BACKGROUND: Follow-up infarct volume (FIV) is a proposed surrogate endpoint for proof-of-concept clinical studies in acute ischemic stroke (AIS). This study aimed to provide clinical validation of an automated FIV algorithm, demonstrating the association of imaging biomarkers with clinical outcomes to support the use of these imaging endpoints in clinical trials. METHODS: Data were gathered for adult AIS patients undergoing mechanical thrombectomy with follow-up imaging 12-96 h from initial assessment. Non-contrast computed tomography was used to quantify infarct volume. Image processing used the AI-powered software Brainomix 360 Stroke (Brainomix Ltd., Oxford, United Kingdom) and Brainomix core lab research software. Measures included total FIV and components-ischemic injury corrected FIV (cFIV), hemorrhagic transformation (HT), anatomical distortion (AD; a marker of edema) and infarct growth (IG). The primary clinical endpoint was modified Rankin Scale (mRS) at 90 days; secondary clinical endpoint was NIH Stroke Scale (NIHSS) score at 24 h. RESULTS: Of 986 patients, 843 (85.5%; median age 72 years, 56.7% male) had complete data and were included in the study analysis. Median baseline NIHSS score was 17 (IQR: 12-21). Median imaging follow-up time was 24 h (IQR 20-28). Median 24 h NIHSS score was 11 (5-17); 34% of patients had mRS 0-2 at 90 days. Median FIV was 30.2 mL (12.5-120.8 mL). FIV was significantly associated with 90-day mRS (concordance = 0.819, p < 0.001) and NIHSS at 24 h (concordance = 0.722, p < 0.001). cFIV, HT, AD, and IG were also significantly associated with good clinical outcomes in both 90-day mRS (concordance = 0.702, p < 0.001; 0.660, p < 0.001; 0.591, p = 0.002; and 0.663, p < 0.001, respectively) and NIHSS at 24 h (0.774, p < 0.001; 0.652, p = 0.004 L; 0.694, p < 0.001; and 0.716, p < 0.001, respectively). In multivariate analysis, FIV remained strongly associated with 90-day mRS. FIV showed a bimodal distribution consistent with success/failure of recanalization during thrombectomy. CONCLUSION: Of the algorithm outputs assessed, FIV was most strongly associated with clinical outcomes. Ischemic injury, HT, edema and IG were also independently significantly associated with clinical outcome. This study validates the prognostic significance of automated FIV and its composites as mechanistic endpoints to improve early-stage trials of therapeutics in AIS.

Beaumont Hospital Dublin Ireland

Brainomix Limited Oxford United Kingdom

CSL Behring King of Prussia PA United States

CSL Behring Marburg Germany

CSL Innovation Melbourne VIC Australia

Department of Neurology 3rd Faculty of Medicine Charles University and University Hospital Kralovske Vinohrady Prague Czechia

Department of Radiology Royal College of Surgeons in Ireland Dublin Ireland

Division of Medical Sciences University of Oxford Oxford United Kingdom

Mayo Clinic Rochester MN United States

Nemocnice AGEL Ostrava Czechia

Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences Centre for Statistics in Medicine University of Oxford Oxford United Kingdom

Oxford University Hospitals NHS FT Oxford United Kingdom

Zobrazit více v PubMed

Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. . Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. (2016) 387:1723–31. doi: 10.1016/S0140-6736(16)00163-X, PMID: PubMed DOI

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. (2009) 45:228–47. doi: 10.1016/j.ejca.2008.10.026, PMID: PubMed DOI

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:e344–418. doi: 10.1161/STR.0000000000000211, PMID: PubMed DOI

Turc G, Bhogal P, Fischer U, Khatri P, Lobotesis K, Mazighi M, et al. . European Stroke Organisation (ESO) - European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischaemic strokeendorsed by Stroke Alliance for Europe (SAFE). Eur Stroke J. (2019) 4:6–12. doi: 10.1177/2396987319832140, PMID: PubMed DOI PMC

Berge E, Whiteley W, Audebert H, De Marchis GM, Fonseca AC, Padiglioni C, et al. . European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. (2021) 6:I–LXII. doi: 10.1177/2396987321989865, PMID: PubMed DOI PMC

Warach SJ, Luby M, Albers GW, Bammer R, Bivard A, Campbell BC, et al. . Acute stroke imaging research roadmap III imaging selection and outcomes in acute stroke reperfusion clinical trials: consensus recommendations and further research priorities. Stroke. (2016) 47:1389–98. doi: 10.1161/STROKEAHA.115.012364, PMID: PubMed DOI PMC

Mead GE, Sposato LA, Sampaio Silva G, Yperzeele L, Wu S, Kutlubaev M, et al. . A systematic review and synthesis of global stroke guidelines on behalf of the world stroke organization. Int J Stroke. (2023) 18:499–531. doi: 10.1177/17474930231156753, PMID: PubMed DOI PMC

Lathia CD, Amakye D, Dai W, Girman C, Madani S, Mayne J, et al. . The value, qualification, and regulatory use of surrogate end points in drug development. Clin Pharmacol Ther. (2009) 86:32–43. doi: 10.1038/clpt.2009.69, PMID: PubMed DOI

Yoo AJ, Zaidat OO, Chaudhry ZA, Berkhemer OA, Gonzalez RG, Goyal M, et al. . Impact of pretreatment noncontrast CT Alberta Stroke Program Early CT Score on clinical outcome after intra-arterial stroke therapy. Stroke. (2014) 45:746–51. doi: 10.1161/STROKEAHA.113.004260, PMID: PubMed DOI

