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Clinical Chemistry 58:1 209–218 (2012

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Proteomics and Protein Markers

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
Matthias Mueller,1 Moritz Biener,1 Mehrshad Vafaie,1 Susanne Doerr,1 Till Keller,2 Stefan Blankenberg,2 Hugo A. Katus,1 and Evangelos Giannitsis1*

BACKGROUND: We evaluated kinetic changes of highsensitivity cardiac troponin T (hs-cTnT) in patients with acute coronary syndrome (ACS) and patients with hs-cTnT increases not due to ACS to rule in or rule out non–ST-segment elevation myocardial infarction (STEMI). METHODS:

or fall of at least 9.2 ng/L in the entire study population and 6.9 ng/L in selected ACS patients seems adequate to rule-out non-STEMI. However, ␦-values are useful to rule-in non-STEMI only in a specific ACS population.
© 2011 American Association for Clinical Chemistry

hs-cTnT was measured serially in consecutive patients presenting to the emergency department. Patients with ACS who had at least 2 hs-cTnT measurements within 6 h and non-ACS patients with hs-cTnT concentrations above the 99th percentile value (14 ng/L) were enrolled to compare absolute and relative kinetic changes of hs-cTnT.

For discrimination of non-STEMI (n ϭ 165) in the entire study population (n ϭ 784), the absolute ␦ change with the ROC-optimized value of 9.2 ng/L yielded an area under the curve of 0.898 and was superior to all relative ␦ changes (P Ͻ 0.0001). The positive predictive value for the absolute ␦ change was 48.7%, whereas the negative predictive value was 96.5%. In a specific ACS population with exclusion of STEMI (n ϭ 342), the absolute ␦ change with the ROC-optimized value of 6.9 ng/L yielded a positive predictive value of 82.8% and a negative predictive value of 93.0%. In comparison to the Ն20% relative ␦ change, the ROCoptimized absolute ␦ change demonstrated a significantly added value for the entire study population and for the ACS cohort (net reclassification index 0.331 and 0.499, P Ͻ 0.0001).
RESULTS: CONCLUSIONS:

Absolute ␦ changes appear superior to relative ␦ changes in discriminating non-STEMI. A rise

The Joint European Society of Cardiology/American College of Cardiology/American Heart Association/ World Heart Federation Task Force for the redefinition of acute myocardial infarction (AMI)3 has recommended that a diagnosis of AMI be made only in the presence of a rise and/or fall of cardiac troponin, with at least 1 value above the 99th percentile reference value (1 ). These findings in conjunction with a clinical context suggesting myocardial ischemia as the underlying mechanism indicate that a diagnosis of AMI should be made. Otherwise, other acute heart disease causing a dynamic cardiac troponin release should be considered (2 ). Recently, Javed et al. reported that fewer than one third of patients with increased cardiac troponin were found to have AMI (3 ). Therefore, knowledge about the magnitude of concentration changes (␦) in AMI in the absence of acute coronary syndrome (ACS) is essential to the definition of an optimal dynamic metric that allows discrimination of acute from a chronic conditions and of AMI from non–ACS-related conditions that cause cardiac troponin increases. Unfortunately, the magnitude at which the increase or decrease is indicative of an acute rather than a chronic cardiac troponin increase is unclear, and it is still debatable whether biological variation plays a role

1

Department of Internal Medicine III, Cardiology, University Hospital Heidelberg, Heidelberg, Germany; 2 Department of General and Interventional Cardiology, The University Heart Center at the University Medical Center HamburgEppendorf, Hamburg, Germany. * Address correspondence to this author at: Medizinische Klinik III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Fax ϩ49-6221-56-5516; e-mail evangelos_giannitsis@med.uni-heidelberg.de. Received July 1, 2011; accepted October 31, 2011.

3

Previously published online at DOI: 10.1373/clinchem.2011.171827 Nonstandard abbreviations: AMI, acute myocardial infarction; ACS, acute coronary syndrome; RCV, reference change value; ED, emergency department; hs-cTnT, high-sensitivity cardiac troponin T; STEMI, ST-segment elevation myocardial infarction; UAP, unstable angina pectoris; PCI, percutaneous coronary intervention; NPV, negative predictive value; PPV, positive predictive value; AUC, area under the curve; NRI, net reclassification index; IQR, interquartile range.

