A clinical prediction model for 90-day functional dependence after minor stroke/TIA with exploratory pharmacogenetic associations: a post-hoc analysis of the INSPIRES trial

Background and purposeDual antiplatelet therapy (DAPT) reduces stroke recurrence after minor stroke/TIA, yet a clinically meaningful proportion of patients remain functionally dependent at 90 days. We developed an interpretable clinical prediction model to define a high-risk subgroup, and separately explored pharmacogenetic associations within this subgroup to generate hypotheses for precision secondary prevention.MethodsIn this post-hoc analysis of the INSPIRES trial (4,439 patients), LASSO logistic regression selected predictors for 90-day functional dependence (mRS > 2). Model performance was assessed by discrimination, calibration, and decision curve analysis. In a genotyped subcohort, CYP1A2 rs762551 and POR rs1057868 were evaluated for outcome association and enrichment in the high-risk subgroup.ResultsLogistic regression achieved the highest AUC point estimate (AUC = 0.727) among the four models evaluated (AUC range: 0.495–0.698; 95% CIs overlapped across models); it was selected as the final model for its interpretability and calibration, rather than for statistical superiority. Key predictors were admission NIHSS, age >65 years, and diabetes. The highest-risk quartile (25% of patients) carried a disproportionate outcome burden, with no effect modification by antiplatelet strategy (p = 0.793). CYP1A2 CC (23.65% vs. 16.28%; Pearson χ2p = 0.0031) and POR TC (54.58% vs. 46.22%; Pearson χ2p = 0.0105) genotypes were enriched in functionally dependent patients; CYP1A2 showed no significant allele-dosage trend (trend p = 0.0821), whereas POR demonstrated a significant allele-dosage trend (p = 0.0032).ConclusionThis clinical prediction model identified a high-risk subgroup accounting for most poor outcomes after minor stroke/TIA. Exploratory analyses identified CYP1A2 and POR variants enriched in this subgroup, generating pharmacogenetic hypotheses for future investigation.