Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9–17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4–14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10–1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05–1.32]), per unit increase log _e IL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09–1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04–1.21], per unit increase log _e hsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04–1.21]; hsCRP, RR, 1.09 [95% CI, 1.04–1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00–1.19]; hsCRP, RR, 1.05 [95% CI, 1.00–1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09–1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07–1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08–1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93–1.43]). Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention. Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after log_e transformation. We then did study-level meta-analysis with comparable published studies not providing IPD. Preferred Reporting Items for Systematic Review and Meta-Analyses IPD guidelines were followed. IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, p = 0.01), stroke of undetermined cause (UND) (RR 1.78, 1.19-2.66, p = 0.005), and small vessel occlusion (SVO) (RR 1.71, 0.99-2.96, p = 0.053) (quarter 4 [Q4] vs quarter 1 [Q1]). No association was observed for stroke due to cardioembolism or other determined cause. Similar results were seen for recurrent stroke and when analyzed per log_e unit increase for MACE (LAA, RR 1.26 [1.06-1.50], p = 0.009; SVO, RR 1.22 [1.01-1.47], p = 0.04; UND, RR 1.18 [1.04-1.34], p = 0.01). High-sensitivity CRP was associated with recurrent MACE in UND stroke only (Q4 vs Q1 RR 1.45 [1.04-2.03], p = 0.03). Findings were consistent on study-level meta-analysis of the IPD results with 2 other comparable studies (20,136 patients). Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.

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.

Introduction: Inflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear. Materials and Methods: We did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup analysis according to timing of phlebotomy after the index event. Results: Eleven studies were included (14,002 patients, 42,800 follow-up years), of which seven provided IPD. Fibrinogen was associated with recurrent MACE on unadjusted (RR 1.35, 95% CI 1.17–1.57, supra-median vs sub-median) and adjusted models (RR 1.21, 95% CI 1.06–1.38). Fibrinogen was associated with recurrent stroke on univariate analysis (RR 1.19, 95% CI 1.03–1.39), but not after adjustment (RR 1.11, 95% CI 0.94–1.31). The association with recurrent MACE was consistently observed in patients with post-acute (⩾14 days) fibrinogen measures (RR 1.29, 95% CI 1.16–1.45), but not in those with early phlebotomy (<14 days) (RR 0.98, 95% CI 0.82–1.18) (P interaction = 0.01). Similar associations were observed for recurrent stroke. Discussion and Conclusion: Fibrinogen was independently associated with recurrence after stroke, but the association was modified by timing of phlebotomy. Fibrinogen measurements might be useful to identify patients who are more likely to derive benefit from anti-inflammatory therapies after stroke.

Despite effective secondary prevention, including oral anticoagulant (OAC) therapy, the risk of recurrent stroke (RS) in patients with atrial fibrillation (AF) remains substantial with an annualized risk of 3.2%-6.5% per year. The reasons for this high residual risk are unclear. There is growing need for improved risk prediction tools to identify patients at greatest risk of RS in AF and to find new therapeutic targets for secondary prevention. Our objective was to perform a systematic review to investigate the association of clinical factors and echocardiographic, blood, and neuroimaging biomarkers, with stroke recurrence after AF-related stroke. We searched Embase/Ovid Medline until August 2023. Studies were included irrespective of OAC use. Risk ratios (RRs) were pooled using random effects. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Of 5,427 records searched, 42 reports from 28 studies including 52,798 patients (5,046 RS events during follow-up) were identified. In addition to the CHA₂DS₂-Vasc score (RR 1.22, 95% CI 1.15-1.30, per point) and its individual components, the clinical factors associated with recurrence were a qualifying stroke despite OAC (RR 1.55, 1.23-1.94 [vs OAC-naïve]), sustained AF (RR 1.44, 1.19-1.75 [vs paroxysmal]), hyperlipidemia (RR 1.27, 1.05-1.53), chronic kidney disease (RR 1.86, 1.19-2.92), and malignancy (RR 4.36, 1.85-10.78). NIH Stroke Scale scores (RR 0.97, 0.95-0.99) and Asian ethnicity (RR 0.59, 0.36-0.97) were associated with a reduced risk of recurrence. Known AF was not associated with a higher risk of stroke compared with AF detected after stroke (RR 1.20, 0.93-1.55). Neuroimaging markers associated with RS included chronic lacunar (RR 1.91, 1.29-2.84) or embolic-appearing (RR 2.76, 1.32-5.77) infarcts and cerebral microbleeds (RR 1.29, 1.04-1.59). Echocardiographic markers included atrial size (RR 1.40, 1.12-1.75 per cm/m²), intracardiac thrombus (RR 1.99, 1.38-2.87), spontaneous left atrial appendage (LAA) echocardiographic contrast (RR 2.91, 1.21-6.17), or low LAA intensity variation (RR 2.81, 1.48-5.32). Data were limited for blood biomarkers. We identified several clinical factors associated with recurrence after AF-related stroke, with AF burden and stroke despite OAC of particular clinical relevance. Biomarkers of atrial cardiopathy, small vessel disease, or previous infarction were also associated with RS. Collaborative efforts are needed to identify and validate new risk factors and biomarkers of RS in AF.