Abstract Body: Background: Current guidelines for ischemic stroke recommend initiating intravenous thrombolytic therapy within 4.5 hours after stroke onset or the last known well time. However, advancements in imaging techniques, such as CT perfusion and perfusion-diffusion magnetic resonance imaging (MRI), have improved diagnostic accuracy. These modalities can identify viable brain tissue beyond the 4.5-hour window, and reperfusion through thrombolysis has been shown to enhance functional outcomes in patients with salvageable brain tissue beyond this timeframe.
Objective: The aim of this study is to assess the efficacy and safety of thrombolysis administered more than 4.5 hours after the onset of ischemic stroke.
Methods: We conducted a comprehensive search of the Cochrane Central Registry of Controlled Trials, PubMed, Embase, Web of Science, and clinicalTrials.gov databases for all randomized controlled trials (RCTs) published up to July 2024 comparing thrombolysis (TPA) > 4.5 h to standard of care. The primary functional outcome was the absence of disability measured as a modified Rankin scale of 0-1. The secondary clinical endpoints included symptomatic intracranial hemorrhage (ICH), 90-day mortality, reperfusion at 24 hours, and functional independence at 90 days. The odds ratio (OR) with a 95% confidence interval (CI) was calculated for the outcomes of interest. The protocol was registered in PROSPERO (CRD42024564522).
Results: Four RCTs were included in the analysis, comprising a total of 1,268 patients (TPA > 4.5h, n = 643; standard, n = 625) with a mean age of 70 years and 56% males. TPA > 4.5h was associated with a 42% reduction in the frequency of functional disability (OR: 1.42 [95% CI, 1.12-1.82]; p = 0.004; I² = 0%). There was also a 35% increase in functional independence at 90 days (OR: 1.35 [95% CI, 1.08-1.69]; p = 0.009; I² = 0%), and a 46% increase in reperfusion at 24 hours (OR: 1.46 [95% CI, 1.14-1.87]; p = 0.003; I² = 0%). There was, however, a significant increase in the risk of symptomatic ICH (OR: 2.82 [95% CI, 1.25-6.38]; p = 0.01; I² = 14%), but there was no significant difference in 90-day mortality (OR: 1.11 [95% CI, 0.80-1.53]; p = 0.53; I² = 0%).
Conclusion: Thrombolysis administered beyond 4.5 hours after the onset of ischemic stroke is associated with improved functional outcomes and increased reperfusion rates. However, this benefit is accompanied by a higher risk of symptomatic intracranial hemorrhage.