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Risk of selection bias assessment in the NINDS rt-PA stroke study

OBJECTIVES: The NINDS rt-PA Stroke Study is frequently cited in support of alteplase for acute ischemic stroke within 3 h of symptom onset. Multiple post-hoc reanalyses of this trial have been published to adjust for a baseline imbalance in stroke severity. We performed a risk of selection bias asse...

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Autores principales: Garg, Ravi, Mickenautsch, Steffen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202115/
https://www.ncbi.nlm.nih.gov/pubmed/35705913
http://dx.doi.org/10.1186/s12874-022-01651-4
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author Garg, Ravi
Mickenautsch, Steffen
author_facet Garg, Ravi
Mickenautsch, Steffen
author_sort Garg, Ravi
collection PubMed
description OBJECTIVES: The NINDS rt-PA Stroke Study is frequently cited in support of alteplase for acute ischemic stroke within 3 h of symptom onset. Multiple post-hoc reanalyses of this trial have been published to adjust for a baseline imbalance in stroke severity. We performed a risk of selection bias assessment and reanalyzed trial data to determine if the etiology of this baseline imbalance was more likely due to random chance or randomization errors. METHODS: A risk of selection bias assessment was conducted using signaling questions from the Cochrane Risk of Bias 2 (ROB 2) tool. Four sensitivity analyses were conducted on the trial data based on the randomization process: assessment of imbalances in allocation in unique strata; adherence to a pre-specified restriction on randomization between time strata at each randomization center; assessment of differences in baseline computed tomography (CT) results in unique strata; and comparison of baseline characteristics between allocation groups within each time strata. A multivariable logistic regression model was used to compare reported treatment effects with revised treatment effects after adjustment of baseline imbalances identified in the sensitivity analyses. RESULTS: Based on criteria from the ROB 2 tool, the risk of bias arising from the randomization process was high. Sensitivity analyses found 11 of 16 unique strata deviated from the expected 1:1 allocation ratio. Three randomization centers violated an apriori rule regarding a maximum difference in allocation between the time strata. Three unique strata had imbalances in baseline CT results that prognostically favored alteplase. Four imbalances in baseline characteristics were identified in the 91–180-min time stratum that all prognostically favored alteplase and were consistent with a larger alteplase treatment effect size compared to the 0–90-min time stratum. After adjustments for baseline imbalances, all reported treatment effects were reduced. Three out of seven originally positive reported results were revised to non-significant. CONCLUSION: This risk of selection bias assessment revealed a high risk of selection bias in the NINDS rt-PA Stroke Study. Sensitivity analyses conducted based on the randomization process supported this assessment. Baseline imbalances in the trial were more likely due to randomization errors than random chance. Adjusted analyses accounting for baseline imbalances revealed a reduction in reported treatment effects supporting the presence of selection bias in the trial. Treatment decisions and guideline recommendations based on the original treatment effect reported in the NINDS rt-PA Stroke Study should be done cautiously.
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spelling pubmed-92021152022-06-17 Risk of selection bias assessment in the NINDS rt-PA stroke study Garg, Ravi Mickenautsch, Steffen BMC Med Res Methodol Research OBJECTIVES: The NINDS rt-PA Stroke Study is frequently cited in support of alteplase for acute ischemic stroke within 3 h of symptom onset. Multiple post-hoc reanalyses of this trial have been published to adjust for a baseline imbalance in stroke severity. We performed a risk of selection bias assessment and reanalyzed trial data to determine if the etiology of this baseline imbalance was more likely due to random chance or randomization errors. METHODS: A risk of selection bias assessment was conducted using signaling questions from the Cochrane Risk of Bias 2 (ROB 2) tool. Four sensitivity analyses were conducted on the trial data based on the randomization process: assessment of imbalances in allocation in unique strata; adherence to a pre-specified restriction on randomization between time strata at each randomization center; assessment of differences in baseline computed tomography (CT) results in unique strata; and comparison of baseline characteristics between allocation groups within each time strata. A multivariable logistic regression model was used to compare reported treatment effects with revised treatment effects after adjustment of baseline imbalances identified in the sensitivity analyses. RESULTS: Based on criteria from the ROB 2 tool, the risk of bias arising from the randomization process was high. Sensitivity analyses found 11 of 16 unique strata deviated from the expected 1:1 allocation ratio. Three randomization centers violated an apriori rule regarding a maximum difference in allocation between the time strata. Three unique strata had imbalances in baseline CT results that prognostically favored alteplase. Four imbalances in baseline characteristics were identified in the 91–180-min time stratum that all prognostically favored alteplase and were consistent with a larger alteplase treatment effect size compared to the 0–90-min time stratum. After adjustments for baseline imbalances, all reported treatment effects were reduced. Three out of seven originally positive reported results were revised to non-significant. CONCLUSION: This risk of selection bias assessment revealed a high risk of selection bias in the NINDS rt-PA Stroke Study. Sensitivity analyses conducted based on the randomization process supported this assessment. Baseline imbalances in the trial were more likely due to randomization errors than random chance. Adjusted analyses accounting for baseline imbalances revealed a reduction in reported treatment effects supporting the presence of selection bias in the trial. Treatment decisions and guideline recommendations based on the original treatment effect reported in the NINDS rt-PA Stroke Study should be done cautiously. BioMed Central 2022-06-15 /pmc/articles/PMC9202115/ /pubmed/35705913 http://dx.doi.org/10.1186/s12874-022-01651-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Garg, Ravi
Mickenautsch, Steffen
Risk of selection bias assessment in the NINDS rt-PA stroke study
title Risk of selection bias assessment in the NINDS rt-PA stroke study
title_full Risk of selection bias assessment in the NINDS rt-PA stroke study
title_fullStr Risk of selection bias assessment in the NINDS rt-PA stroke study
title_full_unstemmed Risk of selection bias assessment in the NINDS rt-PA stroke study
title_short Risk of selection bias assessment in the NINDS rt-PA stroke study
title_sort risk of selection bias assessment in the ninds rt-pa stroke study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202115/
https://www.ncbi.nlm.nih.gov/pubmed/35705913
http://dx.doi.org/10.1186/s12874-022-01651-4
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