Abstract Body (Do not enter title and authors here): Introduction: Atherosclerotic cardiovascular disease (ASCVD) has many well-established risk factors; clinical risk tools (CRTs) aggregate these to estimate future disease risk. In 2023 the American Heart Association endorsed a new PREVENT CRT to guide preventive management. Previous work has shown that combining CRTs with a polygenic risk score (PRS), summarising the contribution of thousands of common variants, improves risk prediction, and that statin efficacy is increased in high PRS individuals. But while genetics is known to be a major risk factor, it is not currently incorporated into PREVENT or other CRTs.

Research question: Does an integrated risk tool (IRT), combining a PRS with PREVENT 10yr risk for ASCVD, improve clinical utility?

Methods: We assessed IRT performance on ASCVD outcomes within the Kaiser-Permanente Research Biobank, a large, US-based health system research cohort (n~450,000, n=59,823 used for testing, including 2,543 10-year incident ASCVD cases - defined as acute myocardial infarction, ischemic stroke or fatal CHD).

Results: Individuals often experienced large changes in risk: 13.6% had an IRT risk more than double or less than half their PREVENT risk; and 23.1% had an IRT risk at least 2 percentage points greater or smaller, which the HEART study showed could positively impact management decisions. These changes significantly improved prediction accuracy at a 7.5% actionable risk threshold (overall Net Reclassification Improvement 6.0% (95% CI 4.7-7.4%)). Similar results were observed across age and sex subgroups. Individuals with borderline PREVENT scores (5.0-7.5%) especially benefitted from the addition of PRS: the observed 10y ASCVD rate moved from 4.8% (4.0-5.7%) to 8.8% (7.7-10.0%) in low (bottom 20%) versus high (top 20%) PRS individuals, an odds ratio of 1.9.

A primary use case for ASCVD risk prediction is to prioritise individuals for statins. Restricting to a statin-naive subset, the addition of PRS to PREVENT up-classified 337 cases per 100,000 individuals to above the 7.5% risk threshold. Statin treatment of this group would prevent up to 151 major ASCVD events per 100,000 individuals over 10 years, assuming a higher efficacy in high-PRS individuals.

Conclusion: Combining a PRS with PREVENT results in substantial and beneficial changes in individual risk of ASCVD. Predictive performance is improved, both overall and especially for those at borderline risk, presenting opportunities to prevent future ASCVD events.