AHA PREVENT Equations and Lipoprotein(a) for Cardiovascular Disease Risk: Insights from MESA and the UK Biobank

Importance: Lipoprotein(a) [Lp(a)] is independently associated with atherosclerotic cardiovascular disease (ASCVD) risk but is not included in the new American Heart Association Predicting Risk of Cardiovascular Disease Events (PREVENT) equations for CVD risk assessment. Objective: To evaluate the performance of these equations in individuals with elevated Lp(a). Design, Setting, and Participants: Cohort study involving 314783 participants from the multicenter Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2018; n = 6670) and the population-based UK Biobank (UKB, 2006-2022; n = 308113) without known cardiovascular disease with available Lp(a) measurements. Analyses were conducted March 25, 2025. Exposure: Elevated Lp(a) level of 125 nmol/L or higher. Main Outcomes and Measures: Coronary heart disease (CHD), ASCVD, heart failure (HF), and total CVD. Participants were categorized as low (<5%), borderline (5% to <7.5%) intermediate (7.5% to <20%), and high (≥20%) risk of each outcome. Ten-year observed event rates were calculated, and the association between elevated Lp(a) and outcomes overall and by risk category was evaluated in age- and sex-adjusted Cox proportional hazards models. Improvement in risk prediction with the addition of elevated Lp(a) was evaluated using continuous and categorical net reclassification improvement (NRI) (using the above cut points). Results: Among the 314783 participants (mean [SD] age, 62.1 [10.2] years and 3523 females [53%] in MESA; mean [SD] age, 56.3 [8.1] years; 169648 females [55%] in the UKB), observed 10-year ASCVD event rates generally fell within the bounds of predicted risk categories regardless of Lp(a) level, although participants with elevated Lp(a) had higher event rates than did those with nonelevated Lp(a) (hazard ratio [HR], 1.30; 95% CI, 1.22-1.38) with similar results for CHD, HF, and total CVD. For CHD, the strongest association was among low-risk individuals (P for interaction =.31). The addition of elevated Lp(a) values to PREVENT modestly improved ASCVD risk prediction (category-free NRI, 0.058; 95% CI, 0.043-0.065; categorical NRI, 0.006, 95% CI, 0.004-0.011) with the greatest improvement in borderline-risk; when Lp(a) was evaluated continuously, the greatest improvement in prediction was among individuals at low risk. For CHD, the greatest improvement in prediction was in low- and high-risk individuals. Conclusions and Relevance: In this analysis of 2 cohort studies, the novel PREVENT equations performed well for risk prediction overall, including among individuals with elevated Lp(a). However, Lp(a) values remain independently associated with higher risk, and Lp(a) may improve personalized risk assessment, particularly among specific subgroups.