Interleukin-6, C-Reactive Protein, and Recurrence After Stroke: A Time-Course Analysis of Individual-Participant Data
John McCabe, Cathal Walsh, Sarah Gorey, Markus Arnold, Gian Marco De Marchis, Katie Harris, Pablo Hervella, Ramón Iglesias‐Rey, Christina Jern, Mira Katan, Linxin Li, Nobukazu Miyamoto, Joan Montaner, Francisco Purroy, Peter M. Rothwell, Tara M. Stanne, Cathie Sudlow, Yuji Ueno, Mikel Vicente‐Pascual, William Whiteley, Mark Woodward, Peter J. Kelly
Abstract
BACKGROUND: Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction. METHODS: Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship. RESULTS: There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P <0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19–1.41], per unit log e IL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98–1.25]; P interaction =0.03). After adjustment for risk factors/medication, the association remained for postacute IL-6 when analyzed per log e unit (risk ratio, 1.16 [CI, 1.05–1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19–2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP. CONCLUSIONS: Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies.