Key result
High baseline risk score linked to ~5.2-fold higher odds of 90-day functional dependence.
Why the study?
Although dual antiplatelet therapy reduces stroke recurrence after minor stroke or TIA, a clinically meaningful proportion of patients remain functionally dependent at 90 days, motivating the development of an interpretable clinical prediction model to define this high-risk subgroup and explore pharmacogenetic associations.
Does a multimodal clinical prediction model accurately stratify 90-day functional dependence risk and identify effect modification by dual antiplatelet therapy or pharmacogenetic enrichment in patients with minor ischemic stroke or high-risk TIA?
Cohort (n=4,439)
Double-blind (in parent INSPIRES trial)
2x2 factorial randomization (in parent INSPIRES trial)
Yes
Does a multimodal clinical prediction model accurately stratify 90-day functional dependence risk and identify effect modification by dual antiplatelet therapy or pharmacogenetic enrichment in patients with minor ischemic stroke or high-risk TIA?
An interpretable clinical model using admission NIHSS, age, hypertension, and diabetes stratifies 90-day functional dependence risk after minor stroke/TIA (AUC 0.727), showing that residual functional disability is not modified by DAPT versus aspirin alone and is enriched for CYP1A2 and POR genetic variants.
Answers are grounded in this paper and cite their sources.
Risk model stratifies 90-day dependence after minor stroke/TIA without DAPT modification; hypothesis-generating for CYP1A2/POR enrichment requiring prospective validation.
Background and purpose Dual 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. Methods In 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. Results Logistic 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 χ 2 p = 0.0031) and POR TC (54.58% vs. 46.22%; Pearson χ 2 p = 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). Conclusion This 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.
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Wang et al. (2026) conducted a cohort in Acute mild-to-moderate ischemic stroke or high-risk transient ischemic attack (TIA) (n=4,439). Model-derived baseline risk stratification (per increasing risk quartile) vs. Lower baseline risk quartiles (and DAPT vs. aspirin alone across strata) was evaluated on 90-day functional dependence (modified Rankin Scale [mRS] > 2) (OR 5.16, 95% CI 3.81-6.99, p=<0.0001). Model-derived baseline risk stratification strongly predicted 90-day functional dependence (OR 5.16, 95% CI 3.81-6.99; AUC 0.727) without effect modification by DAPT (p=0.793).
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