1. Absolute and Relative Kinetic Changes of High-Sensitivity Cardiac Troponin T in Acute Coronary Syndrome and in Patients with Increased Troponin in the Absence of Acute Coronary Syndrome M. Mueller, M. Biener, M. Vafaie, S. Doerr, T. Keller, S. Blankenberg, H.A. Katus, and E. Giannitsis January 2012 www.clinchem.org/content/58/1/209.full © Copyright 2012 by the American Association for Clinical Chemistry

2. © Copyright 2009 by the American Association for Clinical Chemistry Introduction  High-sensitivity cardiac troponin T (hs-cTnT) > Earlier rule-in and rule-out of acute myocardial infarction (AMI) > Identification of more AMI patients > Improvement of risk stratification in AMI > Prediction of long-term prognosis in non-ACS  CAVEAT: reduced clinical specificity

3. © Copyright 2009 by the American Association for Clinical Chemistry  ESC/ACC/AHA/WHF task force redefinition of AMI (1)  Detection of cardiac troponin with at least one value above 99th percentile with evidence of myocardial ischemia  Presence of a rise and/or fall Magnitude of rise and/or fall still under debate! Introduction (cont.)  Aims of the study  Evaluation of kinetic changes in troponin within 3-6 hours after admission in ACS patients and in non-ACS patients with increased hs- cTnT  Identification of parameters to rule-in or rule-out non-STEMI

4. © Copyright 2009 by the American Association for Clinical Chemistry Introduction (cont.)  Rise and/or fall for discrimination of AMI Previous finding: > 20% in 6-9 h after presentation: NACB guidelines, Wu et al. (2) > 30% change in ACS to improve specificity: Apple et al. (3) > 243% within 6 h in evolving AMI: Giannitsis et al. (4) > 235% for prediction of AMI or death at 30 days: Kavsak et al. (5) > 20% combined with absolute change of 5 ug/l: Eggers et al. (6) > Reference change values (RCV) determined from biological variability: 46-90% for increasing, 36-57% for decreasing values: Wu et al., Vasile et al., Frankenstein et al. (7-9)

5. © Copyright 2009 by the American Association for Clinical Chemistry Introduction (cont.)  Questions: > Is there a chance to discriminate acute myocardial infarction from other causes of increased hs-cTnT by examining kinetic changes? > What is the optimal kinetic change threshold (absolute or relative) to identify AMI?

6. © Copyright 2009 by the American Association for Clinical Chemistry Methods & Material  Study design > Inclusion criteria: > Consecutive patients presenting to the emergency department (chest pain unit) of the University of Heidelberg, Germany over a 6 month interval > Second blood draw within 3-6 hours > All patients with retrospectively confirmed acute coronary syndrome (ACS) > All patients with increased hs-cTnT in non-ACS conditions > Exclusion criteria: > Patients with STEMI (not biomarker defined) > Patients with hs-cTnT increases following percutaneous coronary intervention (PCI).

7. © Copyright 2009 by the American Association for Clinical Chemistry Serial measurementNon-STEMI (n=165)UAP (n=177)Non-ACS (n=442) ≥99 th percentile 0h159 (96.4%)89 (50.3%)*418 (94.6%) ≥99 th percentile 0-6h165 (100%)91 (51.4%)*442 (100%) hsTnT 0h (baseline) [ng/L]92.0 (27.3-312.3)14.0 (5.1-26.8)*31.5 (19.5-60.4)* hsTnT 3h [ng/L]130.3 (46.4-378.5)11.6 (5.0-25.5)*31.3 (19.4-62.1)* hsTnT 6h [ng/L]188.8 (62.4-555.1)10.8 (3.8-25.3)*31.4 (19.3-63.6)* Relative change [%] 0-6 h53.9 (20.0-200.3)14.2 (7.9-22.4)*15.6 (8.1-28.8)* Absolute change [ng/L] 0-6 h56.5 (18.2-250.0)2.8 (1.1-5.6)*5.1 (2.6-11.3)* Results  Baseline 784 patients (165 with NSTEMI,177 with unstable angina(UAP), 442 with non-ACS conditions) Table 1. Baseline hs-cTnT, maximum absolute and relative changes. * vs. non-STEMI, p≤0.0001

8. © Copyright 2009 by the American Association for Clinical Chemistry Distribution of absolute and relative δ-changes in different patient groups A B Figure 1. Distribution of absolute (A) and relative (B) change in patients with a final diagnosis of non-STEMI (n=165), UAP (n=177) and in patients with increased hs-cTnT due to non-ACS conditions (n=442). Compared to UAP and non-ACS conditions, patients with non-STEMI showed significantly elevated absolute changes (P<0.0001, respectively) and relative changes (P<0.0001, respectively).

