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Abstract
Background Infarct growth on multimodal imaging is a common lead outcome in phase 2 proof-of-concept and dose-optimization neuroprotective agent stroke trials. However, the effect size in infarct growth reduction that correlates with clinically meaningful differences in clinical global disability outcomes has not been well delineated.
Methods A systematic literature search identified all endovascular thrombectomy randomized trials reporting magnitude of treatment effect on both infarct growth reduction and increase in functional independence (modified Rankin Scale (mRS) 0–2). Data aggregation determined the size of infarct growth reductions salient to four types of clinically meaningful effect sizes of increase in functional independence: (1) the minimal clinically important difference (MCID)–outcome specific; (2) the MCID–practice changing; (3) the realistic target difference; and (4) the reasonable comparability effect size.
Results A systematic search identified four trials enrolling 612 imaged participants. Across the trials, the amount of functional independence (mRS 0–2) increase associated with each 1 mL reduction in infarct growth was mean 2.3±0.6%. An infarct growth reduction of 0.57 mL correlated with the mRS 0–2 increase MCID of 1.3%. Infarct growth reductions of 2.27 mL, 4.35 mL, and 6.53 mL correlated with realistic effect and reasonable comparability effects sizes of mRS 0–2 increases of 5%, 10%, and 15%, respectively.
Conclusion In formal meta-analysis of randomized treatment trials, every 1 mL reduction in infarct growth was associated with a 2.3% increase in functional independence (mRS 0–2) at 3 months. This conversion factor can inform selection of infarct growth effect size targets for phase 2 trials of neuroprotective agents.
- Thrombectomy
- Stroke
- CT perfusion
- MR perfusion
- Statistics
Data availability statement
The guarantor accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
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Data availability statement
The guarantor accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Footnotes
Contributors In accordance with the guidelines provided by the International Committee of Medical Journal Editors (ICMJE), we hereby specify the contributions of each author to this manuscript: NCL: participation in the study design and methodology; literature searching and review; acquisition, analysis, and interpretation of data; drafting of initial manuscript; revision of the manuscript; final approval of the version to be published. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MBH: participation in the study design and methodology; data analysis and interpretation; revision of the manuscript for important revised content. Final approval of the version to be published. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JLS: conception and design of the study; data interpretation; critical review and editing of the manuscript; critical revision of the manuscript for important revised content. Final approval of the version to be published. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JLS, the study guarantor, accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests JLS has received, for service on clinical trial steering committees and DSMBs advising on rigorous study design and conduct, contracted hourly payments from Medtronic, Abbott, NeuroVasc, Phillips Medical, Bayer, Biogen, Roche, BrainsGate, BrainQ, and Occlutech, and stock options from Rapid Medical and QuantalX.
Provenance and peer review Not commissioned; externally peer reviewed.
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