Intravenous thrombolysis with 0.9 mg/kg alteplase for acute ischaemic stroke: a network meta-analysis of treatment delay

Objectives The aim of this study was to evaluate the effect of alteplase in intravenous thrombolysis of acute ischaemic stroke (AIS) regarding the different time windows of treatment (<3 hours, 3-4.5 hours, >4.5 hours). Methods A systematic literature search was conducted from PubMed, Cochrane Library and Embase. 12 clinical randomised controlled trials with 3402 patients with AIS met the inclusion criteria. The primary, secondary and tertiary outcomes were modified Rankin Scale (mRS) scores 0-1, mortality at 90th day after treatment and symptomatic intracerebral haemorrhage within 36 hours, respectively. Network meta-analysis and conventional meta-analysis were carried out for calculating odds ratio (OR), the surface under cumulative ranking curve (SUCRA) and the probabilities of being the best. Results For mRS, alteplase regardless of time delay was significantly more effective than placebo (OR 1.33-2.17). However, alteplase used within 3 hours after AIS occurrence (SUCRA=98.3%) was significantly more effective (OR=1.64) than that at 3-4.5 hours (SUCRA=43%) and showed the trend of priority (OR=1.47) compared with that beyond 4.5 hours (SUCRA=58%). For the mortality, compared with placebo (SUCRA=64.7%), alteplase within 3 hours was similar to that of 3-4.5 hours whereas alteplase beyond 4.5 hours (SUCRA=7.3%) showed the trend of significantly increasing 85% mortality. For the tertiary outcome, alteplase within 3 hours (SUCRA=19.0%) was comparable with placebo (SUCRA=99.9%) whereas alteplase beyond 3 hours significantly increased (OR 5.89-6.67) the symptomatic intracerebral haemorrhage. Conclusions Alteplase within 3 hours should be recommended as the best treatment delay for its best efficacy among all the intervention and equivalent safety compared with placebo. Alteplase beyond 3 hours was less effective compared with that within 3 hours and increased the risk of mortality on 3 months as well as symptomatic intracerebral haemorrhage at 36 hours. More head-to-head clinical trials are needed to confirm those findings.