9. © Copyright 2009 by the American Association for Clinical Chemistry Figure 2. Comparison of AUC of baseline hs-cTnT, peak hs-cTnT, ROC-optimized relative (38.9%) and absolute change in hs-cTnT (9.2 ng/L) for prediction of non-STEMI in the entire study population (A) and a specific ACS population (B). In direct comparison, absolute change was superior to all other studied parameters in discriminating non-STEMI for both, the entire study population and the specific ACS population. Comparison of performance of different parameters for prediction of non-STEMI

10. © Copyright 2009 by the American Association for Clinical Chemistry Performance of kinetic changes in hs-cTnT within the initial 6 hours for rule-in and rule-out of non-STEMI in the entire study population Table 1. The ROC-based optimal cut-off value of ≥9.2 ng/L for absolute δ-change showed a diagnostic sensitivity of 89.7% with a NPV of 96.5%. Compared to a ≥20% relative δ-change, only the ROC-optimized absolute δ-change of 9.2 ng/L (NRI=0.311, P<0.0001) demonstrated a significant added value. Sensitivity (CI)Specificity (CI)PPV (CI)NPV (CI)NRI b Change ≥20%75.2 (67.8-81.5)58.1 (54.1-62.0)32.4 (27.7-37.3)89.8 (86.4-92.5)- Change ≥30%63.6 (55.8-71.0)75.1 (71.5-78.5)40.5 (34.5-46.8)88.6 (85.5-91.2)0.055 Change ≥39.8% a 57.6 (49.7-65.2)83.0 (79.8-85.9)47.5 (40.4-54.6)88.0 (85.1-90.5)0.072 Change ≥50%52.7 (44.8-60.5)87.5 (84.7-90.0)53.1 (45.1-60.9)87.4 (84.5-89.9)0.070 Change ≥100%35.4 (28.1-43.2)95.3 (93.3-96.8)66.7 (55.8-76.4)84.8 (81.9-87.3)-0.029 Change ≥250%23.2 (17.0-30.4)99.2 (98.1-99.7)88.4 (74.9-96.1)83.0 (80.0-85.6)-0.110 Change ≥ 9.2 ng/L a 89.7 (84.0-93.9)74.8 (71.2-78.2)48.7 (42.9-54.5)96.5 (94.4-97.9)0.311* a ROC-based optimal cut-off for discrimination of non-STEMI b NRI (net reclassification index) vs. relative delta change ≥20%, * P<0.001

11. © Copyright 2009 by the American Association for Clinical Chemistry Figure 3. Performance related to hs-cTnT baseline concentrations at admission (A) and time from symptom onset to admisson (B). The data demonstrate a significantly better performance of absolute changes than relative changes at baseline hs-cTnT concentrations <14 ng/L and baseline concentrations of ≥100 ng/L. Moreover, the performance of absolute changes was independent of time from symptom onset to admission, whereas the performance of relative changes declined 4 h after symptom onset. Performance of δ-changes related to hs-cTnT baseline concentrations and symptom onset AB

12. © Copyright 2009 by the American Association for Clinical Chemistry Results  Questions: > What is your explanation for the superiority of absolute δ-changes compared to relative δ-changes in the cohort studied? > Is rule-in of non-STEMI possible in a cohort with high prevalence of hs-cTnT increases based on kinetic changes? What are the implications concerning rule-out?

13. © Copyright 2009 by the American Association for Clinical Chemistry Conclusions  Absolute changes in hs-cTnT were superior to relative changes in discriminating non-STEMI within 3-6 hours, especially in patients with low and high baseline hs-cTnT concentrations  Performance of absolute changes in hs-cTnT was independent to time from symptom onset to admission, whereas relative changes showed inferior performance in patients presenting later than 4 h after symptom onset  Rise and/or fall in hs-cTnT of at least 9.6ng/L is adequate to rule-out non-STEMI in our study population  Rule-in of non-STEMI based on kinetic changes alone, is extremely difficult in a study population consisting of ACS and non-ACS-related hs-cTnT increases

14. © Copyright 2009 by the American Association for Clinical Chemistry 1. Thygesen K et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-53. 2. Wu AH et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines: use of cardiac troponin and B-type natriuretic peptide or N-terminal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure. Clin Chem 2007; 53: 2086-96. 3. Apple FS et al. Role of monitoring changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events. Clin Chem 2009; 55: 930-7. 4. Giannitsis E et al. High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. Clin Chem 2010; 56: 642-50. 5. Kavsak PA et al. 2007 Universal myocardial infarction definition change criteria for risk stratification by use of a high-sensitivity cardiac troponin I assay. Clin Chem 2010; 56: 487–9. 6. Eggers KM et al. Clinical implications of the change of cardiac troponin I levels in patients with acute chest pain - an evaluation with respect to the Universal Definition of Myocardial Infarction. Clin Chim Acta. 2011; 412: 91-7. 7. Wu AH et al. Shortand long-term biological variation in cardiac troponin I measured with a high-sensitivity assay: implications for clinical practice. Clin Chem 2009; 55: 52– 8. 8. Vasile VC et al. Biological and analytical variability of a novel high-sensitivity cardiac troponin T assay. Clin Chem. 2010; 56: 1086-90. 9. Frankenstein L et al. Biological variation and reference change value of high-sensitivity troponin T in healthy individuals during short and intermediate follow-up periods. Clin Chem. 2011; 57: 1068-71. References

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