TY - JOUR
T1 - Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis
AU - McCabe, John J.
AU - Harris, Katie
AU - Walsh, Cathal
AU - Gorey, Sarah
AU - Arnold, Markus
AU - De Marchis, Gian Marco
AU - Hervella, Pablo
AU - Iglesias-Rey, Ramon
AU - Jern, Christina
AU - Katan, Mira
AU - Li, Linxin
AU - Miyamoto, Nobukazu
AU - Montaner, Joan
AU - Purroy, Francisco
AU - Rothwell, Peter M.
AU - Stanne, Tara M.
AU - Sudlow, Cathie
AU - Ueno, Yuji
AU - Vicente-Pascual, Mikel
AU - Whiteley, William
AU - Woodward, Mark
AU - Kelly, Peter J.
N1 - Publisher Copyright:
© 2025 American Heart Association, Inc.
PY - 2025/9/1
Y1 - 2025/9/1
N2 - BACKGROUND: Uncertainty remains whether inflammation is implicated in poststroke recurrence in patients without atherosclerosis. We evaluated the contribution of atherosclerosis status to the association between inflammatory markers and major adverse cardiovascular events (MACE) poststroke. METHODS: We performed an individual-participant data meta-analysis of 11 prospective cohorts (12 countries, 1995–2017). Studies included patients with ischemic stroke/transient ischemic attack and measured IL (interleukin)-6/hsCRP (high-sensitivity C-reactive protein) postevent. We analyzed the association between IL-6/hsCRP and recurrent stroke/MACE using multivariable Cox regression analyses (conditional logistic regression for 1 study). Analyses were stratified by the presence/absence of atherosclerosis (definition: prior history of coronary disease, peripheral artery disease, or large artery atherosclerotic stroke) and adjusted for cardiovascular risk factors/preventative medication. RESULTS: Overall 10148 patients (3448 [34.0%] had atherosclerosis) with 21177 years of follow-up were included (1707 MACE outcomes/1353 recurrent strokes). In patients with atherosclerosis, IL-6 was independently associated with MACE (risk ratio [RR], 1.22 [95% CI, 1.08–1.37]; per logeunit increase) and recurrent stroke (RR, 1.23 [95% CI, 1.08–1.41]). Compared with patients in the bottom quarter, those in the top quarter of IL-6 levels had double the risk of MACE (RR, 2.05 [95% CI, 1.37–3.08]) and stroke (RR, 1.97 [95% CI, 1.28–3.05]). IL-6 was also associated with MACE (RR, 1.11 [95% CI, 1.01–1.23]) but not stroke (RR, 1.08 [95% CI, 0.98–1.20]; per logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=0.25 and 0.13 for MACE/recurrent stroke, respectively). hsCRP was associated with MACE in patients with (RR, 1.12 [95% CI, 1.05–1.21]; per logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01–1.14]; Pinteraction=0.28). No association with recurrent stroke was observed for hsCRP with (RR, 1.06 [95% CI, 0.98–1.14]) or without atherosclerosis (RR, 0.97 [95% CI, 0.91–1.04]; Pinteraction=0.18). CONCLUSIONS: IL-6/hsCRP were associated with poststroke recurrence irrespective of atherosclerosis. These data support the inclusion of patients in trials of anti-inflammatory therapies after stroke with elevated IL-6 or hsCRP, including those without prior atherosclerotic events.
AB - BACKGROUND: Uncertainty remains whether inflammation is implicated in poststroke recurrence in patients without atherosclerosis. We evaluated the contribution of atherosclerosis status to the association between inflammatory markers and major adverse cardiovascular events (MACE) poststroke. METHODS: We performed an individual-participant data meta-analysis of 11 prospective cohorts (12 countries, 1995–2017). Studies included patients with ischemic stroke/transient ischemic attack and measured IL (interleukin)-6/hsCRP (high-sensitivity C-reactive protein) postevent. We analyzed the association between IL-6/hsCRP and recurrent stroke/MACE using multivariable Cox regression analyses (conditional logistic regression for 1 study). Analyses were stratified by the presence/absence of atherosclerosis (definition: prior history of coronary disease, peripheral artery disease, or large artery atherosclerotic stroke) and adjusted for cardiovascular risk factors/preventative medication. RESULTS: Overall 10148 patients (3448 [34.0%] had atherosclerosis) with 21177 years of follow-up were included (1707 MACE outcomes/1353 recurrent strokes). In patients with atherosclerosis, IL-6 was independently associated with MACE (risk ratio [RR], 1.22 [95% CI, 1.08–1.37]; per logeunit increase) and recurrent stroke (RR, 1.23 [95% CI, 1.08–1.41]). Compared with patients in the bottom quarter, those in the top quarter of IL-6 levels had double the risk of MACE (RR, 2.05 [95% CI, 1.37–3.08]) and stroke (RR, 1.97 [95% CI, 1.28–3.05]). IL-6 was also associated with MACE (RR, 1.11 [95% CI, 1.01–1.23]) but not stroke (RR, 1.08 [95% CI, 0.98–1.20]; per logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=0.25 and 0.13 for MACE/recurrent stroke, respectively). hsCRP was associated with MACE in patients with (RR, 1.12 [95% CI, 1.05–1.21]; per logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01–1.14]; Pinteraction=0.28). No association with recurrent stroke was observed for hsCRP with (RR, 1.06 [95% CI, 0.98–1.14]) or without atherosclerosis (RR, 0.97 [95% CI, 0.91–1.04]; Pinteraction=0.18). CONCLUSIONS: IL-6/hsCRP were associated with poststroke recurrence irrespective of atherosclerosis. These data support the inclusion of patients in trials of anti-inflammatory therapies after stroke with elevated IL-6 or hsCRP, including those without prior atherosclerotic events.
KW - atherosclerosis
KW - atrial fibrillation
KW - coronary disease
KW - inflammation
KW - interleukins
UR - https://www.scopus.com/pages/publications/105010861530
U2 - 10.1161/STROKEAHA.125.052091
DO - 10.1161/STROKEAHA.125.052091
M3 - Article
C2 - 40677223
AN - SCOPUS:105010861530
SN - 0039-2499
VL - 56
SP - 2588
EP - 2596
JO - Stroke
JF - Stroke
IS - 9
ER -
