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
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
ISIS-2: 17,000 patients with acute MI
Rapid change in clinical practice. Thrombolysis for MI increased markedly after publication of
megatrials in ‘86 & ‘87
GISSI
ISIS-2GISSI
AIMS
ISIS-2
ASSET
Ketley and Woods Lancet 1993: 342: 891-4
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 930
rt-PA aged > 80 years 42
Previous trials of rt-PA
Review of trials of thrombolysis with rt-PA 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)
More with control More with rt-PA
Cochrane Database of Systematic Reviews 2004
< 3 hours
3 – 6 hours
rt-PA < 6hrs RISK: effects on death
Non-significant 16% increase in deaths (95% CI, 6% reduction to 44%
increase)
rt-PA saves lives rt-PA kills
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 rt-PA 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
Harm
3 hours 6 hours
Upper and lower 95% confidence limits
Line of no effect
Only a small, variable proportion of patients are treated with rt-PA
Country no. no. % treated hospitals 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% (0-5%)
Germany 104 13,440 3.0% (0-18%)
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
Effect of stroke severity (NIHSS) on good outcome with rt-PA
1.2
2.61.9 2.1 2.5 2.1
0.1
1
10
0-5 6-10 11-15 16-20 > 20 AllPatients
Baseline NIHSS Score
Lo
g (
OR
) g
oo
d o
utc
om
e
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.
1.92.6
1.4
0.1
1
10
0 1 >=2Number of SICH Risk Factors
Lo
g (
OR
)
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
Outcome by no. of SICH risk factors,
adjusted for co-variates
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
4 hours 24 hours
Hypodensity : loss of grey/white differentiation, loss of the lentiform nucleus
Swelling : effacement of sulci, compression of ventricle
‘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
0
10
20
30
40
50
60
rt-P
A f
or
str
ok
e p
er
millio
n p
op
'n
Finland
Austria
SwedenNorway
Belgium
Spain
GermanyNetherlands
Denmark
Italy
UK
GreeceFrance
Portugal
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
0
100
200
300
400
500
600
700
May
200
0
Nov 2
000
May
200
1
Nov 2
001
May
200
2
Nov 2
002
May
200
3
Nov 2
003
May
200
4
Nov 2
004
May
200
5
Nov 2
005
May
200
6
Nov 2
006
May
200
7
Num
ber o
f pat
ient
s
.
Recruitment
Recruitment at 28.10.06: 648 patients from 65 centres in 9 countries.
Recruitment by countryCountry 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
120 patients aged over 80
Age at randomisation
020406080
100120140160180200
50 orunder
51-60 61-70 71-80 81-90 91-100 Over100
Age in years at randomisation
Num
ber o
f pat
ient
s
192 patients aged > 80 = increased world evidence base 5 x!
Delay between stroke onset and randomisation
0
20
40
60
80
100
120
140
160
180
1 or less 1 to 2 2 to 3 3 to 4 4 to 5 5 to 6Hours between stroke onset and randomisation
Num
ber o
f pat
ient
s
Median = 4.1 hours
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 (%) p
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
ASPECTS score, mean 5.0 6.3 <0.001
Follow-up CT: ischaemic change and swelling in patients with and without persisting hyperdense
artery
Hyperdense artery
persisted
n (%)
Hyperdense artery
disappearedn (%) 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
Lots of new features on the website!www.ist3.com
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 #2The 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 IST-3.
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
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-get feedback
•Do all six batches - get 5 CPD credits
IST-3: Training to read CT scans
what you, the reference standard, five experts and all other 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
4 hours 24 hours
Hypodensity : loss of grey/white differentiation, loss of the lentiform nucleus
Swelling : effacement of sulci, squashing the ventricle
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?
CT ‘at 2 hrs’ after onset.On closer questioning, true onset
was at least 8 hrs before CT.48 hrs
How hypodense?
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.
Baseline < 3 hoursEarly left basal ganglia hypodensity
Follow-upHaemorrhagic transformation
Is this too much hypodensity?
Swelling without density change? (CT at 2 hrs)
5 hrs: swelling + density change
4 days – infarct in density change and swelling areas
IST3 00188
5 hrs - then swelling + density change
Dense artery sign: what does it predict?
IST3 00338 24 hours later – persistent dense MCA (thrombus)
Dense MCA & haemorrhagic transformation
4.5 hours after acute left hemiparesis
IST3 00343
48 hours later – persistent MCA occlusion
Persistent dense MCA & massive swelling
Acute right hemiparesis 4 hours ago
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
• 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