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The study was performed according to the principles of the Declaration of Helsinki and approved by the local ethics committee. Previous studies have investigated patients presenting with chest pain or more selected ACS populations and thus have not provided data on dynamic changes of cardiac troponin in other acute heart diseases for which patients commonly present to an emergency department (ED). In addition. Several investigators have proposed higher relative ␦ changes between 30%–250% to increase the diagnostic specificity and thus improve diagnosis of AMI (5– 8 ). Reasons for increased hs-cTnT in the absence of ACS were categorized into cardiac. A diagnosis of unstable angina pectoris (UAP) was made if ACS was suspected clinically but hs-cTnT concentrations were consistently below the 99th percentile value during serial sampling for at least 6 h. Cardiac causes comprised acutely decompensated heart failure. and uncertain. we did not exclude patients with increased baseline hs-cTnT and declining values after PCI. which are the relative changes determined from biological variability of cardiac troponin (9 –11 ). LABORATORY MEASUREMENTS We measured cardiac troponin on COBAS E411 using the hs-cTnT assay (Roche Diagnostics). coronary intervention. laboratory. In addition. AMI. without further differentiation into type I or type II. and imaging findings adjudicated by an expert committee of 2 independent cardiologists blinded to the investigational biomarker results. To discriminate procedure-related MI. and atrial or ventricular tachyarrhythmias. and the underlying reason of myocardial damage was actively sought. Tako-Tsubo cardiomyopathy. was diagnosed according to the criteria of the universal definition with detection of a rising and/or falling pattern of hs-cTnT and evidence of myocardial ischemia (1 ). or further diagnostic work-up were left to the discretion of the attending cardiologist. pulmonary embolism. Final diagnosis of ACS or non-ACS was based on all available clinical. We determined the diagnostic accuracy of absolute and relative ␦ changes of cardiac troponin in discrimination of AMI.and whether absolute or relative ␦ change is the ideal metric for cardiac troponin measurement. or objective evidence of myocardial ischemia on stress testing. increased hs-cTnT was interpreted as unrelated to AMI. A third cardiologist refereed in situations of disagreement. extracardiac. Because the magnitude of the rise and/or fall for the diagnosis of AMI is still not established. In the absence of clinical variables suggestive of myocardial ischemia. we excluded patients who underwent percutaneous coronary intervention (PCI) and developed subsequent hscTnT increases after PCI before a final diagnosis of unstable angina or non-STEMI could be made. an absolute concentration change of Ն5 ng/L between baseline and the highest consecutive value was required to diagnose AMI. Follow-up was accomplished via telephone contact or questionnaire at least 6 months after discharge. Moreover. which is com- . we evaluated dynamic ␦ changes of high-sensitivity cardiac troponin T (hs-cTnT) in patients with ACS and cardiac troponin increases in the absence of ACS who presented with acute symptoms to an ED. including all available hs-cTnT measurements within 24 h after the initial blood draw. the diagnosis of UAP required the presence of typical symptoms together with a history of coronary artery disease and previous coronary intervention or detection of a culprit lesion of Ն50% on coronary angiogram. Recent study results suggest the use of reference change values (RCVs). but this recommendation is based on analytical considerations only in the subset of patients with end-stage renal disease or other conditions with low baseline-concentration increases of cardiac troponin (4 ). In contrast. Written informed consent was obtained from all participating patients. patients with increased hs-cTnT and a typical presentation of ACS but without a relative ␦ change Ն20% or an absolute concentration difference of Ͻ5 ng/L were found to have UAP with hs-cTnT increases due to underlying chronic cardiac damage or severe renal failure. Patients with ACS who received a second blood draw within 6 h and patients with non-ACS conditions with at least 1 hs-cTnT concentration above the 99th percentile value (14 ng/L) qualified for evaluation of relative or absolute ␦ changes within 3– 6 h after admission to rule in or rule out non–ST-segment elevation myocardial infarction (non-STEMI). We excluded patients with ST-segment elevations or new left bundle-branch block on presentation be210 Clinical Chemistry 58:1 (2012) cause the diagnosis of STEMI is made by electrocardiogram and biomarker testing is not recommended for STEMI patients. we used a 20% rise and/or fall as a minimum to define an acute change. Extracardiac causes included severe kidney dysfunction/end-stage renal disease and sepsis. myocarditis. decompensated valve disease. Methods During a 6-month period we measured hs-cTnT serially on presentation and at least after 3 or 6 h in all consecutive patients presenting to the internal medicine ED and chest pain unit of the University Hospital Heidelberg. Therefore. The National Academy of Clinical Biochemistry has recommended a ␦ change in cardiac troponin of Ն20% 6 –9 h after presentation. All medical decisions including the need and timing of coronary angiography.

