the Cochrane review of the rt-PA trials. It is
also comparable with the absolute benefit seen with
thrombolytic therapy for acute MI.
• If 3500 patients were recruited, the trial could detect a
4% absolute difference in the primary outcome.
• A sample size of 1000 patients could detect a 7%
absolute difference in the primary outcome, which is
consistent with the effect size among patients
randomised within 3 hours of stroke in the Cochrane
review.
Which imaging method to select
patients for thrombolysis?
Do we need to see ‘mismatch’ with CT
Perfusion/MR-DWI/PWI? –NO!
1. No reliable evidence that patients with
mismatch benefit from thrombolysis –
DIAS trial +
2. 50% of patients without mismatch get
lesion growth, so could still benefit from
treatment
3. Extra imaging increases delays to start
of treatment
4. No consensus on definition of
mismatch or how to assess perfusion
•
•
•
•
Do we need to see a blocked artery
with CTA, MRA, IAA? – NO!
Dogma: “only treat a blocked artery…”
Block may be below resolution of imaging
(No obvious block on CTA, MRA, IAA does
not exclude a blocked vessel)?
Lacunar stroke - Lacunar infarcts in NINDS
benefited as much as other stroke
subgroups
Its not just the big vessels – what about the
microcirculation – it needs to be unblocked
too.
Further technique-specific issues
CT Perfusion/CTA
•
Contrast agents delay clot lysis times by >50%
(Morcos Eur Radiol 2005;15:1463, Pislaru J Am Coll Cardiol 1998;32:1102,
Dehmer J Am Coll Cardiol 1995;25:1069)
DWI/PWI
•
20-30% of acute stroke patients cannot be scanned for
medical reasons or MR contraindications
(Hand et al JNNP 2005, Barber et al JNNP 2005, Singer Neurology
2004;62:1848)
IST imaging strategy
• Plain CT is the primary method, but MRI
permitted.
• Need to gain maximal information from CT
• Imaging sub-studies planned
CT scanning
IST-3: Training to read CT scans
web-based CT reading and feedback system:
• Log on to www.neuroimage.co.uk
• Register
• Do first 20 scans (2 batches)
- get 1 CPD credit
what you, the reference standard,
-get feedback
five experts and all other
•Do all six batches
- get 5 CPD credits
specialties said about that scan,
and a follow-up scan to see where
the infarct appeared
IST-3 Imaging: Training materials to read scans
Early infarct signs on CT
Hypodensity : loss of grey/white differentiation,
loss of the lentiform nucleus
Swelling
: effacement of sulci, squashing the ventricle
4 hours
24 hours
IST-3. CT scan at baseline:
Joanna Wardlaw’s opinion
Acute ischaemic change
72%
Hyperdense artery
44%
Periventricular lucencies
40%
Old vascular lesion
39%
Normal
4%
Non-stroke lesion*
1%
Haemorrhage
0%
categories are not mutually exclusive: a patient may have more than
one feature. *both lesions were small incidental meningiomas
IST3 plans for CT analysis and
international CT reading panel and
its methods
Maximising information from CT. Need
to clarify relationships between:
Treatment risk (haemorrhage) and:
• presence of ‘early infarct’ signs
• white matter lesions
• old infarcts/haemorrhages
Treatment benefit and ‘early infarct’ signs
• how much density change = irreversible infarction?
• is swelling without hypodensity important?
• how important is dense artery sign?
How hypodense?
CT ‘at 2 hrs’ after onset.
On closer questioning, true onset
was at least 8 hrs before CT.
48 hrs
This is ‘marked hypodensity’: Lessons
from this case
1. Infarct has very clearly
demarcated edges, and marked
hypodensity = ?irreversible
infarction
2. Patients with right hemisphere
symptoms may not notice when
their stroke starts due to “neglect”
(anosognosia).
3. Always review the patient’s
history if CT suggests that the
infarct is older than the stated time
of onset would suggest.
Is this too much hypodensity?
Baseline < 3 hours
Early left basal ganglia hypodensity
Follow-up
Haemorrhagic transformation
Swelling without density change? (CT at 2 hrs)
5 hrs: swelling + density change
5 hrs - then swelling + density change
4 days – infarct in density change and swelling areas
IST3 00188
Dense artery sign: what does it
predict?
Dense MCA & haemorrhagic transformation
4.5 hours after acute left hemiparesis
IST3 00338
24 hours later – persistent dense MCA (thrombus)
Persistent dense MCA & massive swelling
Acute right hemiparesis 4 hours ago
IST3 00343
48 hours later – persistent MCA occlusion
Dense artery sign: what does it
predict?
A persistently dense MCA at 24-48 hrs may
predict adverse events (bleeding or massive
swelling)
IST-3 will establish whether rt-PA causes
disappearance of dense MCA sign and
reduces these adverse outcomes
What about microhaemorrhages,
which can be seen on CT
(sometimes)?
CT
MR GRE
Old haemorrhage on CT, and rt-PA
White linear density; slit-like hole
haemosiderin
Purpose of central CT reading.
Clarify relationships between:
• Early infarct signs and haemorrhage risk
• Early infarct signs and treatment benefit
- how much density change?
- how much swelling?
• White matter lesions & haemorrhage risk
• Old infarcts/haemorrhages and risk
• Appearance/disappearance of dense
artery sign and response to treatment
IST3 – plans for CT reading
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Central collection = potentially 12, 000 CT’s!
Electronic storage
Reading by panel of 20 experts
Web-based CT reading system developed from
ACCESS study
All scans read once
Subset read by all readers
CT reading advisory group met 6th October, panel
of 20 experts being assembled
Preliminary analyses on first 500 patients being
submitted for Lancet
Edinburgh