C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: 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 Purroy; Peter M Rothwell; Catherine Sudlow; Yuji Ueno; Mikel Vicente-Pascual; William Whiteley; Mark Woodward; Peter J Kelly

doi:10.1161/STROKEAHA.122.040529

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

Stroke. 2023 May;54(5):1289-1299. doi: 10.1161/STROKEAHA.122.040529. Epub 2023 Apr 7.

Authors

John J McCabe^#^{1

2

3}, Cathal Walsh^#^{1

4}, Sarah Gorey^{1

2

3}, Katie Harris⁵, Pablo Hervella⁶, Ramon Iglesias-Rey⁶, Christina Jern^{7

8}, Linxin Li⁹, Nobukazu Miyamoto¹⁰, Joan Montaner^{11

12

13

14}, Annie Pedersen^{7

8}, Francisco Purroy^{15

16}, Peter M Rothwell⁹, Catherine Sudlow^{17

18}, Yuji Ueno¹⁰, Mikel Vicente-Pascual^{15

16}, William Whiteley^{19

18}, Mark Woodward^{5

20}, Peter J Kelly^{1

2

21}

Affiliations

¹ Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI), Dublin, Ireland (J.J.M., C.W., S.G., P.J.K.).
² School of Medicine, University College Dublin (UCD), Ireland (J.J.M., S.G., P.J.K.).
³ Department of Geriatric Medicine (J.J.M., S.G.), Mater Misericordiae University Hospital, Dublin, Ireland.
⁴ Health Research Institute and Mathematics Applications Consortium for Science and Industry (MACSI), Department of Mathematics and Statistics, University of Limerick, Ireland (C.W.).
⁵ George Institute for Global Health, University of New South Wales, Sydney, Australia (K.H., M.W.).
⁶ Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neuroscience Research Laboratory, Health Research Institute of Santiago de Compostela, Spain (P.H., R.I.-R.).
⁷ Department of Laboratory Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Sweden (C.J., A.P.).
⁸ Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden (C.J., A.P.).
⁹ Wolfson Centre for the Prevention of Stroke and Dementia (L.L., P.M.R.), University of Oxford, United Kingdom.
¹⁰ Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan (N.M., Y.U.).
¹¹ Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain (J.M.).
¹² Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Neurology, Spain (J.M.).
¹³ Virgen Macarena Hospital, Neurology, Sevilla, Spain (J.M.).
¹⁴ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Spain (J.M.).
¹⁵ Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain (F.P., M.V.-P.).
¹⁶ Department of Clinical Neurosciences, Institut Reserca Biomèdica Lleida, University of Lleida, Spain (F.P., M.V.-P.).
¹⁷ Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics (C.S.), University of Edinburgh, United Kingdom.
¹⁸ Centre for Clinical Brain Sciences (C.S., W.W.), University of Edinburgh, United Kingdom.
¹⁹ Nuffield Department of Population Health (W.W.), University of Oxford, United Kingdom.
²⁰ George Institute for Global Health, Imperial College London, United Kingdom (M.W.).
²¹ Department of Neurology (P.J.K.), Mater Misericordiae University Hospital, Dublin, Ireland.

^# Contributed equally.

PMID: 37026458
DOI: 10.1161/STROKEAHA.122.040529

Abstract

Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines.

Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis.

Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase log_eIL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase log_ehsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43]).

Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Keywords: coronary artery disease; infarction; inflammation; ischemic stroke; thrombosis.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

C-Reactive Protein / analysis
Humans
Interleukin-6
Ischemic Attack, Transient* / prevention & control
Ischemic Stroke*
Prospective Studies
Recurrence
Stroke* / prevention & control

Substances

Interleukin-6
C-Reactive Protein