4% of patients with non-ACS conditions (n ϭ 276) and 75. Reference interval values were established from a multicenter reference study and the 99th percentile value was determined at 14 ng/L (13 ). at 20 h [interquartile range (IQR) 12– 48 h] vs 12 h (IQR 1– 48 h) (P ϭ 0.7–589.8% of patients with a final diagnosis of non-STEMI (n ϭ 41) did not fulfill this diagnostic criterion within the initial 6 h. Thus. As expected. We determined optimal thresholds for relative and absolute ␦ changes from ROC curves on the basis of the continuously measured biomarker concentrations.05 was considered statistically significant.Kinetics in Non-STEMI and Non-ACS cTnT mercially available in Germany (not yet available in the US). We calculated diagnostic sensitivities. In addition. Along with admission values. All tests were 2-tailed.6%). and uncertain causes in 131 patients (29. Non-STEMI was diagnosed in 165 patients (19. (14 ). both groups within the ACS spectrum showed significant differences. The interassay CV was 8% at 10 ng/L and 2. The categories included baseline hs-cTnT concentrations of Ͻ14 ng/L.04).9 –201. P Ͻ 0. To demonstrate an added value of other kinetic changes compared to a 20% relative change. SERIAL CHANGES During a 6-month recruitment period a total of 863 patients qualified for the kinetic study. we determined net reclassification index (NRI) according to the method by Pencina et al. Results BASELINE ponin increases were not due to ACS (non-ACS conditions).4%).4%) presenting with ST-segment elevations or new left bundle-branch block on electrocardiogram.0 and MedCalc 11. UAP. To compare areas under the curve (AUCs) we used the test of DeLong et al. STATISTICAL ANALYSIS Continuous variables were tested for normal distribution and were presented either as mean (SD) or as medians with 25th and 75th percentiles. All analyses on performance were executed for the entire population and in 4 categories of incremental baseline hs-cTnT intervals to adjust for the effects of absolute baseline concentrations. Conversely. Moreover. absolute ␦ change between highest hs-cTnT concentration from 3. We excluded 64 patients (7.5%). but did spontaneously during subsequent sampling within 24 h. where C is hs-cTnT concentration] given as percentage change in either direction (rise or fall) of hscTnT from baseline. SPSS 15. 24. diagnostic specificities.001]. The intraassay CV was 5% at 10 ng/L and 1% at 100 ng/L (12 ). Fig.2% of patients with non-STEMI (n ϭ 124) fulfilled the 20% ␦ change criterion. and positive predictive values (PPVs) for relative and absolute ␦ changes for classification of final diagnosis of non-STEMI.7%) who underwent PCI and developed increasing hs-cTnT values after PCI but before the final diagnosis was made. 1 shows the maximal individual relative and absolute ␦ changes within 6 h for patients with non-STEMI. Within this time frame. patients with non-STEMI and patients with hs-cTnT increases not due to ACS differed with respect to most baseline demographic characteristics and laboratory and angiographic findings. the entire study population consisted of 784 patients. 50 –99 ng/L.4 ng/L (IQR 131.or 6-h sample and baseline [Cmax 3h or 6h Ϫ Cbaseline] expressed as nanograms per liter. 62.2%) cardiac tro- The median number of hs-cTnT measurements per individual was 3 (25th to 75th percentile: 2–3). (15 ). Reasons for cardiac troponin increases in non-ACS conditions comprised cardiac diseases in 152 (34. including patients with ACS and non-ACS conditions. More details on baseline characteristics are provided in the Data Supplement that accompanies the online version of this article at http://www. All 165 patients with non-STEMI and non-ACS conditions as well as 91 patients with UAP (51.1%) and UAP in 177 patients (20. We compared groups by using the ␹2 test for categorical variables and ANOVA for continuous variables. and peak hs-cTnT concentration within 6 h. Table 2 demonstrates hs-cTnT concentrations on presentation and during consecutive sampling.5% at 100 ng/L.7 ng/L (IQR 20.0%). The ACS study population consisted of 342 patients with non-STEMI and UAP. and showed higher hs-cTnT on presentation [306. and Ն100 ng/L. extracardiac diseases in 159 (36. Compared to non-STEMI patients with a relative ␦ change Ն20%. In 442 patients (51. Clinical Chemistry 58:1 (2012) 211 . several kinetic metrics were calculated from serial measurements including relative ␦ change [(Cmax(3 h or 6h) Ϫ Cbaseline)/Cbaseline ϫ 100.org/content/vol58/issue1.1 statistical software packages were used. negative predictive values (NPVs). The baseline characteristics of the entire study population (n ϭ 784) subdivided by final diagnosis are displayed in Table 1. we excluded 15 patients (1.4%) had hs-cTnT concentrations Ն99th percentile in a least 1 sample during the initial 6 h.clinchem. mainly in angiographic baseline characteristics.4). 14 – 49 ng/L.2) vs 45. or non-ACS conditions. and a P value Ͻ0. The limit of the blank (3 ng/L) and limit of detection (5 ng/L) were determined in accordance with CLSI guideline EP17-A. as well as maximal absolute and relative ␦ changes. those patients with a ␦ change Ͻ20% presented later after onset of symptoms.

