Persistence of Association of Blood Biomarkers with Risk of Recurrent Stroke on Long-Term Follow-Up: Population-Based Study

BACKGROUND:Raised inflammatory biomarkers predict an increased short-term risk of recurrent vascular events after stroke or transient ischemic attack, but it is uncertain whether the hazard is maintained thereafter. In the absence of previous population-based studies, we aimed to determine the predictive value of biomarkers for the long-term risk of recurrent stroke in intensively treated patients following transient ischemic attack or stroke. METHODS:We studied 12 blood biomarkers related to inflammation, neuronal cell damage, and thrombosis soon after transient ischemic attack or stroke in a population-based study (OXVASC [Oxford Vascular Study]; 2002-2011) with follow-up to 2025. We used Cox and negative binomial regressions to assess associations between each log-transformed biomarker (per SD increase) and recurrent stroke (first event and total number), adjusted for age, sex, and baseline vascular risk factors. RESULTS:Of 1292 consecutive patients (mean/SD age, 73.1/13.2 years; 47.8% male), 365 recurrent strokes occurred in 280 patients during 11 336 patient-years. All inflammatory biomarkers were associated with 10-year risk of recurrence, with little impact of adjustment for other risk factors (adjusted incidence rate ratio: IL-6 [interleukin-6], 1.21 [95% CI, 1.04-1.42]; CRP [C-reactive protein], 1.29 [95% CI, 1.11-1.49]; TNFR-1 [tumor necrosis factor receptor-1], 1.24 [95% CI, 1.05-1.46]; and NGAL [neutrophil gelatinase-associated lipocalin], 1.15 [95% CI, 0.99-1.33]). Moreover, number of elevated (top quartile) inflammatory markers was associated with higher burden of recurrence (incidence rate ratio, 1.31 [95% CI, 1.15-1.50]; P<0.001), with no diminution over time (90 days: hazard ratio, 1.24 [95% CI, 0.98-1.57]; 90 days-1 year: 1.24 [95% CI, 0.95-1.62]; 1-5 years: 1.22 [95% CI, 1.01-1.47]; and 5-10 years: 1.34 [95% CI, 1.06-1.68]), and similar associations for transient ischemic attack and minor stroke. Biomarkers related to neuronal cell damage or thrombosis were generally less predictive of recurrent stroke. CONCLUSIONS:Inflammatory biomarkers were more predictive of long-term recurrent stroke than neuronal or thrombotic biomarkers, particularly when several inflammatory markers were raised. Predictive value was independent of other vascular risk factors and did not diminish with duration of follow-up, supporting trials of anti-inflammatory strategies for long-term secondary prevention.