by Simone Salemme
For September we have chosen Palaiodimou L, Papageorgiou NM, Romoli M, et al. IV Thrombolysis in the Extended Time Window for Acute Ischemic Stroke: An Updated Systematic Review and Meta-Analysis. Neurology. 2026 107 (3) e218294 doi:10.1212/WNL.0000000000218294
Intravenous thrombolysis is an established treatment for acute ischaemic stroke within 4.5 hours of symptom onset or last known well, but many patients present later, including those with wake-up or unknown-onset stroke. Advances in neuroimaging have increasingly challenged a strictly time-based approach, supporting tissue-based selection strategies that identify patients who may still benefit from reperfusion beyond the conventional window. In this updated systematic review and meta-analysis, Palaiodimou and colleagues evaluated the efficacy and safety of IV thrombolysis beyond 4.5 hours from last known well in patients with acute ischaemic stroke.
The authors searched MEDLINE, Scopus, and ClinicalTrials.gov for randomised controlled trials and individual patient-data meta-analyses of randomised trials comparing IV thrombolysis plus best medical therapy with best medical therapy alone. Eligible patients presented more than 4.5 hours after last known well, and studies could include alteplase or tenecteplase, with or without endovascular treatment. The primary efficacy outcome was excellent functional outcome at 90 days, defined as modified Rankin Scale score 0–1; the primary safety outcome was symptomatic intracranial haemorrhage. Prespecified subgroup analyses considered thrombolytic agent, treatment window, imaging selection strategy, vascular territory, and endovascular treatment.
The meta-analysis included 13 studies, comprising 2,456 patients treated with IV thrombolysis and 2,411 controls. IV thrombolysis significantly improved excellent functional outcome at 90 days compared with best medical therapy alone (risk ratio 1.23, 95% CI 1.15–1.33; I²=0%; number needed to treat=13). It also improved good functional outcome (risk ratio 1.15, 95% CI 1.05–1.25) and reduced disability across the modified Rankin Scale distribution (common odds ratio 1.26, 95% CI 1.13–1.39). These efficacy findings were consistent across the main prespecified subgroups, with no significant differences by thrombolytic agent, time window, imaging strategy, affected vascular territory, or use of endovascular treatment.
The main safety signal was an increased risk of symptomatic intracranial haemorrhage among patients receiving IV thrombolysis (risk ratio 2.11, 95% CI 1.36–3.28; number needed to harm=75). However, rates of any intracranial haemorrhage and all-cause mortality at 90 days did not significantly differ between groups. Leave-one-out analyses supported the stability of the efficacy and main safety findings, and trial sequential analysis indicated that the cumulative evidence for excellent functional outcome crossed the efficacy boundary, supporting a robust treatment effect.
Overall, this study supports IV thrombolysis in selected patients presenting beyond the traditional 4.5-hour window, with a favourable functional benefit despite increased symptomatic haemorrhagic risk. The findings reinforce the shift from rigid time-based eligibility toward more nuanced clinical and imaging-based decision-making.
In appropriately selected patients, extended-window IV thrombolysis may improve functional outcomes without increasing mortality, but its use requires careful assessment of benefit, haemorrhagic risk, imaging context, and access to contemporary reperfusion pathways.
