Can patients be too mild, too severe or too old for thrombolysis?Professor Peter Sandercock University of EdinburghESC Hamburg 27th May 2011DisclosuresI am co-chief investigator of the IST3 trialI chair the DMC for the SYNTHESIS trial

OutlineOpinion- or evidence-based practice?Routine iv thrombolysis, influence of age severityEvidence from randomised trialsMeta-analysesUnanswered questions: current trials

Opinion- or evidence-based practice?15 million acute strokes/ year world wide -> we need RELIABLE evidenceExpert opinion varies about whether to treat patients over 80 years Mild (NIHSS 0-5) / severe (NIHSS > 25)Routine practice varies between centresBest evidence comes from randomised trials and systematic reviews of trials

Routine care: the older you are, the less likely you are to get rt-PA for stroke: Germany (similar in USA)Frch. Stroke 2009;40:1900-2Age

Randomised controlled trial (RCT) evidenceSubgroup 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

RCTs of iv thrombolysis vs control in acute myocardial infarct (MI) and in acute strokePlacebo-controlled trials of thrombolysis in acute MITotal 199460,000Placebo-controlled trials of thrombolysis in acute strokeAll agents (26 trials) 20097,100 rt-PA(11 trials)20094,000**Largest stroke trial included just 800 patients RCT data on only 67 patients aged >80

Ingall, T. J. et al. Stroke 2004;35:2418-2424NINDS subgroups: effect of baseline NIHSS on likelihood of favourable outcome (mRS)

Mishra, N. K. et al. Stroke 2010;41:2612-2617Non-randomised data: VISTAfunctional outcomes x baseline NIHSS

Conclusion?Very few mild and severe strokes included in randomised trials Effects in mild and severe strokes UNCLEARNINDSNon-randomised VISTA database analysis European approval for iv rtPA excludes mild and severe strokesPooled 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 subgroupsLees et al Lancet 2010

Two viewsWe 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 > 80yrsNIHSS 15, NHSS >25Conclusion: We need both clinical experience and RCT evidence

Ongoing randomised trials iv rt-PA vs control*CT, MR perfusion/angiography optional

Trial nameAge (y)Time from onset (h)ImagingSample sizeEXTEND18+3-9MismatchDWI/PWI 400

TESPI80+0-3CT or MR600150 to dateIST318+0-6CT or MR*3100PRISMSPlanned180-6CT or MRNIHSS

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 criteriaPrimary outcome: the proportion of patients alive and independent at six monthsRandomisation by telephone or internetImaging: CT or MR, perfusion/angio data if available. Blinded central review of all scans

AgeAlready over 1200 patients aged > 80 years in study!

NIHSS

IST-3 will report its results at ESC 2012 in LisbonMain resultsPrimary outcome all cases 0-6hMain subgroupsEffect x time 0- 6hEffect x age ~ 1500 patients aged > 80 years). Effect x severity: ~ 600 with NIHSS < 5 (mild) ~ 400 with NIHSS > 24 (severe)

Conclusion: iv thrombolysisThere is no reliable randomised trial evidence about optimum stroke severity or age limit for iv treatmentUncertainty aboutAge: 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

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