Extended window thrombolysis (4.5-24 hours) in acute ischaemic stroke- a systematic review and meta-analysis of randomised control trials

Background Intravenous thrombolysis (IVT) for ischaemic stroke may be beneficial upto 24 hours after onset. This is an up-to-date meta-analysis of late window IVT trials, including alteplase and tenecteplase in light of new evidence. Methods Aggregate data from randomised control trials in the 4.5-24 hour window, with patient-level data from one trial were included.. Random effects meta-analysis was performed for excellent functional outcome (90-day modified Rankin Score-mRS- of 0-1) as the primary outcome. Secondary outcomes were early neurological improvement (ENI), good functional outcome (90-day mRS 0-2), and safety outcomes. Pre-specified subgroup analyses were conducted by EVT being available/permitted and treatment agent. Results 8 RCTs with n= 2548 patients (mean age 67.7 years, median NIHSS 9.5) were included. All but one trials used tissue mismatch imaging for patient selection. IVT significantly increased the odds of achieving the primary outcome (90-day mRS 0-1) ((OR,1.45 [95% CI, 1.23–1.72]; P<0.0001). For secondary outcomes, ENI was increased (OR,1.59[95% CI,1.02–2.46];p=0.04) while good functional outcome was not (OR,1.27[95% CI,0.96–1.67];p=0.10). IVT increased the risk of symptomatic intracranial haemorrhage (3%vs1.2%,OR,2.2 [95% CI,1.17–4.13];p=0.01), with no difference in 90-day mortality (10%vs9.8%,OR,1.01[95% CI,0.77–1.32];p=0.94) or poor functional outcome (OR,0.91[95% CI,0.72–1.14];p=0.40. Subgroup analyses did not demonstrate an interaction p<0.05 for the primary outcome. Discussion The current meta-analysis of late window IVT shows overall benefit on clinical outcomes between 4.5-24 hours after stroke onset, despite increase in intracranial haemorrhage. Subgroup analyses are underpowered and further data are needed to determine if there are clinically significant interactions by EVT status.