Third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke

Abstract

Background: Intravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit.

Design: International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With 3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit. TRIAL PROCEDURES: Patients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24-48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0-2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol).

Trial registration: ISRCTN25765518.

Figure 1

Results of a systematic review of the randomised trials of thrombolysis with rt-PA in acute ischaemic stroke. Effects on death at the end of follow-up. The estimate of treatment effect for each trial is expressed as an odds ratio (solid square) and its 95% confidence interval (horizontal line). The size of the black square is proportional to the amount of information available. An odds ratio of 1.0 corresponds to a treatment effect of zero, an odds ratio of less than 1.0 suggests treatment is better than control, and an odds ratio of greater than 1.0 suggests treatment is worse than control. The overall result and its 95% CI is represented by a diamond. (from Wardlaw et al [9]). Copyright Cochrane Collaboration, reproduced with permission.)

Figure 2

The adjusted odds ratio of the chance of a favourable outcome (modified Rankin score of 0–1, Barthel Index 95–100, NIHSS 0–1) at day 90 following thrombolysis with rt-PA by stroke onset to treatment time, derived from an analysis of individual patient data from the main randomised trials of rt-PA in acute ischaemic stroke. (from rt-PA Study group investigators [10], copyright Elsevier and the Lancet, reproduced with permission).