Development of an optimized multimarker strategy for early risk assessment of patients with acute coronary syndromes

Background: A multitude of biomarkers have been suggested for early risk-assessment in patients admitted to the emergency department with suspected acute coronary syndromes. We used logistic regression synergistically with classification and regression tree (CART) analysis to define a multimarker strategy and the cut-off values and sequencing needed to optimize risk stratification in a low to moderate risk population of the emergency department. Methods: 432 unselected patients (59.7 ± 14.5 y, 60.4% male) admitted to the emergency department (ED) with acute coronary syndromes (ACS) were enrolled. Cardiac troponin I (cTnI), N-terminal pro-B-Type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), placental growth factor (PlGF), lipoprotein-associated phospholipase A₂ (Lp-PLA₂) and D-dimers were measured by immunoassay and whole blood choline (WBCHO) and plasma choline (PLCHO) were measured using LC/MS from baseline samples. Logistic regression and CART analysis were used to define the importance of the various biomarkers tested and to define their hierarchy with respect to the prediction of major adverse cardiac events (MACE; cardiac death, non-fatal MI, unstable angina, CHF requiring admission, urgent PCI and CABG) over the 42-day follow-up period. Results: A combination of NT-proBNP, WBCHO and Lp-PLA2 with cutoffs identified by CART-analysis was optimal for risk-stratification and superior to all other possible combinations of markers. Increased concentrations of both NT-proBNP (> 1400 ng/l) and WBCHO (> 21 μmol/l) identified patients with very high risk (RR = 2.4, 39% primary endpoint) while low concentrations of NT-proBNP (≤ 1400 ng/l), WBCHO (≤ 17 μmol/l) and LP-PLA2 (≤ 210 μg/l) indicated very low risk (0% primary endpoint). WBCHO > 17 μmol/l additionally identified a subgroup with intermediate risk (RR = 3.0, 13.5% primary endpoint) in patients with NT-proBNP concentrations ≤ 1400 ng/l. Troponin when increased was highly prognostic but was not often positive in this early cohort. Conclusions: A multimarker strategy defined synergistically by logistic regression and by classification and regression tree (CART) analysis can stratify patients into risk groups ranging from very low risk (0% MACE) to very high risk (39.5% MACE) based on admission values.