Transcript Can patients be too mild, too severe or too old for thrombolysis?

Can patients be too mild, too
severe or too old for
thrombolysis?
Professor Peter Sandercock
University of Edinburgh
ESC Hamburg 27th May 2011
Disclosures
I am co-chief investigator of the IST3 trial
I chair the DMC for the SYNTHESIS trial
Outline
• ‘Opinion-’ or ‘evidence-based’ practice?
• ‘Routine’ iv thrombolysis, influence of
– age
– severity
• Evidence from randomised trials
– Meta-analyses
– Unanswered questions: current trials
‘Opinion-’ or ‘evidence-based’ practice?
• 15 million acute strokes/ year world wide ->
we need RELIABLE evidence
• Expert opinion varies about whether to treat
– patients over 80 years
– Mild (NIHSS 0-5) / severe (NIHSS > 25)
• Routine practice varies between centres
• ‘Best evidence’ comes from randomised
trials and systematic reviews of trials
Percentage
Routine care: the older you are, the less
likely you are to get rt-PA for stroke:
Germany (similar in USA)
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
25–34 35–44 45–54 55–64 65–74 75–84 85+
Age
all
ages
Förch. Stroke 2009;40:1900-2
Randomised controlled trial
(RCT) evidence
Subgroup analyses:
What is the effect of age & NIHSS
on response to iv rt-PA?
Trials need to be large!
…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 subgroup are to be assessed
reliably)’.
Collins, Lancet 2001; volume 357: 373
RCT’s of iv thrombolysis vs control in acute
myocardial infarct (MI) and in acute stroke
Placebo-controlled trials of thrombolysis in acute MI
Total
1994
60,000
Placebo-controlled trials of thrombolysis in acute stroke
All agents (26 trials)
2009
7,100
rt-PA (11 trials)
2009
4,000*
*Largest stroke trial included just 800 patients
RCT data on only 67 patients aged >80
NINDS subgroups: effect of baseline NIHSS
on likelihood of favourable outcome (mRS)
Ingall, T. J. et al. Stroke 2004;35:2418-2424
Non-randomised data: VISTA
functional outcomes x baseline NIHSS
Mishra, N. K. et al. Stroke 2010;41:2612-2617
Conclusion?
• Very few mild and severe strokes included in
randomised trials
• Effects in mild and severe strokes UNCLEAR
– NINDS
– Non-randomised VISTA database analysis
• European approval for iv rtPA excludes mild
and severe strokes
• Pooled analysis of RCTs would be helpful…
Pooled analysis of 7 rt-PA trials (n= 3670)
Time to treatment and odds of ‘good outcome’ (mRS 0-1)
Lees et al Lancet 2010
Pooled analysis, authors conclusions:
• ‘We need to understand better the factors
that prevent alteplase from being effective in
individual patients… clinical variables e.g.:
age, stroke severity, …
• ‘..these factors must have a role in the
success of thrombolysis, but are poorly
understood’
• No analyses were performed to assess
effects of age / NIHSS on response to
rtPA in specific subgroups
Lees et al Lancet 2010
Two views
• We already know who to treat: ‘There is
no need to continue with randomised trials,
we now can treat at any age, any severity
and up to 4.5 hours (or even beyond)’
• The evidence is not as clear as some
experts make out: ‘We need randomised
evidence on the effects in:
– people > 80yrs
– NIHSS 15, NHSS >25’
• Conclusion: We need both clinical
experience and RCT evidence
Ongoing randomised trials
iv rt-PA vs control
Trial name
Age (y)
Time from
onset (h)
Imaging
Sample size
EXTEND
18+
3-9
Mismatch
DWI/PWI
400
TESPI
80+
0-3
CT or MR
600
150 to date
IST3
18+
0-6
CT or MR*
3100
PRISMS
Planned
18
0-6
CT or MR
NIHSS <6
1500
*CT, MR perfusion/angiography optional
Third International Stroke Trial.
A large randomised trial to answer the
question: can a wider variety of patients be
treated with iv thrombolytic therapy?
Main features of IST - 3
• Randomised, open, blinded outcomes study of
i.v. rt-PA vs control,
• Target 3100 patients < 6 h of acute ischaemic
stroke (n=2902 by today)
• No age or severity exclusion criteria
• Primary outcome: the proportion of patients
alive and independent at six months
• Randomisation by telephone or internet
• Imaging: CT or MR, perfusion/angio data if
available.
• Blinded central review of all scans
Age
1000
Number
800
600
400
200
0
18-50
51-60
61-70
71-80
Age
81-90
91-100
Already over 1200 patients aged >
80 years in study!
NIHSS
700
600
500
400
300
200
100
0
0 to 5
6 to 10
11 to 15 16 to 20 21 to 35
IST-3 will report its results at
ESC 2012 in Lisbon
Main results
• Primary outcome all cases 0-6h
Main subgroups
• Effect x time 0- 6h
• Effect x age
~ 1500 patients aged > 80 years).
• Effect x severity:
~ 600 with NIHSS < 5 (mild)
~ 400 with NIHSS > 24 (severe)
Conclusion: iv thrombolysis
• There is no reliable randomised trial
evidence about optimum stroke severity or
age limit for iv treatment
• Uncertainty about
– Age: how old is ‘too old’ ?
– Severity: too mild ? / too severe?
• Current trials (IST-3, TESPI, ?PRISM) will
help resolve these uncertainties
Acknowledgements:
The patients, the >115 hospitals in the IST-3 group,
who have recruited at least 1 patient, the Data
Monitoring Committee, the MRC Steering Committee,
Image reading panel, International Advisory Board,
Event adjudication panel