laboratory.4%) 76 (42. n (%) Coronary artery disease. PAD.1%) 228 (51.2%) 23 (13. c P Ͻ0.0%) 105 (63.1%)a 2943 (994. n (%) CHF CAD PCI CABG PAD Stroke COPD Risk factors.8%) 133 (75. and angiographic characteristics of hs-cTnT elevation in non-STEMI. AUCs were determined from ROC analysis for continuous values 212 Clinical Chemistry 58:1 (2012) including baseline hs-cTnT concentrations and maximum hs-cTnT concentrations within 6 h as well as relative and absolute ␦ changes.4%) 13 (2.7)c 129 (29.2%) 105 (63.5%) 81 (18.1%) 14 (7.3 (31.3) 58 (32. coronary artery disease.0%) 38 (8. mean (range).8%) 146 (33.3%) 133 (30. n (%) Male sex. n (%) Angina pectoris Dyspnea Syncope Other History.9%) 2 (1.0%) 106 (59.0%)a 1 (0. CHF.3%) 19 (11. PERFORMANCE OF SERIAL ␦ CHANGES FOR RULE-IN AND RULE-OUT OF NON-STEMI In the entire study population (n ϭ 784). n (%) Diabetes mellitus Cholesterolemia Hypertension Active smoking Ex-smoker Family history GRACE score.5%) 2 (1.1%) 7 (4.9%) 22 (13. Baseline demographic. coronary artery bypass graft.0 (43.8%)c 124 (70.4 (59.6)c 202 (45.9%) 594.2%) 33 (20. COPD.9%) 0 67 (37.1 (24.0 (200–3629) 69. CABG.5%) 58 (35. N-terminal pro-B type natriuretic peptide.1%) 9 (5.0%) 54 (32. n (%) NT-proBNP.9%) 119.0%) 166 (93.0001 vs non-STEMI.1–77.b mean (range). NT-proBNP.7%)a 55 (12.9%)c c c 74.0%) 24 (13.5%)a 121 (27.6%) 88 (20.5%) 129.9%) 12 (7. n (%) Leading symptom. chronic obstructive pulmonary disease.0%) 5 (3.8) 147 (89.2%) 21 (12. d P Ͻ0.6%) 139 (84. and non-ACS patients.5–7982.7) 64 (39.0) 73. eGFR.7%) 18 (10.2) 205 (46.2%) 37 (22.6%) 351 (79.6–81.9%)a P Ͻ0.01 vs non-STEMI.3%) 21 (11.0 (33.4 (61.3%)d 60 (33.Table 1.5%) 121 (73.5) 52 (31.6%) 44 (10. Comparison of AUC values demonstrated a significantly better performance of .7%)a 58 (13.9%) 43 (24. peripheral artery disease.1%)a 149 (33. estimated glomerular filtration rate.7%) 14 (8.8%)d 20 (11. chronic heart failure.4%) 44 (10. years Age Ͼ75 years.1 (66.2%) 99 (55.9%) 28 (19.3–80.4%) 28 (17.5%) 63 (38.9%) 140.0%) 254 (57.9%) 23 (13.7%) 138 (78.6%) 71.6%)c 206 (46. CAD.9%) 65 (36. Non-STEMI (n ‫ ؍‬165) UAP (n ‫ ؍‬177) Non-ACS (n ‫ ؍‬442) Age. mean (SD) or (range) eGFR Ͻ60.8–78. vessel disease.6%) 33 (7. VD.7%)d 29 (6.5%) 13 (7.3%) 559.0%) 0 37 (20.2%)a 109 (24. n (%) 0 VD 1 VD 2 VD 3 VD Left main trunk PCI a b 70.9%) 16 (3. mean (SD) Coronary angiography.7) 58 (35.9%) 14 (7.0%) 61 (13. unstable angina.3%) 94 (57.4%) 173 (39.5 (209.2%) 13 (2.6%) 13 (7.2%) 113 (68.5)a 63.0%) 151 (91.2 (30.05 vs non-STEMI.4%) 39 (8.0–1294.6 (32.3%) 149 (84. ng/L eGFR.0) 127 (71.1%) 146 (88.

