A methodological assessment of randomization integrity in alteplase for acute ischemic stroke individual patient data meta-analyses
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Date
2025
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
Objectives Little is known about the integrity of randomization for randomized controlled trials (RCT) included in alteplase for stroke meta-analyses. If the RCTs were not properly randomized, the results could not be accepted at face value. The objective was to assess the integrity of randomization in individual patient data (IPD) meta-analyses supporting alteplase for acute ischemic stroke. Methods We assessed randomization reporting, performed qualitative risk of bias assessments arising from the randomization process, and performed fixed effects meta-analyses of baseline variables for which zero heterogeneity is expected if all included RCTs have unbiased randomization. Fixed-effects meta-analyses of baseline age, weight, and National Institute of Health Stroke Scale (NIHSS) score were performed. If heterogeneity was present (I2 > 0%), trials were systematically removed, starting with the RCT with the largest t-statistic until the I2 value was 0%. Results The NINDS rt-PA Stroke Study had a high risk of bias, the ECASS-3 RCT had some concerns, and all other trials were graded as low risk according to the Cochrane Risk of Bias (ROB-2) tool. The NINDS rt-PA Stroke Study contributed to heterogeneity in age and weight meta-analyses, and the ECASS-3 RCT contributed to heterogeneity in the NIHSS score meta-analysis. Removal of suspect trials resulted in the expected I2 value of 0%. Conclusions: The NINDS rt-PA Stroke Study and ECASS-3 trials contributed to heterogeneity in fixed effects meta-analyses of baseline variables while there should have been none. These RCTs are likely a source of selection bias in IPD meta-analyses due to suspect randomization.
Description
Keywords
ECASS-3 RCT, Objectives, RCTs, National Institute of Health Stroke Scale (NIHSS), Fixed-effects
Citation
Garg, R., Torrealba-Acosta, G., Mickenautsch, S. and Berger, V.W., 2025. A methodological assessment of randomization integrity in alteplase for acute ischemic stroke individual patient data meta-analyses. PloS one, 20(3), p.e0315342.