Key result
Low-dose aspirin cuts ischemic stroke risk ~51% in older adults with high polygenic risk.
Why the study?
Low-dose aspirin is no longer routinely recommended for primary prevention in older adults due to bleeding risks, prompting investigation into whether an integrative polygenic score can identify a subgroup deriving net benefit for ischemic stroke prevention.
Does aspirin 100 mg daily reduce ischemic stroke without excess bleeding in older adults (>70 years) with high polygenic risk for ischemic stroke?
RCT (n=12,031)
Double-blind
Randomized
Yes
Does aspirin 100 mg daily reduce ischemic stroke without excess bleeding in older adults (>70 years) with high polygenic risk for ischemic stroke?
An integrative polygenic risk score identifies a subgroup of older adults who experience significant ischemic stroke reduction with low-dose aspirin without excess bleeding, suggesting a role for genomic stratification in primary prevention.
May support aspirin in high-polygenic-risk older adults; hypothesis-generating and requires prospective validation before practice change.
BACKGROUND: Low-dose aspirin is no longer recommended for routine primary prevention in older adults due to bleeding risks outweighing vascular benefits. We hypothesized that an integrative polygenic score (iPGS) could identify a subgroup of older individuals who derive net benefit from aspirin for the primary prevention of ischemic stroke. METHODS: We performed post hoc analysis of the ASPREE randomized, placebo-controlled trial (Aspirin in Reducing Events in the Elderly) of daily 100-mg aspirin, in 12 031 genotyped participants of European ancestry aged >70 years without prior cardiovascular disease. The iPGS was derived from >1.2 million variants and evaluated both continuously and by quintiles. Cox models assessed associations between polygenic risk, ischemic stroke, and major bleeding events, and tested the interaction between the iPGS and treatment allocation, with adjustment for baseline lifestyle and clinical covariates. In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (hazard ratio, 0.49 [95% CI, 0.28-0.85]) without significantly increasing major bleeding (hazard ratio, 1.15 [95% CI, 0.71-1.88]). No benefit was observed in the overall cohort or in lower-risk quintiles. CONCLUSIONS: Among older adults, high polygenic risk identifies individuals who may experience substantial stroke reduction with aspirin, with no excess bleeding. These findings raise the possibility that genomic risk stratification may enable targeted aspirin use for the primary prevention of ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
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Yu et al. (2026) conducted an RCT in Primary Prevention of Ischemic Stroke (n=12,031). Aspirin vs. Placebo was evaluated on Incident ischemic stroke in the highest polygenic risk quintile (Q5) (HR 0.49, 95% CI 0.28-0.85, p=0.011). In older adults with high polygenic risk, daily low-dose aspirin reduced the risk of ischemic stroke by 51% (HR 0.49) compared to placebo, without a significant increase in major bleeding.
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