752.902.2 ng/L.6%) 344 (88.1–28.1)a 31.8 (32. At baseline concentrations of 14 – 49 ng/L (n ϭ 404) the relative ␦ change was significantly superior to absolute ␦ change in identifying patients with non-STEMI using a cutoff value of 43.2%) 233 (63. baseline to 6 h ng/L a b 5 (4–6) 3 (2–3) 1 (1–1) 133 (80. ng/L hsTnT 3 h.0 (20.9)a 92. performance of absolute ␦ changes was superior to relative ␦ changes independent of time to symptom onset. we observed an inferior performance of relative ␦ changes among patients presenting later than 4 h after onset of symptoms.3 (19.5) 14.521) (Fig.3%)a 79 (47.0%) 91 (51.001).8)a 5.5–642.695.3)a a a 104 (58.1) 16.5% (95% CI 94. and the ROC-optimized ␦ change of 9.1 (114.5) for the absolute ␦ change of 9.5–59.0001). P Ͻ 0. Baseline hs-cTnT. P Ͻ 0.4%) 121 (92. Analysis taking into consideration baseline hscTnT concentrations demonstrated a better performance of absolute changes than relative ␦ changes at baseline hs-cTnT concentrations Ͻ14 ng/L (n ϭ 118 patients) with an ROC-based optimal cutoff for absolute changes of 4.2%)b 365 (82.1–871.0 (5.7–134.1) 341.1 (2.9%) 159 (96.2) 410.2%) 390 (88.0) 398. P ϭ 0.5 (19.2 ng/L for absolute ␦ change showed a diagnostic sensitivity of 89.799.5)a 10. 3).0–25.185.0001) (Fig.2–250.3)a P Յ 0. In contrast. P Ͻ 0. ng/L hsTnT 24 h.0–200. Compared to a Ն20% relative ␦ change.5 (74.9).7 ng/L (AUC ϭ 0. absolute ␦ changes (AUC ϭ 0.272.8%)a 442 (100%) 31.9%) 142 (80. Moreover.3) 56. ng/L Early peak (0–6 h).9%)a a 14.2–31. Serial measurement Non-STEMI (n ‫ ؍‬165) UAP (n ‫ ؍‬177) Non-ACS (n ‫ ؍‬442) No. P Ͻ 0. The diagnostic performance of different ␦ changes with Clinical Chemistry 58:1 (2012) 213 .9) with a NPV of 96. maximum absolute and relative ␦ changes.3 (6.1 (22.8–25.0) 4 (3–4) 3 (3–3) 1 (0–1) a 3 (2–4)a 2 (2–3) 0 (0–1)a a 168 (94.4)a 2.0001).4 (11. and maximum hs-cTnT concentrations within 6 h (AUC ϭ 0.2 (27.1) 54.3–312.6 ng/L (AUC ϭ 0.1–907.2 (6. ng/L hsTnT 6 h.2 (116.5–83.5) 188. P Ͻ0.3 (28. of samples 24–72 h Sample at 3 h Sample at 6 h Any sample at 24–72 h Ն99th percentile 0 h Ն99th percentile 3 h Ն99th percentile 6 h Ն99th percentile 0–6 h hsTnT 0 h (baseline).8 (1.9 (20. % Absolute change.5–60.3–63.5 (18.830. The ROC-based optimal cutoff value of Ն9.9–22.0 –93.7–1315.6)a 35.4%) 132 (92.6–11.96 vs AUC ϭ 0. yielding PPVs of 48. baseline hs-cTnT (AUC ϭ 0. By comparing performance of relative and absolute ␦ changes related to time from symptom onset to admission.2 ng/L (NRI ϭ 0.6 (5.6)a 49.4–184.8 (3.1–69.6–91.013) and baseline concentrations of Ն100 ng/L (n ϭ 155) with a cutoff value for absolute change of 47. ng/L hsTnT 48 h. The diagnostic sensitivities. 2A).7–197.3) 130.898) than relative ␦ changes (AUC ϭ 0.0) 245.6)a 61. the absolute ␦ change of Ն5 ng/L (NRI ϭ 0.001).4)a 31.1–101.7% (95% CI 42.8 (62.0 (27. P ϭ 0.9 –54.4–62.7 (20.3%) 165 (100%) 92. baseline to 6 h.731.311. of samples total No.0001) demonstrated a significant added value.2) 53.4–555. In the baseline concentration range of 50 –99 ng/L (n ϭ 107) no significant difference was found between absolute and relative ␦ changes (AUC ϭ 0.009).7%) 145 (87.4) a 24. no significant difference was found for performance of absolute ␦ changes related to the time from symptom onset to admission (see online Supplemental Fig.3 (46.8%)a 418 (94.2 (7.8)a 11.4–378.6%) 207 (46.777 vs 0.6–258. 1).6 (8. P Ͻ 0.2–1148.4 –97.1%) 143 (86. P Ͻ 0.7% (95% CI 84. ng/L Relative change. Ն20 ng/L (NRI ϭ 0.1–5.3) a a 18.9)a 15.0 (31.0001 vs non-STEMI.0047).4 (19. P ϭ 0.928 vs 0.81 vs 0.1–26.6)a 68.05 vs non-STEMI.6) a 52.0) 381.5% for relative ␦ changes (AUC ϭ 0. of samples 0–6 h No. PPVs and NPVs derived from ROC-based optimal cutoff values for relative and absolute ␦ changes as well as for other relevant ␦ changes are displayed in Table 3.8%)a 89 (50.4%) a 68 (47.1 (152.0 (124. diagnostic specificities. Diagnostic specificities were lower. P ϭ 0.Kinetics in Non-STEMI and Non-ACS cTnT Table 2.815. ng/L hsTnT 72 h. ng/L Late peak (24–72 h).

respectively) and relative ␦ changes (P Ͻ 0.Fig.0001) and peak hs-cTnT concentrations (AUC ϭ 0. P Ͻ 0. The performance of ␦ changes for rule-in and rule-out of non-STEMI in the specific ACS population is shown in online Supplemental Data Table 2. patients with non-STEMI showed significantly increased absolute ␦ changes (P Ͻ 0.941) than relative ␦ changes (AUC ϭ 0. P Ͻ 0. A value of 6.741.9 ng/L was detected as the ROC-optimized absolute ␦ change. particularly relative ␦ changes. absolute ␦ changes outperformed relative ␦ changes (AUC ϭ Fig. Comparison of areas under the curve of baseline hs-cTnT. 1. respectively).894. 2.0001) (Fig. In direct comparison of kinetic changes. P Ͻ 0.836. peak hs-cTnT within 6 hours. relative ␦ change and absolute ␦ change for prediction of non-STEMI in the entire study population (A) and ACS population (B). comparison of AUC values demonstrated a significantly better performance of absolute (AUC ϭ 0.0001. Distribution of absolute (A) and relative (B) ␦ change in patients with a final diagnosis of non-STEMI (n ‫؍‬ 165) or UAP (n ‫ ؍‬177) and in patients with increased hs-cTnT due to non-ACS conditions (n ‫ ؍‬442). Compared to UAP and non-ACS conditions.0001) as well as baseline (AUC ϭ 0. In a specific ACS population (n ϭ 342). addition of the 99th percentile cutoff value for hs-cTnT are shown in online Supplemental Table 1. Discussion Our findings demonstrate the superiority of absolute ␦ changes in identification of non-STEMI within 3– 6 h in a population of consecutive patients presenting to an ED with ACS and troponin increases due to non-ACS conditions. 2B). Concentration changes of hs-cTnT were significantly higher in non-STEMI than in other acute cardiac or extracardiac disease and there was a wide overlap of ␦ values.0001. 214 Clinical Chemistry 58:1 (2012) .

