Abstract

Tirilazad mesylate is neuroprotective in experimental models of ischaemic stroke suggesting it might be of benefit clinically.

To assess whether tirilazad mesylate is safe and effective at improving outcome in patients with acute ischaemic stroke.

Trials of tirilazad were identified from searches of the Cochrane Stroke Group Trials Register (last searched: May 2001) and the Cochrane Controlled Trials Register (CENTRAL/CCTR). In addition, we contacted the Pharmacia & Upjohn company, the manufacturer of tirilazad, to identify unpublished studies and further information.

Truly and quasi-randomised unconfounded placebo or open controlled trials of tirilazad administered within 24 hours onset of suspected or proven acute ischaemic stroke.

Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and QTc were extracted by treatment group from published data and company reports.

Six trials (four published, two unpublished) assessing tirilazad in 1757 patients with presumed acute ischaemic stroke were identified; all were double-blind and placebo-controlled in design. Tirilazad did not alter early case fatality (odds ratio (OR) 1.11, 95% confidence intervals (CI) 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). Tirilazad increased the odds of being dead or disabled by about one fifth, though the result was only just statistically significant; the odds ratios were similar whether the expanded Barthel Index or Glasgow Outcome Scale were used to assess outcome (OR 1.23, 95% CI 1.01 to 1.51; OR 1.23, 95% CI 1.01 to 1.50 respectively). Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (EBI) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a non-significant worse outcome was also seen in patients with mild-moderate stroke (OR 1.40, 95% CI 0.99 to 1.98).

Tirilazad mesylate increased the combined end-point of ‘death or disability’ by about one-fifth, but did not alter case fatality, when given to patients with acute ischaemic stroke. Although further trials of tirilazad are now not warranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischaemic stroke.