C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype: An Individual Participant Data Meta-Analysis

John J McCabe; Cathal Walsh; Sarah Gorey; Katie Harris; Pablo Hervella; Ramon Iglesias-Rey; Christina Jern; Linxin Li; Nobukazu Miyamoto; Joan Montaner; Annie Pedersen; Francisco F Purroy; Peter M Rothwell; Cathie L Sudlow; Yuji Ueno; Mikel Vicente-Pascual; Will N Whiteley; Mark Woodward; Peter J Kelly

doi:10.1212/WNL.0000000000208016

C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype: An Individual Participant Data Meta-Analysis

Neurology. 2024 Jan 23;102(2):e208016. doi: 10.1212/WNL.0000000000208016. Epub 2023 Dec 19.

Authors

John J McCabe¹, Cathal Walsh¹, Sarah Gorey¹, Katie Harris¹, Pablo Hervella¹, Ramon Iglesias-Rey¹, Christina Jern¹, Linxin Li¹, Nobukazu Miyamoto¹, Joan Montaner¹, Annie Pedersen¹, Francisco F Purroy¹, Peter M Rothwell¹, Cathie L Sudlow¹, Yuji Ueno¹, Mikel Vicente-Pascual¹, Will N Whiteley¹, Mark Woodward¹, Peter J Kelly¹

Affiliation

¹ From the Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI) (J.J.M., C.W., S.G., P.J.K.), Dublin; School of Medicine (J.J.M., S.G., P.J.K.), University College Dublin (UCD); Stroke Service (J.J.M., S.G.), Department of Geriatric Medicine and Department of Neurology (P.J.K.), Mater Misericordiae University Hospital, Dublin; Health Research Institute and Mathematics Applications Consortium for Science and Industry (MACSI) (C.W.), Department of Mathematics and Statistics, University of Limerick, Ireland; George Institute for Global Health (K.H.), University of New South Wales, Sydney, Australia; Neuroimaging and Biotechnology Laboratory (NOBEL) (P.H., R.I.-R.), Clinical Neuroscience Research Laboratory, Health Research Institute of Santiago de Compostela, Spain; Department of Laboratory Medicine (C.J., A.P.), Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg; Department of Clinical Genetics and Genomics (C.J., A.P.), Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden; Wolfson Centre for the Prevention of Stroke and Dementia (L.L., P.M.R.) and Nuffield Department of Population Health (W.N.W.), University of Oxford, United Kingdom; Department of Neurology (N.M., Y.U.), Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology (J.M.), Hospital Universitari Vall d'Hebron, Barcelona; Institute de Biomedicine of Seville (J.M.), IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Neurology; Virgen Macarena Hospital (J.M.), Neurology, Sevilla; Neurovascular Research Laboratory (J.M.), Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona; Department of Neurology (F.F.P., M.V.-P.), Hospital Universitari Arnau de Vilanova; Department of Clinical Neurosciences (F.F.P., M.V.-P.), Institut Reserca Biomèdica Lleida, University of Lleida, Spain; Centre for Medical Informatics (C.L.S., W.N.W.), Usher Institute of Population Health Sciences and Informatics; Centre for Clinical Brain Sciences (C.L.S.), University of Edinburgh; and George Institute for Global Health (M.W.), Imperial College London, United Kingdom.

PMID: 38165328
DOI: 10.1212/WNL.0000000000208016

Abstract

Background and objectives: Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention.

Methods: Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after log_e transformation. We then did study-level meta-analysis with comparable published studies not providing IPD. Preferred Reporting Items for Systematic Review and Meta-Analyses IPD guidelines were followed.

Results: IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, p = 0.01), stroke of undetermined cause (UND) (RR 1.78, 1.19-2.66, p = 0.005), and small vessel occlusion (SVO) (RR 1.71, 0.99-2.96, p = 0.053) (quarter 4 [Q4] vs quarter 1 [Q1]). No association was observed for stroke due to cardioembolism or other determined cause. Similar results were seen for recurrent stroke and when analyzed per log_e unit increase for MACE (LAA, RR 1.26 [1.06-1.50], p = 0.009; SVO, RR 1.22 [1.01-1.47], p = 0.04; UND, RR 1.18 [1.04-1.34], p = 0.01). High-sensitivity CRP was associated with recurrent MACE in UND stroke only (Q4 vs Q1 RR 1.45 [1.04-2.03], p = 0.03). Findings were consistent on study-level meta-analysis of the IPD results with 2 other comparable studies (20,136 patients).

Discussion: Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.

Publication types

Meta-Analysis

MeSH terms

Anti-Inflammatory Agents* / therapeutic use
Atherosclerosis / pathology
C-Reactive Protein* / analysis
Cerebral Infarction / pathology
Humans
Interleukin-6* / analysis
Recurrence
Stroke* / drug therapy
Stroke* / pathology
Systematic Reviews as Topic

Substances

Anti-Inflammatory Agents
C-Reactive Protein
Interleukin-6