Lipoprotein(a) and Coronary Artery Disease Polygenic Risk Scores Do Not Improve Secondary Manifestations of Arterial Disease Score Prediction of Coronary Events After Ischemic Stroke

BACKGROUND: Survivors of ischemic stroke are at high risk for coronary artery disease (CAD), but individual risk varies. Lipoprotein(a) [Lp(a)] and CAD polygenic risk scores (CAD-PRS) improve risk prediction in primary prevention; however, their prognostic value after stroke remains uncertain. We assessed whether Lp(a) and CAD-PRS add predictive value to the Secondary Manifestations of Arterial Disease (SMART) secondary prevention score. METHODS: We analyzed 1202 UK Biobank participants of European ancestry with prior ischemic stroke and no CAD at baseline (2006-2022). Baseline clinical characteristics, Lp(a), and CAD-PRS were recorded. The primary outcome was incident CAD, identified from hospital, primary care, and death records. Competing-risk models compared SMART alone with SMART plus Lp(a), CAD-PRS, or both. Ten-year model performance was assessed using the area under the receiver operating characteristic curve and Brier score. Prespecified subgroup analyses examined age, sex, diabetes, and low-density lipoprotein cholesterol. RESULTS: During a median follow-up of 13.4 years, 155 participants (12.9%) developed CAD. SMART alone provided moderate discrimination (area under the receiver operating characteristic curve, 0.69 [95% CI, 0.64-0.75]) and a Brier score of 0.08. Adding Lp(a), CAD-PRS, or both did not improve prediction (change in area under the receiver operating characteristic curve, ≤0.002; all P>0.6; continuous net reclassification improvement, ≤0.03; all P>0.20). Results were consistent across subgroups, with no significant interactions after correction for multiple comparisons. CONCLUSIONS: Among survivors of ischemic stroke without CAD, neither Lp(a) nor CAD-PRS improved prediction of incident CAD beyond the SMART score. These findings do not support their incremental use for coronary risk stratification in this population.