PROJECT Summary Lp(a) is a highly prevalent, independent, genetic and likely causal risk factor for cardiovascular disease. The population at risk represents 20-30% of individuals in the United States, or >100,000,000 people, and an estimated 1.4 billion people globally. Lp(a) is associated with increased CVD risk in primary prevention settings and in patients on statins and PCSK9 inhibitors in secondary prevention settings. Lp(a) is a preferential carrier of OxPL, the content of which in plasma can be measured by the assay OxPL-apoB. There are no approved pharmacological therapies to treat elevated Lp(a). In primary prevention settings, clinical equipoise exists in the use of aspirin in adults with elevated Lp(a) (>30 mg/dL or >75 nmol/L), and physicians do not have enough information to treat such patients with aspirin, particularly those with a strong family history of CVD. We hypothesize that elevated Lp(a) will identify a large subgroup of individuals that may benefit from aspirin in primary prevention settings and propose to test this hypothesis in the ASPREE and ASCEND trials. We propose to test the hypothesis that aspirin modifies the risk of incident atherothrombotic CVD events in high-risk primary prevention settings to a different extent in people with high Lp(a) or OxPL-apoB levels than in people with lower Lp(a) levels. SubAim 1 will test this hypothesis in elderly individuals in the ASPREE trial. SubAim 2 will test this hypothesis in individuals with type 2 diabetes in the ASCEND trial. We will also perform a meta-analyses of the effects of aspirin on the risk of incident atherothrombotic CVD events in high-risk primary prevention settings in people with high versus lower Lp(a) levels and in people with high versus lower OxPL-apoB levels in the ASPREE and ASCEND trials, using the most comprehensive relevant outcome in each trial, as used in Aim 1 and Aim 2.