Thrombolysis For Ais In The Unwitnessed Or Extended Therapeutic Time Window: A Systematic Review And Meta-Analysis

Introduction: We sought to assess the utility of intravenous thrombolysis (IVT) treatment in acute ischemic stroke (AIS) patients with unclear symptom onset time or outside the 4.5 hour time window, selected by advanced neuroimaging. Methods: We performed random-effects meta-analyses on the unadjusted and adjusted for potential confounders associations of IVT (alteplase 0.9 mg/kg) with the following outcomes: 3-month favorable functional outcome [FFO, modified Rankin Scale (mRS) scores: 0-1], 3-month functional independence (FI, mRS-scores: 0-2), 3-month mortality, 3-month functional improvement (assessed with ordinal analysis on the mRS-scores), symptomatic intracranial hemorrhage (sICH) and complete recanalization (CR). Results: We identified 4 eligible RCTs (859 total patients). In unadjusted analyses IVT was associated with higher likelihood of 3-month FFO (OR=1.48, 95%CI:1.12-1.96), FI (OR=1.42, 95%CI:1.07-1.90), sICH (OR=5.28, 95%CI:1.35-20.68) and CR (OR=3.29, 95%CI:1.90-5.69), with no significant difference in the odds of all-cause mortality risk at three months (OR=1.75, 95%CI: 0.93-3.29). In the adjusted analyses IVT was also associated with higher odds of 3-month FFO (OR adj =1.62, 95%CI:1.20-2.20), functional improvement (OR adj =1.42, 95%CI: 1.11-1.81) and sICH (OR adj =6.22, 95%CI: 1.37-28.26). There was no association between IVT and FI (OR adj =1.61, 95%CI: 0.94-2.75) or all-cause mortality at three months (OR adj =1.75, 95%CI: 0.93-3.29). No evidence of heterogeneity was evident in any of the analyses (I 2 =0). Conclusion: IVT in AIS patients with unknown symptom onset time or elapsed time from symptom onset more than 4.5 hours, selected with advanced neuroimaging, results in a higher likelihood of complete recanalization and functional improvement at three months despite the increased risk of sICH.