Multimarker Strategy for Short-Term Risk Assessment in Patients With Dyspnea in the Emergency Department: The MARKED (Multi mARKer Emergency Dyspnea)-Risk Score

Study Questions:

Can short-term risk for patients presenting to the emergency department (ED) with dyspnea be better estimated using a risk score based on multiple biomarkers as well as clinical/demographic factors?


The authors assessed the prognostic value of the biomarkers N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), cystatin-C (Cys-C), high-sensitivity C-reactive protein (hs-CRP), and galectin-3 (Gal-3) for 90-day mortality among subjects presenting to the ED of the Maastricht University Medical Center between June 2007 and October 2009. Multivariable analyses were performed for clinical covariates and biomarkers separately, including variables that were univariably associated with 90-day mortality, creating separate clinical and biomarker models. The biomarkers were then added in a step-wise fashion, and the final model was evaluated using the C-statistic, the Hosmer-Lemeshow statistic, the integrated discrimination improvement, and the net reclassification index.


Among 603 subjects presenting to the ED with dyspnea, hs-CRP, hs-cTnT, Cyst-C, and NT-proBNP were independent predictors of 90-day mortality (hazard ratio, 2.94 per biomarker; 95% confidence interval [CI], 2.29-3.78; p < 0.001). The final model dyspnea risk score (MARKED-risk score) incorporating age ≥75 years, systolic blood pressure <110 mm Hg, history of heart failure, dyspnea, New York Heart Association functional class IV, hs-cTnT ≥0.04 g/L, hs-CRP ≥25 mg/L, and Cys-C ≥1.125 mg/L was a strong predictor of 90-day mortality (area under the curve, 0.85; 95% CI, 0.81-0.89). A score of <3 points; ≥3 or <5 points; and ≥5 points corresponded to 90-day mortality of 2%, 14%, and 44%, respectively (p < 0.001).


The authors concluded that a multimarker strategy provided superior risk stratification beyond any single-marker approach. They further opined that the MARKED-risk score that incorporates hs-cTnT, hs-CRP, and Cys-C, along with clinical risk factors, accurately identifies patients with very low, intermediate, and high risk.


This study has some limitations (e.g., single center, no external validation), but appears to be a robust analysis, incorporating clinical variables and biomarkers into a diagnosis-independent risk prediction tool for patients presenting to the ED with a complaint of dyspnea. It is unclear if this score will remain as potent in other populations. More unclear is what role such a risk score tool would play clinically. Currently, we lack data on what to do with the results, and how the score should influence clinical decision making. This score confirms the additive power of the biomarkers tested, and their importance in short-term outcomes. Further study is clearly needed to determine if such a score can be used to guide therapeutic decisions to improve outcomes. Obviously, it would be most useful if the biomarker/clinical factor risk scoring could be used to identify specific interventions or treatment to improve outcomes. Much more work is required for that.

Clinical Topics: Heart Failure and Cardiomyopathies, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Cysteine, Cysts, Cystatins, Troponin T, Blood Pressure, Dyspnea, Galectin 3, New York, Heart Diseases, Prognosis, C-Reactive Protein, Biological Markers, Troponin I, Heart Failure, Risk Assessment, Natriuretic Peptide, Brain

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