ABSTRACT NUMBER: ESOC2026A1169 DECREASED RISK OF STROKE IN RANDOMISED CONTROLLED TRIALS OF ET-1 ANTAGONISTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and aims Cerebral small vessel disease (cSVD) is responsible for 30% of all-cause stroke. Endothelin-1 (ET-1) is the most potent cerebral endothelial vasoconstrictor. ET-1 is elevated during acute stroke and predicts cognitive outcomes. However, its potential in stroke prevention remains undetermined. We therefore performed a meta-analysis of stroke incidence in randomised controlled trials (RCTs) of ET-1 antagonists. Methods MEDLINE, EMBASE and CENTRAL were searched from inception until October 2025, including RCTs of ET-1 antagonists versus placebo/standard care (≥12 weeks) which reported stroke incidence. We excluded trials requiring large vessel cerebrovascular pathologies (subarachnoid haemorrhage, Moya-moya etc). Results were combined by inverse-variance weighted random effects meta-analysis. Results 6/7 eligible RCTs (N=4,177) reported lower incidence of stroke during ET-1 inhibition versus controls (pooled incidence rate ratio (IRR)=0.35, 95% CI:0.19-0.66, p=0.00113; I2=0, p-heterogeneity=0.979), although event rates were low in most trials. Effects were consistent in trials with ≥52 weeks of follow-up (pooled IRR=0.301, 95% CI:0.143-0.634, p=0.0016; I2=0, p-heterogeneity=0.99). Although no longer significant (pooled IRR=0.48, p=0.177), the effect was similar when excluding the large SONAR trial in chronic kidney disease (CKD) which independently demonstrated a significant benefit using atrasentan (IRR= 0.296, p=0.0024; 8 vs 27 events in 2,648 participants). Conclusions ET-1 antagonism was associated with reduced incidence of stroke in RCTs of populations at risk of cSVD, consistent with a significant effect in the large SONAR trial in CKD which dominated results. Endothelin-1 antagonism warrants testing as a novel target to reduce risk of cSVD-related stroke. Conflict of interest Caoimhe Byrne: PhD funded by the Alzheimer's Society Doctoral Training Centre for Vascular and Immune Contributors to Dementia (VIDA). Prof Webb: Nothing to disclose. Figure 1 - belongs to Results