Polygenic Risk Identifies Older Adults Who May Benefit From Aspirin for the Primary Prevention of Ischemic Stroke
Chenglong Yu1,2, Sultana Monira Hussain1, Peter D Fransquet1
1School of Public Health and Preventive Medicine (C.Y., S.M.H., P.D.F., C.T., A.M.T., M.R.N., C.M.R., J.T.N., J.J.M., P.L.), Monash University, Melbourne, Victoria, Australia.
Insights
An integrative polygenic score (iPGS) identified older adults at high risk for ischemic stroke who benefit from low-dose aspirin for primary prevention. This genomic approach may enable targeted aspirin use, reducing stroke risk without increasing bleeding.
Area of Science:
- Genetics and Cardiovascular Disease
- Preventive Medicine
- Gerontology
Background:
- Low-dose aspirin is generally not recommended for primary prevention in older adults due to bleeding risks.
- Existing guidelines do not account for individual genetic predispositions to vascular events.
- A need exists to identify subgroups who may still benefit from aspirin for primary stroke prevention.
Purpose of the Study:
- To investigate if an integrative polygenic score (iPGS) can identify older adults who derive net benefit from low-dose aspirin for ischemic stroke prevention.
- To assess the interaction between polygenic risk and aspirin treatment allocation in a primary prevention cohort.
Main Methods:
- Post hoc analysis of the ASPREE randomized trial involving 12,031 genotyped participants (aged >70 years).
- Development and application of an integrative polygenic score (iPGS) derived from over 1.2 million genetic variants.
- Cox proportional hazards models were used to assess risks of ischemic stroke and major bleeding, and test for treatment interactions.
Main Results:
- Higher iPGS was associated with increased ischemic stroke risk (HR, 1.39 per SD increase).
- A significant interaction between iPGS and aspirin was observed for ischemic stroke (P=0.04).
- In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (HR, 0.49) without a significant increase in major bleeding (HR, 1.15).
Conclusions:
- High polygenic risk in older adults identifies individuals who may benefit significantly from aspirin for stroke reduction.
- Genomic risk stratification using iPGS may allow for targeted aspirin use in primary stroke prevention.
- This approach could personalize preventive strategies, balancing vascular benefits against bleeding risks.
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.
Results:
The mean age of participants was 75.1 years, and 54.9% were women. Over a median of 4.6 years, 187 ischemic strokes and 373 major bleeds occurred, including 101 intracranial bleeds (46 hemorrhagic strokes). Each 1-SD increase in the iPGS was associated with higher incident ischemic stroke risk (hazard ratio, 1.39 [95% CI, 1.20-1.62]). An interaction between the continuous iPGS and aspirin allocation was observed for ischemic stroke (P=0.04) but not major bleeding. 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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