RATIONALE: Intravenous thrombolysis with recombinant tissue Plasminogen 
Activator improves outcomes in patients treated early after stroke but at the 
risk of causing intracranial hemorrhage. Restricting recombinant tissue 
Plasminogen Activator use to patients with evidence of still salvageable tissue, 
or with definite arterial occlusion, might help reduce risk, increase benefit 
and identify patients for treatment at late time windows.
AIMS: To determine if perfusion or angiographic imaging with computed tomography 
or magnetic resonance help identify patients who are more likely to benefit from 
recombinant tissue Plasminogen Activator in the context of a large multicenter 
randomized trial of recombinant tissue Plasminogen Activator given within 
six-hours of onset of acute ischemic stroke, the Third International Stroke 
Trial.
DESIGN: Third International Stroke Trial is a prospective multicenter randomized 
controlled trial testing recombinant tissue Plasminogen Activator (0·9 mg/kg, 
maximum dose 90 mg) started up to six-hours after onset of acute ischemic 
stroke, in patients with no clear indication for or contraindication to 
recombinant tissue Plasminogen Activator. Brain imaging (computed tomography or 
magnetic resonance) was mandatory pre-randomization to exclude hemorrhage. Scans 
were read centrally, blinded to treatment and clinical information. In centers 
where perfusion and/or angiography imaging were used routinely in stroke, these 
images were also collected centrally, processed and assessed using validated 
visual scores and computational measures.
STUDY OUTCOMES: The primary outcome in Third International Stroke Trial is alive 
and independent (Oxford Handicap Score 0-2) at 6 months; secondary outcomes are 
symptomatic and fatal intracranial hemorrhage, early and late death. The 
perfusion and angiography study additionally will examine interactions between 
recombinant tissue Plasminogen Activator and clinical outcomes, infarct growth 
and recanalization in the presence or absence of perfusion lesions and/or 
arterial occlusion at presentation. The study is registered ISRCTN25765518.