Prognostic Value of Undetectable hs Troponin T in Suspected Acute Coronary Syndrome Mehrshad Vafaie, MD, Anna Slagman, VD, MSc, Martin Möckel, MD, PhD,

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Prognostic Value of Undetectable hs Troponin T in Suspected Acute Coronary Syndrome Mehrshad Vafaie, MD, Anna Slagman, VD, MSc, Martin Möckel, MD, PhD, Christian Hamm, MD, PhD, Kurt Huber, MD, PhD, Christian Müller, MD, Jörn O. Vollert, MD, MBA, Stefan Blankenberg, MD, PhD, Hugo A. Katus, MD, PhD, Christoph Liebetrau, MD, Evangelos Giannitsis, MD, PhD, Julia Searle, MD, MPH The American Journal of Medicine Volume 129, Issue 3, Pages 274-282.e2 (March 2016) DOI: 10.1016/j.amjmed.2015.10.016 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Patient flow. In the Biomarkers in Cardiology (BIC)-8 main trial, 902 patients were enrolled. Of these, 20 patients did not have high-sensitivity troponin T (hsTnT) or copeptin values available at admission. Thus, the study population of this BIC-8 substudy consists of 882 patients with complete biomarker results at admission. Patients were divided by their biomarker test. Relative and absolute frequencies are shown in the respective boxes. The American Journal of Medicine 2016 129, 274-282.e2DOI: (10.1016/j.amjmed.2015.10.016) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Hazards over time as a result of Kaplan-Meier analysis in high-sensitivity troponin T (hsTnT) and copeptin subgroups. The results of a Kaplan-Meier survival analysis are depicted. Hazards over time are shown for 3 biomarker-related subgroups: 1) hsTnT below limit of detection (LoD) (<5 ng/L), 2) hsTnT low (5 < 14 ng/L), and copeptin negative (<10 pmol/L) and 3) hsTnT low (5 < 14 ng/L) and copeptin positive (≥10 pmol/L). CI = confidence interval; HR = hazard ratio. The American Journal of Medicine 2016 129, 274-282.e2DOI: (10.1016/j.amjmed.2015.10.016) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Hazard ratios (HRs) from univariate proportional hazards regression analysis for the combined endpoint (death and myocardial infarction) as well as for single endpoint components: 1) high-sensitivity troponin T (hsTnT) in 3 categories (<5 ng/L, 5 < 14 ng/L, and ≥14 ng/L); reference category is hsTnT < 5 ng/L. 2) Copeptin in 2 categories (<10 pmol/L and ≥10 pmol/L); reference category is copeptin < 10 pmol/L. 3) Copeptin in patients with hsTnT below the limit of detection and 4) hsTnT 5 < 14 ng/L; the reference category is copeptin < 10 pmol/L. 5) Copeptin in patients with hsTnT at or above 14 ng/L; reference category is copeptin < 10 pmol/L. 6) HsTnT and copeptin combined in 5 categories (a: hsTnT < 5 ng/L, b: hsTnT 5 < 14 ng/L and copeptin < 10 pmol/L, c: hsTnT 5 < 14 ng/L and copeptin ≥ 10 pmol/lL, d: hsTnT ≥ 14 ng/L and copeptin < 10 pmol/L, e: hsTnT ≥ 14 ng/L and copeptin ≥ 10 pmol/L). Reference category in this analysis was the lowest risk category (hsTnT < 5 ng/L) and HRs can be interpreted as per increase in one category. nmiss = number of missing values. CI = confidence interval; HR = hazard ratio; MI = myocardial infarction. The American Journal of Medicine 2016 129, 274-282.e2DOI: (10.1016/j.amjmed.2015.10.016) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 4 Potential algorithm. This figure summarizes the potential use of high-sensitivity troponin T (hsTnT) below the limit of detection (LoD) based on a postrandomization cohort of the randomized Biomarkers in Cardiology (BIC)-8 process study. It is proposed that one hsTnT value < LoD alone may be sufficient for safe discharge from the emergency department (ED). This strategy, however, should be tested prospectively before implementation in clinical routine. Copeptin may be useful in patients with detectable hsTnT levels below the 99th percentile cut-off, copeptin values below 10 pmol/L may indicate a low risk and could potentially be part of an early rule-out strategy in these patients. The American Journal of Medicine 2016 129, 274-282.e2DOI: (10.1016/j.amjmed.2015.10.016) Copyright © 2016 Elsevier Inc. Terms and Conditions

Supplementary Figure 1 Hazards over time as a result of Kaplan-Meier-Analysis in hsTnT subgroups. CI = confidence interval; HR = hazard ratio; hsTnT = high-sensitivity troponin T. The American Journal of Medicine 2016 129, 274-282.e2DOI: (10.1016/j.amjmed.2015.10.016) Copyright © 2016 Elsevier Inc. Terms and Conditions

Supplementary Figure 2 Receiver operating curve analysis in all patients. hsTnT = high-sensitivity troponin T. The American Journal of Medicine 2016 129, 274-282.e2DOI: (10.1016/j.amjmed.2015.10.016) Copyright © 2016 Elsevier Inc. Terms and Conditions