Adjustment of the SMART risk score by bioactive adrenomedullin enables a more accurate prediction of mortality in patients with ASCVD

Abstract Background Bioactive adrenomedullin 1-52 (bio-ADM) is a dynamic blood biomarker for real-time assessment of endothelial function. Bio-ADM was recently shown to be a prognostic marker in patients with acute heart failure and cardiogenic shock. The SMART (Second Manifestations of Arterial Disease) score is a validated tool for risk assessment in patients with established atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to assess whether measurement of bio-ADM adds incremental value to the SMART score in stable patients with ASCVD. Methods Circulating bio-ADM levels were assessed in n=695 stable patients with ASCVD in an all-comer cohort. Endpoints evaluated were all-cause mortality and cardiovascular mortality; follow up was 3 years. Results Bio-ADM was higher in non-survivors (all-cause death: n=54, median 33.1 pg/mL) compared to survivors (n=641, median 17.9 pg/mL; p<0.0001). Univariable Cox regression analyses showed bio-ADM to be associated with adverse outcome [standardized hazard ratio (HR) of bio-ADM values: All-cause death: 2.4, 95% confidence interval (CI): 2.0-2.9; p<0.001, cardiovascular death: 2.5, 95% CI: 1.9-3.3; p<0.001]. This association remained significant in various multivariable Cox regression models. Bio-ADM was found to be a strong marker for mortality (c-index: 0.80, Chi²: 54.1) and proved to be superior to other markers including hs-Troponin T (c-index: 0.61, Chi²: 2.0) and eGFR CKD-EPI 2021 (c-index: 0.687, Chi²: 33.5). Addition of bio-ADM to the SMART score significantly improved model performance in predicting mortality (SMART score: c-index: 0.717, Chi²: 24.73; SMART score + bio-ADM: c-index: 0.832, Chi²: 63.24; Delta c-index: 0.115; Delta Chi²: 38.51; all p<0.001) and showed net reclassification improvement in risk categorization with 11.6% in the group of survivors and 9.8% for non-survivors. Conclusion Bio-ADM provides incremental added value (improved discrimination, calibration and reclassification) on top of the SMART risk score in patients with ASCVD.