Tirilazad mesylate in acute ischemic stroke - A systematic review

Background and Purpose-Tirilazad is a nonglucocorticoid, 21-aminosteroid th at inhibits lipid peroxidation. Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a re sult, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke. We performed a system atic review of randomized, controlled trials that assessed the safety and e fficacy of tirilazad in patients with acute ischemic stroke. Methods-Trials of tirilazad were identified from searches of the Cochrane L ibrary and communication with the Pharmacia & Upjohn company, the manufactu rer of tirilazad. Data relating to early and end-of-trial case fatality, di sability (Barthel Index and Glasgow Outcome Scale), phlebitis, and correcte d QT interval were extracted by treatment group from published data and com pany reports and analyzed by using the Cochrane Collaboration meta-analysis software REVMAN. Results-Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; ail were dou ble-blind and placebo controlled in design. Tirilazad did not alter early c ase fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1. 56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). A just-si gnificant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1.23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functio nal outcome (expanded Barthel Index) was significantly worse in prespecifie d subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subject s receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignifi cant worse outcome was also seen in patients with mild to moderate stroke ( OR 1.40, 95% CI 0.99 to 1.98). Conclusions-Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further t rials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke.