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BACKGROUND: For acute ischemic stroke, national practice guidelines recommend thrombolysis within a 4.5-h time window from symptom onset. Randomized trials with advanced neuroimaging have now examined extended thrombolytic time windows, and multiple meta-analyses have provided positive endorsements. However, these previous meta-analyses have not fully exploited the available data, examined quality of life, or reported the probability of clinically meaningful effects. This meta-analysis addresses these potential shortcomings.

METHODS: We performed a i) systematic literature review up to August 1, 2025, of all randomized controlled trials comparing thrombolysis (alteplase or tenecteplase) with the assistance of advanced neuroimaging to standard, non-thrombolytic therapy in acute ischemic stroke patients with unknown time or beyond 4.5 h since symptom onset and ii) an umbrella review of previous meta-analyses addressing this issue. Our primary outcome was the mean difference in the utility-weighted modified Rankin Scale (uw-mRS) scores. Secondary outcomes were the absolute risk difference (ARD) for minor disability status and mortality. Bayesian random effects meta-analyses were performed assuming a normal-normal hierarchical model with non-informative priors, which permitted probability calculations for benefit, harm, and regions of practical equivalence (ROPE).

RESULTS: Six original randomized trials of extended thrombolysis and 7 meta-analyses were identified but none had considered a uw-mRS score or reported direct probability statements regarding benefit or harm. Our primary uw-mRS outcome showed a ROPE probability of 99 % with only a 1 % probability of a clinically beneficial response with extended alteplase. There was also a 72 % probability that mortality increased by at least 1 life / 100 treated with extended thrombolysis.

CONCLUSIONS: In contrast with previous publications, this meta-analysis and umbrella review highlights the uncertainty of clinical benefits from extended thrombolysis treatment windows and the need for further high-quality research before this treatment is accepted into routine practice.

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