Fragility Index Meta-Analysis of Randomized Controlled Trials Shows Highly Robust Evidential Strength for Benefit of <3 Hour Intravenous Alteplase

Abstract

Background: Cumulative fragility index (FI) analysis enables quantification of the evidential strength of intravenous alteplase’s core indication—treatment of disabling acute ischemic stroke within 3 hours of onset. Methods: Meta-analyses were performed (study level) or identified (individual participant level) for freedom-from-disability (modified Rankin Scale [mRS] score 0–1, primary efficacy), functional independence (mRS score 0–2, secondary efficacy), and mortality outcomes. Individual trial and cumulative FI analyses were serially conducted after each successive randomized controlled trial (RCT). FI scores were classified as follows: not robust (FI 0–4), somewhat robust (FI 5–12), robust (FI 13–33), and highly robust (FI >33). Results: Nine randomized controlled trials were identified from 1995 to 2021 of within-3-hour intravenous alteplase for acute ischemic stroke. In study-level meta-analyses, alteplase increased freedom-from-disability outcome (mRS score 0–1), 31.0% versus 22.3%, relative risk, 1.39 (95% CI, 1.20–1.61); P <0.00001; increased functional independence (mRS score 0–2), 39.7% versus 31.2%, relative risk, 1.29 (95% CI, 1.14–1.45), P <0.000; and did not alter mortality, 24.1% versus 26.1%; P =0.23. Overall FIs for study-level meta-analyses were both highly robust at 42 and 40 for mRS score 0–1 and mRS score 0–2, respectively. Serial FI analyses showed robust evidential strength for intravenous alteplase superiority with publication of the 2 NINDS-tPA trials (National Institute of Neurological Disorders and Stroke–tissue-type plasminogen activator) in 1995, increased to highly robust in 2012, and remains highly robust in 2021. Conclusions: Within-3-hour intravenous alteplase for acute ischemic stroke is one of the most robustly proven therapies in medicine. The initial concurrent trials 25 years ago showed robust evidence for benefit and, after additional studies, advanced to highly robust.