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Meta-Analysis
. 2025 Mar 19;20(3):e0315342.
doi: 10.1371/journal.pone.0315342. eCollection 2025.

A methodological assessment of randomization integrity in alteplase for acute ischemic stroke individual patient data meta-analyses

Ravi Garg  1 , Gabriel Torrealba-Acosta  2 , Steffen Mickenautsch  3 , Vance W Berger  4
Affiliations
Meta-Analysis

A methodological assessment of randomization integrity in alteplase for acute ischemic stroke individual patient data meta-analyses

Ravi Garg et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Forest plot of mean differences for baseline age for included trials.
The NINDS rt-PA Stroke Study (NINDS) is the only included study for which the 95% confidence interval did not include the null.
Fig 2
Fig 2. Forest plot of mean differences for baseline weight for included trials.
The NINDS rt-PA Stroke Study was the only included study for which the 95% confidence interval did not include the null.
Fig 3
Fig 3. Forest plot of mean difference for baseline NIHSS for included trials.
The ECASS-3 RCT was the only included study for which the 95% confidence interval did not include the null.
Fig 4
Fig 4. Pooled absolute risk difference for all included trials.
Fig 5
Fig 5. The pooled effect of treatment with and without the NINDS rt-PA Stroke Study and ECASS-3 RCT.
See this image and copyright information in PMC

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References

    1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al.. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344–418. - PubMed
    1. Borzak S, Ridker PM. Discordance between meta-analyses and large-scale randomized, controlled trials: examples from the management of acute myocardial infarction. American College of Physicians. 1995, p. 873–7. - PubMed
    1. Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al.. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ. 2019;366. - PubMed
    1. Berger VW, Weinstein S. Ensuring the comparability of comparison groups: is randomization enough?. Control Clin Trials. 2004;25(5):515–24. doi: 10.1016/j.cct.2004.04.001 - DOI - PubMed
    1. Berger V. Selection bias and covariate imbalances in randomized clinical trials. John Wiley & Sons; 2007. - PubMed

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