Extended thrombolysis in acute ischemic stroke: A Bayesian meta-analysis and umbrella review

Background: For acute ischemic stroke, national practice guidelines recommend thrombolysis within a 4.5-hour time window from symptom onset. Randomized trials with advanced neuroimaging have now examined extended thrombolytic time windows, and multiple metaanalyses 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 hours 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.