Optimize Risk Assessment for Incident and Recurrent Atherosclerotic Cardiovascular Disease

Recent American Heart Association (AHA) and American College of Cardiology (ACC) cholesterol guidelines put atherosclerotic cardiovascular disease (ASCVD) risk assessment at the center of decision-making for initiating and dosing of lipid-lowering therapies including statins, ezetimibe, and PCSK9 inhibitors. Nonetheless, there remains controversy regarding how efficiently this guideline directs medication to those who will receive a large absolute ASCVD risk reduction benefit. For primary prevention, the 2018 AHA/ACC guideline introduced the concept of risk-enhancing factors to identify individuals who have a risk higher than predicted by the pooled cohort equations (PCE). The presence of risk-enhancing factors supports a decision to initiate or intensify statin therapy in patients with borderline and intermediate risk. However, the guideline did not quantify how much a risk-enhancing factor changes an individual's 10-year risk, making decisions to treat or not to treat informed by the risk-enhancing factors ultimately subjective. Social determinants of health (SDOH) are important ASCVD risk factors. The PCE systematically underestimates risk for individuals who are socially deprived; however, SDOH are not included in the PCE or considered as risk-enhancing factors in the current guidelines. Additionally, the PCE's performance is questionable in Hispanics and Asians, the two fastest growing minority groups in the US. For secondary prevention, the 2018 guideline recommends high- intensity statin therapy for the 24 million US adults with established ASCVD, with ezetimibe and PCSK9 inhibitors recommended for a subset with a very high risk for recurrent ASCVD, defined by a history of multiple major ASCVD events or one major event with multiple high-risk conditions. However, recent evidence suggests that this definition may classify too many individuals (>50%) as having very high risk. Additionally, women, racial/ethnic minorities, and those with adverse SDOH may have a higher risk for recurrent ASCVD, but those factors were not considered in the current guideline when defining very high risk of recurrent ASCVD. To address these gaps in the literature and guidelines, our study proposes to 1) quantify how much the presence or absence of each risk-enhancing factor (including SDOH and Hispanic and Asian subgroups) and their combinations change 10-year ASCVD risk beyond PCE predictions; 2) determine the algorithm that optimizes the discrimination of individuals at very high risk for a recurrent ASCVD event; and 3) compare the health, economic, and health equity impact among US adults of selecting individuals for lipid-lowering therapies according to approaches identified in Aims 1 and 2 vs. in the 2018 cholesterol guideline. This study will develop approaches that improve the precision of cholesterol treatment guidelines in US adults, and help direct treatment to ethnic subgroups and groups with a high burden of adverse SDOH who have a high ASCVD risk but may not be recommended treatment by current national cholesterol guidelines. Findings from this study will inform future guidelines, improve cardiovascular outcomes, and narrow health inequities.