Alteplase for Acute Ischemic Stroke Beyond 3 hours: Enthusiasm Outpaces Evidence

2019 national guidelines currently make a "strong" recommendation for alteplase treatment for acute ischemic stroke (AIS) in the 3 to 4.5-hour window and a "moderate" recommendation for alteplase treatment guided by magnetic resonance imaging (MRI) in patients with unknown time of symptom onset. 1 The 3 to 4.5-hour treatment window recommendation is based on a single, randomized clinical trial (RCT): the European Cooperative Acute Stroke Study (ECASS) III. 1 The recommendation for MRI-based treatment with an unknown time of symptom onset is also based on a single RCT: MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset (WAKE-UP).1 Recently, a meta-analysis of RCTs for patients with an unknown time of symptom onset using advanced neuroimaging including the WAKE-UP RCT was published.2 This meta-analysis was composed of four incomplete RCTs and concluded alteplase treatment results in better functional outcome at 90 days.Careful consideration of the methodology of these studies should be considered prior to adapting alteplase use beyond the three-hour time window. Methodological Limitations of "ECASS III"In a 2014 editorial, Shy pointed out a statistical error in ECASS III. 3 The trial's reported adjusted primary analysis did not account for the baseline imbalance in prior stroke status.The ECASS III authors have not addressed this statistical error in the literature.In a recent publication, Alper et al used the raw data to reanalyze the ECASS III data with appropriate adjustments.In a multivariate model adjusted for both baseline National Institutes of Health Stroke Scale (NIHSS) scores (P = .03between groups) and prior stroke status (P = .003between groups) there was a non-significant difference between alteplase and placebo for all efficacy outcomes.4 An unplanned post-hoc reanalysis risks analytical bias by nature.Limitations not considered in the original trial publication, however, support Alper et al's findings.