Interleukin-6, C-reactive protein, fibrinogen, and risk of recurrence after ischaemic stroke: Systematic review and meta-analysis

Abstract

Background Recent randomised trials showed benefit for anti-inflammatory therapies in coronary disease but excluded stroke. The prognostic value of blood inflammatory markers after stroke is uncertain and guidelines do not recommend their routine measurement for risk stratification. Methods We performed a systematic review and meta-analysis of studies investigating the association of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen and risk of recurrent stroke or major vascular events (MVEs). We searched EMBASE and Ovid Medline until 10/1/19. Random-effects meta-analysis was performed for studies reporting comparable effect measures. Results Of 2,515 reports identified, 39 met eligibility criteria (IL-6, n = 10; CRP, n = 33; fibrinogen, n = 16). An association with recurrent stroke was reported in 12/26 studies (CRP), 2/11 (fibrinogen) and 3/6 (IL-6). On random-effects meta-analysis of comparable studies, CRP was associated with an increased risk of recurrent stroke [pooled hazard ratio (HR) per 1 standard-deviation (SD) increase in loge-CRP (1.14, 95% CI 1.06–1.22, p < 0.01)] and MVEs (pooled HR 1.21, CI 1.10–1.34, p < 0.01). Fibrinogen was also associated with recurrent stroke (HR 1.26, CI 1.07–1.47, p < 0.01) and MVEs (HR 1.31, 95% CI 1.15–1.49, p < 0.01). Trends were identified for IL-6 for recurrent stroke (HR per 1-SD increase 1.17, CI 0.97–1.41, p = 0.10) and MVEs (HR 1.22, CI 0.96–1.55, p = 0.10). Conclusion Despite evidence suggesting an association between inflammatory markers and post-stroke vascular recurrence, substantial methodological heterogeneity was apparent between studies. Individual-patient pooled analysis and standardisation of methods are needed to determine the prognostic role of blood inflammatory markers and to improve patient selection for randomised trials of inflammatory therapies.

Dose-Dependent Association of Inflammatory Cytokines with Carotid Atherosclerosis in Transient Ischaemic Attack: Implications for Clinical Trials

“…Furthermore, our study found a significantly increased risk of recurrent stroke in those with a "high" CRP versus those with a "low" hsCRP, a cut-off which could be used to select higher risk patients for inclusion in clinical trials. This is supported by a recent systematic review and meta-analysis, which showed an association between increasing CRP and future risk of major vascular events in stroke survivors [25].…”

“…Furthermore, our findings suggest that patients with a CRP >2 mg/dL are at higher risk of recurrent stroke at 90 days, a cut-off which may be of benefit for the selection of patients for clinical trials of anti-inflammatory medications for stroke prevention. A recent systematic review suggested associations between inflammatory markers with recurrent stroke [25]. A Cochrane systematic review did not identify any studies examining the use of anti-inflammatory medications in the prevention of recurrent stroke or major cardiovascular events in patients with previous minor stroke or TIA [32].…”

Circulating Interleukin-6 Levels and Incident Ischemic Stroke

“…insight into the examined relationship. 44 The results from these meta-analyses, when seen together with Mendelian randomization results supporting associations between lifetime genetically downregulated IL-6 signaling and lower ischemic stroke risk, 12 provide further support in favor of IL-6 signaling as a promising target for lowering stroke risk. An interesting finding from our analysis is the clearly loglinear dose-response relationship between IL-6 levels and stroke risk.…”

Inflammation, Cholesterol, and Stroke Risk: Building Evidence for a Dual Target Strategy for Secondary Prevention

“…4 After a first stroke, studies of inflammatory markers have reported inconsistent associations with recurrent stroke, in part, relating to differing methods and analytic techniques. 5 However, several have reported that CRP and other inflammatory biomarkers are associated with stroke recurrence across all stroke subtypes, including large artery disease, lacunar stroke, and with thromboembolism in atrial fibrillation. 5 In patients with carotid stenosis, high density of inflammatory cells in excised plaque is associated with plaque instability and early stroke recurrence, 6 while positron emission tomography imaging studies have found that plaque inflammation is associated with early recurrent stroke independent of stenosis severity.…”