Perfusion-guided thrombolysis beyond 4.5 hours for acute ischemic stroke: A time-stratified systematic review and...

In the contemporary endovascular thrombectomy (EVT) era, treatment decisions are often made without routine perfusion imaging. However, perfusion remains central to intravenous thrombolysis (IVT) beyond 4.5 hours. Evidence across extended and very late windows remains uncertain.

To evaluate the efficacy and safety of perfusion-guided IVT beyond 4.5 hours after acute ischemic stroke and to assess the robustness of evidence across the 4.5-9 hour and 9-24 hour windows.

Time-stratified systematic review and meta-analysis of phase III randomized controlled trials.

We systematically searched PubMed, Embase, and the Cochrane Library from inception to February 8, 2026. Phase III randomized controlled trials enrolling perfusion-selected AIS patients treated 4.5-24 hours from last known well were included; trials permitting stratification into 4.5-9 and 9-24 hours were prioritized. Outcomes included 90 days excellent outcome (mRS 0-1), favorable (mRS 0-2), good (mRS 0-3), mortality, and symptomatic intracerebral hemorrhage (sICH). Random-effects meta-analysis and trial sequential analysis (TSA) were performed.

Five randomized controlled trials (n=1,798) were included. IVT increased excellent outcome in both the 4.5-9 hour window (n=866; RR 1.30, 95% CI 1.08-1.56; I²=0%; absolute risk difference (ARD)=9.1%; NNT=11) and the 9-24 hour window (n=563; RR 1.41, 95% CI 1.10-1.79; I²=0%; ARD=11.1%; NNT=9). Across 4.5-24 hours, IVT improved favorable (RR 1.18, 95% CI 1.07-1.29; I²=0%) and good outcomes (RR 1.11, 95% CI 1.03-1.21; I²=0%), with no significant effect on mortality (RR 1.14, 95% CI 0.85-1.52; I²=0%). IVT increased sICH risk overall (RR 5.63, 95% CI 2.17-14.57; I²=0%; ARD=approximately 3.0%; NNH=33). TSA suggested that the cumulative evidence has not yet reached the required information size for firm conclusiveness.

In the contemporary EVT era, perfusion-guided IVT may remain clinically relevant for selected patients treated beyond 4.5 hours, particularly those not eligible for thrombectomy or without immediate EVT access. Current phase III randomized evidence suggests improved functional outcomes but increased symptomatic intracerebral hemorrhage. However, TSA indicates that the evidence remains underpowered for definitive conclusions. Evidence for the 9-24 hour window is particularly limited and derived from China-based trials; therefore, these findings should be interpreted as hypothesis-supporting rather than conclusive.