Lipoprotein(a) and Prognostic Nutritional Index Levels Exhibit Interactive and Joint Effects on Mortality Risk in Patients With Coronary Artery Disease: Findings From a Real-World Study

Background: Abnormal lipoprotein(a) (Lp(a)) levels and malnutrition are independent cardiovascular risk factors; however, the associated combined effects on mortality in patients with coronary artery disease (CAD) remain incompletely understood. Thus, this study aimed to evaluate the independent and joint associations of Lp(a) and the prognostic nutritional index (PNI) with all-cause and cardiovascular (CV) mortality in patients with CAD, as well as the associated combined interaction. Methods: A total of 47,482 patients with CAD from the Southern China multicenter Cardiorenal Improvement II cohort (2007–2020) were enrolled. Patients were stratified according to Lp(a) levels (low: <15 mg/dL; middle: 15 to <30 mg/dL; high: ≥30 mg/dL) and PNI (high: ≥45; low: <45). The primary outcomes were all-cause mortality and CV mortality. Restricted cubic splines were used to assess non-linear associations, while multivariable Cox models and Kaplan–Meier analyses were used for risk assessment; receiver operating characteristic (ROC) curves were used to compare predictive performance, and additive interaction analysis was used to evaluate joint effects. Results: During a median follow-up of 5.2 years, 5229 patients (11.01%) died from any cause and 3698 died from CV causes. In fully adjusted models, high Lp(a) combined with low PNI was associated with the highest risk of all-cause mortality (hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.69–2.03) and CV mortality (HR 2.20, 95% CI 1.98–2.46), compared with the low Lp(a)/high PNI reference group. The combined model achieved a higher area under the receiver operating characteristic (AUROC) curve for mortality prediction than either marker alone (p < 0.05). Significant additive interactions between Lp(a) and PNI were observed for all-cause mortality (relative excess risk due to interaction, RERI 0.30, 95% CI 0.14–0.43) and CV mortality (RERI 0.32, 95% CI 0.11–0.52). Conclusions: Lp(a) and PNI are independently associated with increased long-term mortality in patients with CAD and demonstrate a significant additive interaction. Joint assessment of Lp(a) and PNI may help identify high-risk patients with CAD at hospital discharge and may inform clinical risk stratification, optimized management, and personalized follow-up. Clinical Trial Registration: NCT05050877, https://clinicaltrials.gov/study/NCT05050877?cond=NCT05050877&viewType=Card&rank=1.