Association between high-sensitivity C-reactive protein, functional disability, and stroke recurrence in patients with acute ischaemic stroke: A mediation analysis

BACKGROUND: Post-stroke inflammation biomarker high-sensitivity C-reactive protein (hsCRP) increases cerebral infarct size and results in functional disability directly, it also contributes to the formation and maturation of atherosclerotic plaques, which increase the risk of stroke recurrence and results in functional disability indirectly. However, no study has quantified how much functional disability was mediated by stroke recurrence. METHODS: Patients with acute ischaemic stroke within 7 days and admitted to 169 hospitals in the Third China National Stroke Registry were analyzed. Blood samples were collected within 24 h of admission. Stroke recurrence and functional disability (defined as a modified Rankin scale score ≥ 2) were assessed via face-to-face interviews at three months. Mediation analysis under the counterfactual framework was performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between hsCRP and functional outcome. Sensitivity analyses were performed across different subgroups and on different scales of hsCRP measurement. FINDINGS: Of the 7603 analyzed patients (mean [SD] age, 62.3 [11.3] years; 2392 [31.5%] women), the median (interquartile range [IQR]) of NIHSS score was 3.0 (1.0–6.0). The median (IQR) level of hsCRP was 1.73 (0.81–4.38) mg/L. A total of 496 (6.5%) cases of stroke recurrence and 1884 (24.8%) cases of functional disability were observed at the 90-day follow-up. Each SD increase in the concentration of hsCRP was associated with an increased risk of stroke recurrence (adjusted odds ratio [aOR], 1.11; 95% CI, 1.04–1.18) and disability (aOR, 1.14; 95% CI, 1.08–1.20) within 90 days. Of 1884 functionally disabled patients, only 16.0 % (n = 302) of patients experienced stroke recurrence before functional disability. Stroke recurrence during follow-up explained 16.52% (95% CI, 5.79%–27.25%) of the relationship between hsCRP and functional disability. Sensitivity analyses in different subgroups and on different scales of hsCRP measurement showed comparable results. INTERPRETATION: Stroke recurrence mediates less than 20% of the association between hsCRP and functional disability at 90 days among patients with acute ischaemic stroke. In addition to typical secondary prevention strategies for preventing stroke recurrence, more attention should be paid to novel anti-inflammatory therapy to improve functional outcomes. FUNDING: Beijing Natural Science Foundation, the National Key R&D Program of China, the National Natural Science Foundation of China, and the Beijing Municipal Science & Technology Commission.