ASPREE-iPGS
(2026)Objective
Test whether an integrative polygenic score (iPGS) for ischemic stroke can identify older adults who derive net benefit from low-dose aspirin for the primary prevention of ischemic stroke.
Study Summary
• No stroke reduction was seen in the overall cohort (HR 0.76 [0.56–1.02]; P=0.063) or lower iPGS quintiles.
• Significant aspirin×iPGS interaction for ischemic stroke (continuous Pinteraction=0.037; Q5 vs Q1 Pinteraction=0.045), but no interaction for major bleeding.
• Net clinical benefit favored aspirin in Q5 (+2.6 events/1000 person-years averted) but showed net harm in the overall cohort (-1.0) and in Q1 (-5.2).
Intervention
Daily low-dose aspirin 100 mg vs placebo, with polygenic risk stratification using an integrative polygenic score (iPGS) built from 1,204,449 variants across 22 stroke-related GWAS traits.
Inclusion Criteria
Community-dwelling adults ≥70 years (≥65 for US minorities) with no prior atherothrombotic cardiovascular disease, dementia, disability, or life-limiting illness; European ancestry; genotyped ASPREE participants.
Study Design
Arms: Aspirin 100 mg daily vs matching placebo, stratified post hoc by iPGS quintiles (Q1–Q5).
Patients per Arm: 12,031 total genotyped (approximately 6,000 aspirin vs 6,000 placebo, distributed across 5 iPGS quintiles of ~2,406 each).
Outcome
• Ischemic stroke (overall cohort): HR 0.76 [0.56–1.02], P=0.063 — not significant.
• Continuous iPGS: each 1-SD increase raised ischemic stroke risk (HR 1.39 [1.20–1.62]).
• Major bleeding overall: HR 1.30 [1.05–1.61], P=0.014 (harm); Q1: HR 1.72 [1.11–2.65], P=0.015; Q5: HR 1.15 [0.71–1.88] (ns).
• Net benefit–harm per 1000 person-years: Q5 +2.6 (benefit); overall −1.0; Q1 −5.2.
Clinical Question
Can an integrative polygenic score (iPGS) for ischemic stroke identify older adults without prior cardiovascular disease who derive net benefit from low-dose aspirin for primary prevention of ischemic stroke?
Bottom Line
In older adults without prior CVD, individuals in the highest iPGS quintile experienced a 51% relative reduction in ischemic stroke with aspirin (HR 0.49) without increased major bleeding, while no benefit was seen overall or in lower-risk quintiles — supporting polygenic risk stratification as a potential tool to target aspirin for stroke primary prevention.
Major Points
- Post hoc genetic analysis of 12,031 European-ancestry ASPREE participants ≥70 years using an updated integrative PGS (22 stroke-related GWAS traits, 1.2 million variants).
- Each 1-SD increase in iPGS raised ischemic stroke risk (HR 1.39 [1.20–1.62]); Q5 vs Q1 HR 2.62 [1.60–4.28].
- Significant aspirin×iPGS interaction for ischemic stroke (P=0.037 continuous; P=0.045 Q5 vs Q1) but not for major bleeding.
- Aspirin reduced ischemic stroke by 51% only in Q5 (HR 0.49 [0.28–0.85], P=0.011); no benefit in overall cohort (HR 0.76, P=0.063) or lower quintiles.
- Bleeding harm was concentrated in Q1 (HR 1.72 [1.11–2.65], P=0.015); Q5 bleeding was not increased (HR 1.15 [0.71–1.88]).
- Net benefit–harm per 1000 person-years: +2.6 in Q5 (favorable), −1.0 overall, −5.2 in Q1 (harmful).
- Genetic risk scores captured susceptibility not reflected in clinical risk equations (Framingham, SCORE2-OP), which failed to identify aspirin-responsive subgroups in ASPREE.
- Hypothesis-generating: post hoc design, European-ancestry only, no formal multiple-comparison adjustment; requires external multiancestry validation.
Study Design
- Study Type
- Post hoc genetic sub-analysis of a randomized, double-blind, placebo-controlled trial (ASPREE)
- Randomization
- Yes
- Blinding
- Double-blind (parent ASPREE trial)
- Sample Size
- 12031
- Follow-up
- Median 4.6 years (IQR 3.5–5.6) during the randomized controlled period
- Countries
- Australia, United States
Primary Outcome
Definition: Incident ischemic stroke (WHO criteria; acute focal neurological deficit of vascular origin ≥24 h or fatal; imaging- or autopsy-confirmed) during the randomized controlled period, analyzed for aspirin×iPGS interaction.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: overall event rate; Q5 iPGS 7.6/1000 person-years | Aspirin: Q5 iPGS 4.0/1000 person-years | 0.49 (Q5 aspirin vs placebo); 0.76 (overall cohort aspirin vs placebo) (0.28–0.85 (Q5); 0.56–1.02 (overall)) | 0.011 (Q5); 0.063 (overall); Pinteraction=0.037 (continuous iPGS×aspirin), 0.045 (Q5 vs Q1) |
Limitations & Criticisms
- Post hoc, hypothesis-generating design without prespecified aspirin×iPGS interaction analysis; no formal adjustment for multiple comparisons.
- Restricted to European-ancestry participants; generalizability to non-European populations is unknown and requires multiancestry validation.
- ASPREE contributed to the GIGASTROKE consortium used to derive the iPGS (<1% of European samples) — a minor theoretical overfitting risk, though unlikely to bias interaction estimates.
- Insufficient events for clinically important subtype analyses (disabling vs nondisabling stroke; intracranial vs gastrointestinal bleeding).
- Simplified 1:1 net benefit–harm calculation weighting ischemic strokes and major bleeds equally oversimplifies real clinical utility (severity, disability, mortality differ).
- Only genotyped ASPREE participants included (12,031 of 19,114); genotyping selection could introduce bias, though baseline characteristics were similar to the overall cohort (Table S2).
- Findings pertain to primary prevention in older adults (≥70) without prior CVD and cannot be extrapolated to younger patients or secondary prevention.
- Real-world clinical utility, cost-effectiveness, and infrastructure for delivering polygenic risk stratification remain unproven — implementation studies required.
Citation
Stroke. 2026;57(7). Originally Published 8 May 2026. doi:10.1161/STROKEAHA.125.054979