The Additive Prognostic Value of Lipoprotein(a) for All-cause and Cardiovascular Mortality Across the Traditional Cardiovascular Risk Continuum: Analysis from NHANES III (1988–1994) with Follow-Up to 2019

Introduction Lp(a) is an independent risk factor for a variety of cardiovascular (CV) outcomes. However, it remains unclear whether its prognostic value differs between individuals with varying baseline traditional CV risk. This study aims to evaluate the association between Lp(a) levels and all-cause & CV mortality, stratified by baseline CV risk. Methods Using data from NHANES III (1988–1994) with mortality follow-up through 2019, we analysed a nationally representative cohort of U.S. adults. Baseline CV risk was stratified into low, borderline-intermediate, and high groups using the PREVENT equations. Associations between Lp(a) levels and outcomes were assessed using multivariable Cox and Fine–Gray competing risk models. Results A total of 55,050,155 survey-weighted records (4,707 unweighted) were analysed. The mean age was 48 (±13) years, with 51% female. Over a mean follow-up of 22.4 years (±7.07), there were 17,301,805 all-cause and 4,965,456 CV deaths. Elevated Lp(a) (>50 mg/dL) was present in 15% overall, more commonly in the high-risk group (15% vs 11% in low-risk). In the high-risk group, Lp(a) >75 mg/dL was associated with higher all-cause (HR: 1.25; 95% CI: 1.02–1.53) and CV mortality (sHR: 1.21; 95% CI: 1.09–1.36). Lp(a) 50–75 mg/dL showed a borderline association with all-cause mortality (HR: 1.16; 95% CI: 1.00–1.34) but not CV mortality (sHR: 1.06; 95% CI: 0.98–1.15). No significant associations were observed in lower-risk groups. Conclusions Elevated Lp(a) levels (> 75 mg/dL) are associated with increased all-cause and CV mortality among individuals with high baseline traditional CV risk, as defined by the AHA's PREVENT score, independent of traditional risk factors. Our findings highlight the value of Lp(a) particularly among those with elevated baseline risk, where its prognostic utility appears greatest.