Bouslama M, Ravindran K, Harston G, Rodrigues GM, Pisani L, Haussen DC, et al. . Noncontrast computed tomography e-stroke infarct volume is similar to rapid computed tomography perfusion in estimating postreperfusion infarct volumes. Stroke. (2021) 52:634–41. doi: 10.1161/STROKEAHA.120.031651, PMID: PubMed DOI

Brinjikji W, Abbasi M, Arnold C, Benson JC, Braksick SA, Campeau N, et al. . E-aspects software improves interobserver agreement and accuracy of interpretation of aspects score. Interv Neuroradiol. (2021) 27:781–7. doi: 10.1177/15910199211011861, PMID: PubMed DOI PMC

Chen IE, Tsui B, Zhang H, Qiao JX, Hsu W, Nour M, et al. . Automated estimation of ischemic core volume on noncontrast-enhanced CT via machine learning. Interv Neuroradiol. (2022) 32–41. doi: 10.1177/15910199221145487, PMID: PubMed DOI PMC

Mallon DH, Taylor EJR, Vittay OI, Sheeka A, Doig D, Lobotesis K. Comparison of automated ASPECTS, large vessel occlusion detection and CTP analysis provided by Brainomix and RapidAI in patients with suspected ischaemic stroke. J Stroke Cerebrovasc Dis. (2022) 31:106702. doi: 10.1016/j.jstrokecerebrovasdis.2022.106702, PMID: PubMed DOI

Wang J, Sun K, Cheng T, Jiang B, Deng C, Zhao Y, et al. . Deep high-resolution representation learning for visual recognition. IEEE Trans Pattern Anal Mach Intell. (2021) 43:3349–64. doi: 10.1109/TPAMI.2020.2983686, PMID: PubMed DOI

Taghanaki SA, Zheng Y, Kevin Zhou S, Georgescu B, Sharma P, Xu D, et al. . Combo loss: handling input and output imbalance in multi-organ segmentation. Comput Med Imaging Graph. (2019) 75:24–33. doi: 10.1016/j.compmedimag.2019.04.005, PMID: PubMed DOI

Harston GW, Minks D, Sheerin F, Payne SJ, Chappell M, Jezzard P, et al. . Optimizing image registration and infarct definition in stroke research. Ann Clin Transl Neurol. (2017) 4:166–74. doi: 10.1002/acn3.388, PMID: PubMed DOI PMC

Harston GWJ, Carone D, Sheerin F, Jenkinson M, Kennedy J. Quantifying infarct growth and secondary injury volumes: comparing multimodal image registration measures. Stroke. (2018) 49:1647–55. doi: 10.1161/STROKEAHA.118.020788, PMID: PubMed DOI PMC

Tjur T. Coefficients of determination in logistic regression models—a new proposal: the coefficient of discrimination. Am Stat. (2009) 63:366–72. doi: 10.1198/tast.2009.08210 DOI

Olive-Gadea M, Martins N, Boned S, Carvajal J, Moreno MJ, Muchada M, et al. . Baseline aspects and e-aspects correlation with infarct volume and functional outcome in patients undergoing mechanical thrombectomy. J Neuroimaging. (2019) 29:198–202. doi: 10.1111/jon.12564, PMID: PubMed DOI

Abdelkhaleq R, Kim Y, Khose S, Kan P, Salazar-Marioni S, Giancardo L, et al. . Automated prediction of final infarct volume in patients with large-vessel occlusion acute ischemic stroke. Neurosurg Focus. (2021) 51:E13. doi: 10.3171/2021.4.FOCUS21134, PMID: PubMed DOI PMC

Chen X, Lin S, Zhang X, Hu S, Wang X. Prognosis with non-contrast CT and CT perfusion imaging in thrombolysis-treated acute ischemic stroke. Eur J Radiol. (2022) 149:110217. doi: 10.1016/j.ejrad.2022.110217, PMID: PubMed DOI

Nagel S, Joly O, Pfaff J, Papanagiotou P, Fassbender K, Reith W, et al. . e-ASPECTS derived acute ischemic volumes on non-contrast-enhanced computed tomography images. Int J Stroke. (2020) 15:995–1001. doi: 10.1177/1747493019879661, PMID: PubMed DOI PMC

Kis B, Neuhaus AA, Harston G, Joly O, Carone D, Gerry S, et al. . Automated quantification of atrophy and acute ischemic volume for outcome prediction in endovascular thrombectomy. Front Neurol. (2022) 13:13. doi: 10.3389/fneur.2022.1056532, PMID: PubMed DOI PMC

Campbell BC, Tu HT, Christensen S, Desmond PM, Levi CR, Bladin CF, et al. . Assessing response to stroke thrombolysis: validation of 24-hour multimodal magnetic resonance imaging. Research support, non-U.S. Gov't. Arch Neurol. (2012) 69:46–50. doi: 10.1001/archneurol.2011.232, PMID: PubMed DOI

Prabhakaran S, Jovin TG, Tayal AH, Hussain MS, Nguyen TN, Sheth KN, et al. . Posttreatment variables improve outcome prediction after intra-arterial therapy for acute ischemic stroke. Cerebrovasc Dis. (2014) 37:356–63. doi: 10.1159/000362591, PMID: PubMed DOI PMC

Kral J, Cabal M, Kasickova L, Havelka J, Jonszta T, Volny O, et al. . Machine learning volumetry of ischemic brain lesions on ct after thrombectomy-prospective diagnostic accuracy study in ischemic stroke patients. Neuroradiology. (2020) 62:1239–45. doi: 10.1007/s00234-020-02419-7, PMID: PubMed DOI