Triglyceride Polygenic Score Identifies Differential Bleeding and Cardiovascular Risk with Aspirin in Primary Prevention

AimsLow-dose aspirin is no longer routinely recommended for primary prevention in older adults because bleeding risks outweigh cardiovascular benefits. We aimed to investigate whether polygenic scores (PGSs) could modify the effects of aspirin on major bleeding and major adverse cardiovascular events (MACE) in a trial of older individuals. MethodsWe conducted post-hoc genetic analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, placebo-controlled trial in Australia and the United States. Participants aged [≥]70 years ([≥]65 years for U.S. minorities) without cardiovascular disease, dementia, or physical disability were randomized to 100 mg daily aspirin or placebo. Among those with high-quality genotyping data (n=13,571; median follow-up 4.6 years), we tested 572 cardiovascular- and hematologic-related PGSs for interaction with aspirin using Cox proportional hazards models, applying Bonferroni correction. ResultsA triglyceride-related PGS (PGS003144) modified aspirins effect on major bleeding (interaction P=5.9x10-5; Bonferroni-adjusted P=0.034). In the lowest PGS quintile, aspirin increased major bleeding compared with placebo (hazard ratio [HR] 2.28; 95% CI 1.45-3.58) without reducing MACE (HR 1.04; 95% CI 0.67-1.62). In contrast, in the highest quintile, aspirin was associated with lower risks of major bleeding (HR 0.62; 95% CI 0.38-0.97) and MACE (HR 0.66; 95% CI 0.44-0.99). Baseline measured triglyceride levels demonstrated a similar pattern of effect modification. ConclusionA triglyceride-related PGS identifies older adults with divergent bleeding and cardiovascular responses to aspirin, supporting the potential role of genetically-informed strategies for primary cardiovascular prevention. Lay summaryThis study shows that genetic differences related to triglyceride levels may help identify older adults who are more likely to be harmed or to benefit from taking aspirin to prevent heart disease. O_LIIn older adults with certain genetic profiles linked to triglycerides, aspirin increased the risk of serious bleeding without reducing heart attacks or strokes, while in others it was associated with lower risks of both bleeding and cardiovascular events. C_LIO_LIUsing genetic information alongside traditional risk factors could help tailor aspirin use for primary prevention, avoiding unnecessary harm while identifying those most likely to benefit. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/26346656v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@7ac690org.highwire.dtl.DTLVardef@8256c2org.highwire.dtl.DTLVardef@10de40corg.highwire.dtl.DTLVardef@f6e5e9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure, Graphical Abstract:C_FLOATNO Genetic stratification of aspirin benefit and harm using a triglyceride polygenic score. Screening of 572 polygenic scores in the ASPREE trial identified a triglyceride-related PGS that modified aspirin-associated bleeding and cardiovascular risk. Aspirin increased bleeding risk in the lowest PGS quintile but reduced major bleeding and MACE in the highest quintile. Abbreviations: PGS, polygenic score; GI, gastrointestinal; IC, intracranial; MACE, major adverse cardiovascular events. C_FIG