5) 88.7 (65. In addition.9–96. In comparison. onset.2–78.5) 61.4) 100 (97.0 (85. P Ͻ 0.5) 35.7–37.5% in the entire study population and a NPV of 93.5 (73. 0.9) 83.7 (55.6 (30.017 Ϫ0.5% for relative ␦ change.070 Ϫ0.2) 87.7 (97.2–45.2–81.8–81.0% in patients with ACS. Because 24. implementation of dynamic changes only to patients with ACS allows both rule-in and rule-out of non-STEMI with a NPV of 93. the use of the ROC-optimized relative ␦ changes for rule out yielded NPVs of 88.9) 87.3–96.4–92.7 (44.7–36.5 (94.0) 37.7–65.6) 53.2 ng/Lb Change Ն20 ng/L Change Ն50 ng/L Change Ն100 ng/L Change Ն200 ng/L a b 75.2–96.1) 37.4 (32.9) 66.5) 83.5–90.6 (85.3) 83. 3.4) 88. and these patients were more likely to have increased baseline hs-cTnT concentrations with prolonged time from symptom onset to admission.5) 85. i. ROC-based optimal cutoff for discrimination of non-STEMI.7 (84.0 (79.5–89.110 0.5 (40.9–87.898 vs 0.8% of all non-STEMI patients presented with relative ␦ changes Ͻ20% within the initial 6 h.2 (54.6) 98. Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI) NRIa Change Ն20% Change Ն30% Change Ն39.2 ng/L for the entire study population and 6.2 (93.2 ng/L were below this cutoff in the initial 6 h.0%.0) 95.4 (82.0–85. This finding can likely be explained by the relative overlap of kinetic changes in this cohort. with only weak PPVs for the ROC-optimized kinetic change values of 48.9–42.4) 28.7% for absolute and 47.4) 32.4) 96. Performance of absolute and relative ␦ change related to 4 baseline hs-cTnT categories.3% of the nonSTEMI patients using the absolute ␦ change of 9.8) 85. Compared to a Ն20% relative ␦ change.2) 88.4) 88.5) 63.5) 87.1–62.8–60.331 and 0.2–79. only 10.8%b Change Ն50% Change Ն100% Change Ն250% Change Ն5. we found that the ROCoptimized absolute ␦ change was useful to rule out non-STEMI with a NPV of 96.9 ng/L for a specific ACS population demonstrated a significant added value (NRI ϭ 0.1 (65. Performance of kinetic changes in hs-cTnT within the initial 6 h for rule-in and rule-out of non-STEMI in the entire study population.1–43.9–86. thus decreasing their usefulness to rule in non-STEMI in such a population.2–60.8–98.9–54.8–100) 89.055 0.8) 79.2) 52.8 (81.9) 72.3 (93.9–90.4 (28.1–60.001.1) 48.061 Vs relative ␦ change Ն20%.4–97. rule-in of non-STEMI in a population consisting of ACS and non-ACS-related troponin increases is extremely difficult.4–54.6–87.1 (71.4–59.9–94. the conclusion can be made that this group of patients may already have reached a plateau of the cardiac troponin release curve.2) 23.7 (84.8) 99.1) 74.0) 57.5 (68.8–85.0) 58.0001.3–99. 50 –99 ng/L and >100 ng/L. c P Ͻ 0.4) 74.0–93.1 (44.5 (84.0) 75.2 (85. This result may indicate that absolute ␦ changes are also more diagnostically sensitive in the plateau phase of cardiac troponin release.1 (54. respectively). whereas the performance of relative ␦ changes declined 4 h after symptom Fig.185c 0. In contrast. In contrast.752.140 0.3) 40. the performance of absolute ␦ changes was independent of time from symptom onset to admission. More importantly.5 (34.7 (42.3–93.9) 84.7) 55.4 (74.8) 47.5–99.499. 14 – 49 ng/L.8 (86.8–76.0–30.7–90.1–99.311c 0.2 (17.4 (27.9) 92.4) — 0.1–90.8 (71.3 (96.2 (67. <14 ng/L. the ROC-optimized absolute ␦ change of 9.5–78.4 (84.1 (45.5–91.0% for the entire study population.4 (95.072 0.8–71. P Ͻ 0.e.2) 95.4) 52.8–87.0–68.6 (49.6 (55.4 (51.0001).5 (21.8% for the ROC-optimized Clinical Chemistry 58:1 (2012) 215 .2 (98. However.8 (80.4 (89. and a PPV of 82.0 (80.272c 0.5) 98.7) 97.5–46.0 ng/L Change Ն9.Kinetics in Non-STEMI and Non-ACS cTnT Table 3.029 Ϫ0.5) 89.

