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 &gt;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 &lt;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 &lt;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.

Endovascular treatment for anterior circulation large-vessel occlusion ischemic stroke with low ASPECTS: a systematic review and meta-analysis

“…However, the fragility index was calculated at 5 indicating a 'somewhat robust' result (Supplemental eFigure 25). 28 EVT-treated patients also had higher odds of achieving mRS 0-2 at 3 months compared with BMT-treated patients (OR: 2.91; 95% CI: 1.51-5.61; seven studies; I 2 = 62%; p for Cochran's Q = 0.02; p for subgroup differences = 0.10; Supplemental eFigure 26). This significant difference was further accentuated in sensitivity analysis (OR: 3.54; 95% CI: 1.97-6.39; Supplemental eFigure 27).…”

“…The fragility index of this outcome was calculated at 10, suggesting a 'somewhat robust' result (Supplemental eFigure 28). 28 Regarding safety outcomes, sICH occurred more often in EVT-treated patients compared with BMT-treated patients (OR: 2.30; 95% CI: 1.18-4.48; six studies; I 2 = 45%; p for Cochran's Q = 0.11; p for subgroup differences = 0.68; Supplemental eFigure 29). The difference between the two treatment groups was attenuated and became non-significant in the sensitivity analysis (OR: 2.01; 95% CI: 0.97-4.16; Supplemental eFigure 30).…”

Prolonged cardiac monitoring for stroke prevention: A systematic review and meta-analysis of randomized-controlled clinical trials

“…AF detection was significantly more common in the PCM group compared to controls (RR: 3.85; 95% CI: 2.59–5.73; 7 studies; I 2 = 58%; p for Cochran Q = 0.03; Figure 3) and the overall effect was considered highly robust (FI = 73). 29 This association was also significant in the subgroup of RCTs investigating ICM versus conventional monitoring (RR: 3.86; 95% CI: 2.24–6.64; 4 studies; I 2 = 59%; p for Cochran Q = 0.06; Supplemental Figure 8). The sensitivity analysis including four studies with a follow-up duration of ⩾12 months confirmed the overall effect of the primary analysis (Supplemental Figure 9).…”

“…Publication bias across individual studies was assessed when more than four studies were included in the analysis of the outcomes of interest, using both funnel plot inspection and the Egger et al’s linear regression test, 26 and the equivalent z test for each pooled estimate with a two-tailed p value <0.05 was considered statistically significant. Furthermore, analysis of dichotomous outcomes allowed the calculation of the fragility index (FI), 27,28 which was assessed based on the classification by Mun et al 29 suggesting that a FI ⩽ 4 was indicative of a non-robust result; a 4 < FI ⩽ 12 corresponded to a somewhat robust result; a 12 < FI ⩽ 34 indicated a robust result; and, finally, a FI > 34 was suggestive of a highly robust result. It should be noted, though, that FI has been recently criticized and should be interpreted as an additional measure of robustness and in conjunction with the other available statistical summaries that have been also used in the current meta-analysis.…”

Letter to the Editor Regarding CADTH rapid review: Systemic Thrombolysis by Alteplase for Acute Ischemic Stroke

“…In a recent study on the cumulative fragility index of studies on alteplase within the 3-hour window confirmed the evidence is highly robust. 13 The CADTH rapid review suggests "investigating whether there is a need to re-analyze data from other trials," but this has already been extensively done. An independent committee in 2004 8 and multiple other re-analyses of the NINDS trials all confirm the findings of benefit.…”