Late-window intravenous thrombolysis: new evidence beyond the 4.5-hour window

To date, evidence supporting late-window intravenous thrombolysis (IVT) comes from the 2019 individual patient meta-analysis by Campbell et al.¹, which pooled 414 patients. Patients presenting 4.5-9 hours after stroke onset were selected using perfusion imaging demonstrating salvageable brain tissue. IVT showed a benefit (mRS 0-1 at 90 days; aOR 1.86 [1.15-2.99]), despite an increased risk of symptomatic intra-cerebral haemorrhage. However, most patients were treated before endovascular thrombectomy (EVT) became standard practice. Recent randomised trials tried to help define which patients may- or may not- still benefit from IVT beyond the conventional therapeutic window.

LVO – When thrombectomy is available

The TIMELESS² and TNK-PLUS³ trials evaluated late-window IVT in patients with large vessel occlusion (LVO), including M2 occlusions in TIMELESS. Most patients underwent EVT (100% of patients in TNK-PLUS and 77% in TIMELESS). Neither trial demonstrated a functional benefit of IVT administered within 4.5-24 hours after symptom onset. In TIMELESS, IVT did not improve the distribution of functional outcomes (ordinal mRS shift: aOR 1.13, 95% CI [0.82-1.57]), while in TNK-PLUS, there was no significant increase in the proportion of patients achieving mRS 0-2 at 90 days (aRR 1.01, 95% CI [0.83-1.24]). No significant increase in sICH was observed. In both trials, patients were selected using perfusion imaging, and were required to have evidence of salvageable brain tissue with an ischemic core <70 ml.

LVO – When thrombectomy is not available

In settings where EVT is unavailable, the potential role of late-window IVT has also been investigated. The HOPE⁴ and TRACE-III⁵ trials evaluated IVT in patients with proximal vessel occlusion who could not undergo EVT, treating patients within 4.5-24 hours after symptom onset. In both trials, eligibility required evidence of salvageable brain based on perfusion imaging with an ischemic core <70ml. Both studies demonstrated that late-window IVT improved the likelihood of an excellent functional outcome compared with standard medical therapy (TRACE-III RR 1.37 [1.04-1.81]; HOPE aRR 1.52 [1.14-2.02]). The incidence of sICH was numerically higher in the IVT group in both trials, but the difference was statistically significant only in the HOPE trial (aRR 7.34 [1.54-34.84]).

Non-LVO

In contrast, the OPTION trial⁶, focused on patients with non-LVO who were not candidates for EVT. Selected using perfusion imaging (ischemic core volume <50ml with salvageable tissue), IVT administered 4.5-24 hours showed an improved excellent functional outcome (RR 1.28 [95% CI, 1.04-1.57]), although this benefit came at the cost of an increased risk of symptomatic haemorrhagic transformation (RR 2.85 [1.16-5.54]).

Posterior circulation ischemic stroke

Most randomised trials have focused on anterior circulation ischaemic stroke. The TRACE-5⁷ and EXPECTS⁸ trials evaluated IVT in Chinese patients with a posterior circulation stroke (pc-ASPECTS ≥6-7). Both studies reported improved functional outcomes with late-window IVT without increase in sICH. However, the clinical context differed between trials. In EXPECTS, patients considered eligible for EVT were excluded, although 22% of patients had LVO. In contrast, TRACE-5 included patients with basilar artery occlusion, with EVT planned in 56% of patients.

To conclude, IVT beyond 4.5 hours requires highly selected patients, guided by EVT availability, advanced imaging, and vascular territory. Ongoing studies will further define which patients are most likely to benefit and future guidelines will help refine patient selection and treatment strategies.

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