This issue must be addressed in forthcoming trials. tested the impact of ␦-change values of Ն20%. Accordingly. Thus.2 ng/L in direct comparison to the ROC-optimized relative ␦ change of 39. Ն20. particularly in situations with delayed presentation after onset of symptoms. we cannot exclude some bias when evaluating the performance of different absolute and relative ␦ changes. LIMITATIONS Because the reference standard in our study to diagnose non-STEMI was based on the 20% ␦ change within 24 h and not all non-STEMI patients fulfilled the 20% ␦ change within 6 h. in the area of baseline concentrations slightly above the 99thpercentile. Moreover. Moreover. (16 ). in contrast to the study by Reichlin et al.5%. biological variation has not yet been evaluated for discrimination of non-STEMI against non– ACS-related troponin elevations. Therefore the use of relative ␦ change may be more appropriate for baseline hs-cTnT concentrations slightly above the 99thpercentile cutoff than in low or high hs-cTnT baseline concentrations because relative ␦ changes tend to under. data on biological variability of cardiac troponin in healthy individuals assessed by RCV suggested that biological variation may be more important for interpreting minor cardiac troponin concentration increases at or just above the 99thpercentile limit when assays of very high sensitivity are used (9– 11 ). who evaluated kinetic changes among patients with symptoms suggestive of AMI. it appears that the most appropriate strategy to differentiate AMI in a cohort with a high prevalence of acute hs-cTnT increases not due to ACS is rule-out using absolute concentration changes. Our data indicate that absolute ␦ changes were superior only in patients with low and high baseline concentrations and in the cohort that includes all baseline concentrations.or overestimate kinetic changes in these concentration ranges. Data on the impact of absolute ␦ changes on diagnostic performance are sparse. and reported that Ն30% change in cTnI should be used as the optimal change in addition to either the baseline or follow-up concentration to improve specificity in patients presenting with symptoms of ACS (5 ). In contrast to Reichlin et al. which is close to our proposed cutoff value of 9. we selected consecutive patients presenting to an ED with ACS or troponin increases in the absence of ACS. Therefore our study population showed a higher prevalence of patients with cardiac troponin increases at baseline (666 of 784 patients. tested the utility of absolute and relative ␦ changes for early diagnosis of AMI and also found that the performance of absolute ␦ changes was significantly superior to the performance of relative ␦ changes (16 ). relative ␦ changes showed a higher diagnostic accuracy compared to absolute ␦ changes. In addition. and Ն30%. However. we and Reichlin et al. The high prevalence of patients with non–ACS-related cardiac troponin increases in relation to AMI leads to increasing difficulties in diagnosing AMI without kinetic changes. (16 ) we could not demonstrate the diagnostic superiority of absolute ␦ changes independent of the underlying baseline concentration. More recently. proved the feasibility of even small absolute ␦ changes during serial sampling by showing very high diagnostic accuracy. in our study we showed a better diagnostic performance of the ROC-optimized absolute ␦ change of 9. it appears that biological variation may represent a useful metric to discriminate acute from chronic cardiac troponin increases but need further prospective validation. The data suggest that limiting the serial measurement to only 6 h would increase the chance of misclassifying patients with hs-cTnT increases within the initial 6 h but without kinetic changes as non–ACS related conditions instead of nonSTEMI. Hitherto. The optimal cutoff value for absolute ␦ changes from baseline to 2-h follow-up sample was 7. 11 ). However. Our group demonstrated ROC-optimized relative ␦-change values for hs-cTnT between 117% and 243% within 3 and 6 h.8%. PREVIOUS FINDINGS Previously. Apple et al. respectively. tested the utility of percentage changes in cTnI of Ն10. However. an important obstacle with biological variation is the fact that RCVs have to be calculated for every cardiac troponin assay separately. only 1 study has analyzed the diagnostic role of absolute ␦ changes in the diagnosis of AMI. not all patients in our . and Ն100% and found that a change Ն50% would have resulted in more frequent falsenegative results in patients with an index diagnosis of AMI (7 ). Conversely. 84. which is in the range of what has recently been reported for biological short-term variability (9. for diagnosis of AMI in a selected small cohort of patients with evolving AMI (6 ).2 ng/L from baseline to 3– 6 h. Reichlin et al. In addition. Ն50%. whereas rule-in of AMI may not be achieved adequately in this cohort. Moreover. in contrast to 35% of patients 216 Clinical Chemistry 58:1 (2012) in the study by Reichlin et al. For concentrations above the 99thpercentile up to 49 ng/L our data support the usefulness of relative ␦ changes of 43.absolute change. However. our findings indicate a problem that not only the magnitude of rise and/or fall but also the time interval in which the kinetic change should be fulfilled is poorly defined. and RCVs strongly depend on the selection of the reference population.9%). this does not affect patients without hs-cTnT increases in the first 3– 6 h since early rule-out can be accomplished reliably in these patients. Eggers et al.0 ng/L.

