Imaging perfusion deficits, arterial patency and thrombolysis safety and efficacy in acute ischaemic stroke. Anobservational study of the effect of advanced imaging methods in The Third International Stroke Trial (IST-3), arandomised controlled trial
Authors: Wardlaw Joanna M , Carpenter Trevor , Sakka Eleni , Mair Grant , Cohen Geoff , Shuler Kirsten , Palmer Jeb M , Innes Karen , Sandercock Peter A 
Published: July 2014

BackgroundIntravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) improves outcome after an ischaemic stroke but increases the risk of intracranial haemorrhage. Restricting rt-PA to patients with salvageable tissue, or arterial occlusion, might reduce risk, increase benefit and enable treatment at late time windows.ObjectivesTo determine if computed tomography (CT) or magnetic resonance (MR) perfusion or angiography (CTP/CTA; MRP/MRA) imaging provide important information to guide the use of rt-PA up to 6 hours after a stroke.DesignProspective, multicentre, randomised, open, blinded, end-point trial of rt-PA.SettingForty-eight centres (eight countries) performed CTP/CTA; 37 centres (11 countries) performed MRP/MRA.ParticipantsPatients aged over 18 years in whom brain scanning excluded intracranial haemorrhage, with known time of stroke onset and no clear indication for or contraindication to rt-PA, in whom treatment can start within 6 hours of a stroke.Interventionsrt-PA (0.9 mg/kg, maximum dose 90 mg) intravenously (10% bolus, the rest infused over 1 hour) compared with best medical care.Main outcome measuresPrimary – alive and independent (Oxford Handicap Score 0–2) at 6 months; secondary – symptomatic and fatal intracranial haemorrhage, early and late death. All imaging assessed centrally, blind to other data. Perfusion lesion sizes [cerebral blood volume (CBV); cerebral blood flow; mean transit time (MTT); time to maximum flow], angiographic occlusion, associations with plain scan findings, clinical baseline and outcomes, and the interaction with rt-PA were assessed with dichotomous and ordinal analyses.ResultsBaseline characteristics of patients in the Third International Stroke Trial (IST-3) with perfusion and angiography imaging did not differ from those without (95% did not meet the prevailing licence criteria for rt-PA): 151 patients had perfusion imaging and 423 had angiography (141 and 307 obtained at randomisation respectively). Most randomisation imaging was with CT (n = 125/141, 89% perfusion;n = 277/307, 90% angiography) with little MR (n = 16/141, 11% perfusion;n = 39/307, 10% angiography). The median patient age was 81 (interquartile range 71–86) years; perfusion imaging or angiography imaging was performed at median of 3.9 hours after stroke. Perfusion lesion size differed significantly between parameters (MTT lesions largest, CBV lesions smallest;p < 0.0000; 46% had mismatch). Patients scanned earlier, who were older, or with more severe stroke, had larger perfusion lesions. Larger perfusion lesions were associated with poor outcome. Neither perfusion lesion size nor mismatch modified rt-PA effect on haemorrhage or 6-month outcome. Randomisation CTA (n = 253) showed arterial stenosis/occlusion in 42% (95% confidence interval 34% to 47%). Abnormal plain CT and plain CT + CTA were equally associated with worse baseline stroke severity, imaging and functional outcomes. rt-PA accelerated dissolution of arterial thrombus and reduced thrombus extension, but rt-PA effects did not differ between patients with angiographic occlusion compared with those without.ConclusionLarger perfusion lesions and arterial occlusion are associated with severe stroke and worse outcomes. However, patients with perfusion lesions, mismatch or angiographic occlusion had similar benefit and no worse hazard from rt-PA compared with those without. Visual assessment is an effective classification method. Perfusion or angiography imaging may improve diagnostic confidence in acute stroke but this does not improve prediction of prognosis or identify patients who respond differently to rt-PA. Although this trial is larger than others, the conclusion regarding perfusion imaging is limited by the sample size.Trial registrationCurrent Controlled Trials ISRCTN25765518.FundingThis project was funded by the NIHR Efficacy and Mechanism Evaluation programme and the Medical Research Council, and will be published in full inEfficacy and Mechanism Evaluation; Vol. 1, No. 1. See the NIHR Journals Library website for further project information.