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 Pedersén, Francisco Purroy , Peter M. Rothwell, Cathie L M Sudlow, Yuji Ueno, Mikel Vicente-Pascual, William Whiteley, Mark Woodward, Peter J. Kelly

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Interleukin-6, C-Reactive Protein and Recurrence After Stroke: A Time-Course Analysis of Individual-Participant Data from 9,798 Patients.

Background and aims
RCTs of anti-inflammatory therapies for prevention after stroke are ongoing. IL-6 and high-sensitivity CRP are independently associated with major adverse cardiovascular events (MACE) post-stroke and may guide patient selection in future RCTs. Interpretation of IL-6/hsCRP levels may be confounded by the contribution of an inflammatory response to infarction. Optimal timing of hsCRP/IL-6 measurement post-stroke is unknown.

Using individual-participant data from 9,798 patients (11 studies, 19,891 person-years follow-up), we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrence stratified by phlebotomy timing. The post-stroke dynamics of IL-6/hsCRP levels were analysed by plotting their mean concentrations within each tenth of the sampling timeframe. Acute/post-acute phases were defined separately for each marker according to the shape of this relationship.

IL-6 was markedly elevated <24hrs post-event compared with basal levels (≥24hrs) (11.6pg/ml vs. 3.02pg/ml, p<0.001). HsCRP remained elevated for 10days (Fig.1). On univariate analysis, IL-6 was associated with MACE if measured ≥24hrs (Risk ratio [RR] 1.30, CI 1.19-1.41, per unit logeIL-6), but not <24hrs (RR 1.10, CI 0.98-1.25, Pheterogeneity=0.03). After adjustment for risk factors/medication, the association remained for post-acute IL-6 when analysed per logeunit (RR 1.16, CI 1.05-1.66) and per quarter increase (RR 1.55, CI 1.19-2.02, Q4 vs Q1), but not if measured <24hrs, with similar findings for recurrent stroke. There was no evidence of interaction for hsCRP.

The association between IL-6 and recurrence is modified by sample timing. These data will inform future RCT design incorporating biomarker-based selection of patients for anti-inflammatory therapies.
Original languageEnglish
Pages (from-to)1289–1299
Issue number5
Early online date19 Dec 2023
Publication statusPublished - 23 Jan 2024


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