Braun S. Eggers KM. Analytical validation of a high-sensitivity cardiac troponin T assay. Jaffe AS. Wu AH. MacRae AR. Aftab W.Kinetics in Non-STEMI and Non-ACS cTnT study received angiography and had blood samples available exceeding 6 h. both in the entire study population and in the ACS cohort. Katus HA. Jarausch J. Role of monitoring changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events. Ko DT. Katus HA. AACC. Conversely. 2007 universal myocardial infarction definition change criteria for risk stratification by use of a high-sensitivity cardiac troponin I assay. we also cannot exclude that some patients whose illness would have qualified for type 2 MI were classified as non-ACS and vice versa.53:2086 –96.an evaluation with respect to the Universal Definition of Myocardial Infarction. et al. Kurz K. Roche. Saenger AK. that there may be some confounding due to biological variation. ␦-change criteria proved useful for rule-out of nonSTEMI. Expert Testimony: None declared. In addition. Lindahl B.412:748 –54. Finally. Wians FH Jr. Abbott Diagnostics. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission. Roche Diagnostics and BRAHMS. Thygesen K. Wang X. Potential conflicts of interest: Employment or Leadership: S. Mouanoutoua M. Jaffe AS. BRAHMS Biomarkers. BRAHMS Biomarkers. and Mitsubishi Chemicals. Blankenberg. Huang G. Mitsubishi Chemicals. Other: H. Venge P. Beyrau R. Clin Chem 2010.56:487–9. 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. Becker M. 11. Conclusions The use of high-sensitivity cardiac troponin assays revealed that non-STEMI as well as other acute cardiac diseases demonstrated a considerable rise and/or fall of cardiac troponin that may easily exceed 20% with a substantial overlap in non-STEMI and other acute non-ACS conditions. Circulation 2007. (b) drafting or revising the article for intellectual content. Multicenter analytical evaluation of a high-sensitivity troponin T assay. and Thermo Fisher. Stock Ownership: None declared. Roche Diagnostics Ltd. Jaffe AS. Clin Chem 2011. Clin Chem 2010. Giannitsis E. when using any absolute or relative ␦ changes. Wu AH. Consultant or Advisory Role: S.412:91–7. Clin Chim Acta 2011. Javed U. Kaczmarek JM. a rise and/or fall of at least 9. Giannitsis E. 7. Apple FS. and Thermo Fisher Scientific. choice of enrolled patients. Jernberg T. Alpert JS.116: 2634 –53. 5. Frankenstein L. Research Funding: E. Giannitsis. Zdunek D. and Bayer.56:254 – 61. Am J Cardiol 2009. Vasile VC. Germany. Roche Diagnostics. Dolci A. Agewall S. Murakami MM. or analysis and interpretation of data. Katus H. 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. one has to be aware of the situation. Kavsak PA. review and interpretation of data. Kroning JM. Given ambiguous clinical presentation. Saenger AK. Ambrose JA. Todd J. E. all authors completed the Disclosures of Potential Conflict of Interest form. Clinical Diagnostics Division. non-coronary disease. White HD. sampling time was at least 24 h in two thirds of all patients and the angiography rates are in compliance with other ED population studies or contemporary clinical trials (3. However. 56:642–50. guest editor. Morrow DA.32:404 –11. Frequency of elevated troponin I and diagnosis of acute myocardial infarction. and (c) final approval of the published article. Siemens Healthcare. These results explain why relative ␦ changes fail to rule in non-STEMI in a population consisting of ACS patients and patients with acute non–ACS-related troponin increases. This potentially may create a bias for classification of non-STEMI and UAP. Therefore our results from a single observational study have to be confirmed by larger clinical trials.A. Clinical Chemistry 58:1 (2012) 217 . Clin Chem 2010. Giannitsis E. Giannitsis. 3. Roche Diagnostics.2 ng/L for a population consisting of patients with ACS and non-ACS conditions. 12. Apple FS. Galvani M. References 1. acquisition of data. Switzerland. Kurz K. Jesse RL. Giannitsis E. Clin Chem 2007. 13. Role of Sponsor: The funding organizations played no role in the design of study. Siemens. Clinical implications of the change of cardiac troponin I levels in patients with acute chest pain . Moecks J. Giannitsis. et al. Clin Chem 2010. Hallermayer K.9 ng/L for an ACS population seems to be more adequate than relative ␦ changes for ruling out AMI. H. Cooray R. different prevalence of disease in different clinical settings may require other cutoff values for diagnosis of AMI in other populations. Blankenberg. Jaffe AS. With the use of absolute ␦ changes. Jaffe AS. Katus. Novartis. Clin Chem 2009. Honoraria S.104:9 –13. Katus HA. Wu AH. Overall diagnostic performance of absolute ␦ changes was better than performance of relative changes owing to a higher specificity of absolute ␦ changes. or 6. Wians F. 17 ). 2. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design. Lu QA. Troponin elevation in coronary vs. Clin Chem 2009. Siemens Healthcare. Thermo Fisher. Wessel RJ. 10.56:1086 –90. Biological and analytical variability of a novel high-sensitivity cardiac troponin T assay. Smith SW. Pearce LA. Shortand long-term biological variation in cardiac troponin I measured with a high-sensitivity assay: implications for clinical practice. et al. Biological variation and reference change value of high-sensitivity troponin T in healthy individuals during short and intermediate follow-up periods. Freidank H. et al. 6. Clin Chim Acta 2011. 8. Hess G.A. Eur Heart J 2011. or preparation or approval of manuscript. Clinical Chemistry. 57:1068 –71. Universal definition of myocardial infarction. Blankenberg. E. 9. Germany.55: 930 –7. Apple FS. 4. 55:52– 8. Hallermayer K. Jaffe AS. Acknowledgments: We would like to thank Francisco OjedaEchevarria for help with statistical analysis. Francis GL. Katus has developed the cardiac troponin T assay and holds a patent jointly with Roche Diagnostics.

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