Impact of Inflammatory Burden on Outcomes After Breakthrough Ischemic Stroke: Insights From the ASPERA-R Study

BACKGROUND: Patients with atrial fibrillation who experience ischemic stroke despite oral anticoagulation (breakthrough stroke) remain at high risk of recurrent vascular events and death. Although inflammation has been associated with thromboembolic risk, its prognostic role in breakthrough stroke remains unclear. We investigated whether a composite inflammatory burden index was associated with adverse outcomes after breakthrough ischemic stroke. METHODS: We conducted a multicenter retrospective cohort study of consecutive patients with breakthrough ischemic stroke from the ASPERA-R registry. Inflammatory burden was assessed using admission neutrophil-to-lymphocyte ratio, plateletto- lymphocyte ratio, systemic immune–inflammation index, and C-reactive protein. Biomarkers were log-transformed, standardized using Z scores, and combined into a composite inflammatory burden index. Patients were classified as having high (upper tertile) or lower inflammatory burden (lower 2 tertiles). Outcomes included new 90-day ischemic events (recurrent ischemic stroke, transient ischemic attack, or systemic embolism), 24-hour hemorrhagic transformation, and 90-day moderate-to-severe bleeding, intracranial hemorrhage, and mortality. Inverse probability of treatment weighting accounted for center, demographics, vascular risk factors and comorbidities, anticoagulation, competing stroke causes, baseline National Institutes of Health Stroke Scale, prestroke modified Rankin Scale, and time to blood collection. RESULTS: Among 1649 patients enrolled in ASPERA-R, 671 patients from 14 centers had complete biomarker data (median age, 80.1 years [interquartile range, 73.5–85.5]; 52.3% female). Of these, 223 (33.2%) had high inflammatory burden, and 448 (66.8%) had lower inflammatory burden. After weighting, high inflammatory burden was associated with increased risks of ischemic events at 90 days (hazard ratio, 1.53 [95% CI, 1.02–2.30]), all-cause mortality (hazard ratio, 1.70 [95% CI, 1.17–2.47]), moderate-to-severe bleeding (hazard ratio, 2.92 [95% CI, 1.04–8.17]), and hemorrhagic transformation at 24 hours (odds ratio, 2.18 [95% CI, 1.43–3.33]). CONCLUSIONS: In breakthrough ischemic stroke, high inflammatory burden was associated with increased risks of recurrent ischemic events, mortality, hemorrhagic transformation, and major bleeding. A composite of routinely available inflammatory biomarkers may help identify patients with higher residual vascular risk.