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Absolute and Relative Kinetic Changes of High-Sensitivity Cardiac Troponin T in Acute Coronary Syndrome and inPatients with Increased Troponin in the Absence of Acute

Coronary SyndromeMatthias Mueller, 1 Moritz Biener, 1 Mehrshad Vafaie, 1 Susanne Doerr, 1 Till Keller, 2 Stefan Blankenberg, 2

Hugo A. Katus, 1 and Evangelos Giannitsis 1*

BACKGROUND: We evaluated kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) in patientswith acutecoronary syndrome(ACS)andpatientswithhs-cTnT increases not due to ACS to rule in or ruleout nonST-segment elevation myocardial infarction

(STEMI).

METHODS : hs-cTnT was measured serially in consecu-tive patients presenting to the emergency department.Patients with ACSwhohadat least 2 hs-cTnT measure-ments within 6 h and non-ACS patients with hs-cTnTconcentrations above the 99th percentile value (14ng/L) were enrolled to compare absolute and relativekinetic changes of hs-cTnT.

RESULTS: For discrimination of non-STEMI (n 165)in theentirestudy population (n 784), the absolutechange with the ROC-optimized value of 9.2 ng/L yielded an area under the curve of 0.898 and was supe-rior to all relative changes (P 0.0001). The positivepredictive value for the absolute change was 48.7%,whereas the negative predictive value was 96.5%. In aspecific ACSpopulation with exclusionof STEMI (n 342), the absolute change with the ROC-optimizedvalue of 6.9 ng/L yielded a positive predictive value of 82.8% and a negative predictive value of 93.0%. Incomparison to the 20% relative change, the ROC-optimized absolute change demonstrated a signifi-cantly added value for the entire study population andfor theACS cohort (net reclassification index0.331 and

0.499, P

0.0001).CONCLUSIONS : Absolute changes appear superior torelative changes in discriminating non-STEMI. A rise

or fall of at least 9.2 ng/L in the entire study populationand 6.9 ng/L in selected ACS patients seems adequateto rule-out non-STEMI. However, -values are usefulto rule-in non-STEMI only in a specific ACSpopulation. 2011 American Association for Clinical Chemistry

The Joint European Society of Cardiology/AmericanCollege of Cardiology/American Heart Association/WorldHeartFederation Task Force for theredefinitionof acute myocardial infarction (AMI) 3 has recom-mended that a diagnosis of AMI be made only in thepresence of a rise and/or fall of cardiac troponin, withat least1 valueabove the99th percentile referencevalue(1 ). These findings in conjunction with a clinical con-text suggesting myocardial ischemia as the underlying

mechanism indicate that a diagnosis of AMI should bemade. Otherwise, other acute heart disease causing adynamic cardiac troponin release should be considered(2 ). Recently, Javed et al. reported that fewer than onethird of patients with increased cardiac troponin werefound to have AMI (3 ). Therefore, knowledge aboutthe magnitude of concentration changes ( ) in AMI inthe absence of acute coronary syndrome (ACS) is es-sential to the definition of an optimal dynamic metricthat allowsdiscriminationof acute from a chroniccon-ditions and of AMI from nonACS-related conditionsthat cause cardiac troponin increases.

Unfortunately, the magnitude at which the in-crease or decrease is indicative of an acute rather than achronic cardiac troponin increase is unclear, and it isstill 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 Hamburg-Eppendorf, Hamburg, Germany.

* Address correspondence to this author at: Medizinische Klinik III, Im Neuen-heimer Feld 410, 69120 Heidelberg, Germany. Fax 49-6221-56-5516; [email protected].

Received July 1, 2011; accepted October 31, 2011.

Previously published online at DOI: 10.1373/clinchem.2011.1718273 Nonstandard abbreviations: AMI, acute myocardial infarction; ACS, acute cor-

onary syndrome; RCV, reference change value; ED, emergency department;hs-cTnT, high-sensitivity cardiac troponin T; STEMI, ST-segment elevation myo-cardial infarction; UAP, unstable angina pectoris; PCI, percutaneous coronaryintervention; NPV, negative predictive value; PPV, positive predictive value;AUC, area under the curve; NRI, net reclassification index; IQR, interquartilerange.

Clinical Chemistry 58:1209218 (2012)

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and whether absolute or relative change is the idealmetric for cardiac troponin measurement. The Na-tional Academy of Clinical Biochemistry has recom-mendeda change in cardiac troponin of 20%69hafter presentation, but this recommendation is basedon analytical considerations only in the subset of pa-tients with end-stage renal disease or other conditionswith low baseline-concentration increases of cardiactroponin (4 ). Several investigators have proposedhigher relative changes between 30%250% to in-crease the diagnostic specificity and thus improve di-agnosis of AMI (58). Recent study results suggest theuse of reference change values (RCVs), which are therelative changes determined from biological variability of cardiac troponin (911) .

Previous studies have investigated patients pre-senting with chest pain or more selected ACS popula-

tions and thus have not provided data on dynamicchanges of cardiac troponin in other acute heart dis-eases forwhich patients commonly present to an emer-gency department (ED). Therefore, we evaluated dy-namic changes of high-sensitivity cardiac troponin T(hs-cTnT) in patients with ACS and cardiac troponinincreases in the absence of ACS who presented withacute symptoms to anED.We determined thediagnos-tic accuracy of absolute and relative changes of car-diac troponin in discrimination of AMI.

Methods

During a 6-month period we measured hs-cTnT seri-ally on presentation and at least after 3 or 6 h in allconsecutive patients presenting to the internal medi-cine ED and chest pain unit of the University HospitalHeidelberg. Patients with ACS who received a secondblood draw within 6 h and patients with non-ACS con-ditions with at least 1 hs-cTnT concentration above the99th percentile value (14 ng/L) qualified for evaluationof relative or absolute changes within 36 h afteradmission to rule in or rule out nonST-segment ele-vation myocardial infarction (non-STEMI). AMI,without further differentiation into type I or type II,wasdiagnosedaccording to the criteria of the universaldefinition with detection of a rising and/or falling pat-tern of hs-cTnT and evidence of myocardial ischemia(1 ). Because the magnitude of the rise and/or fall forthe diagnosis of AMI is still not established, we used a20% rise and/or fall as a minimum to define an acutechange, including all available hs-cTnT measurementswithin 24 h after the initial blood draw. In addition, anabsolute concentration change of 5 ng/L betweenbaselineand thehighest consecutive valuewasrequiredto diagnose AMI.

We excluded patients with ST-segment elevationsor new left bundle-branch block on presentation be-

cause thediagnosisof STEMI is made by electrocardio-gram and biomarker testing is not recommended forSTEMI patients. A diagnosis of unstable angina pecto-ris (UAP) was made if ACS was suspected clinically buths-cTnT concentrations were consistently below the99th percentile value during serial sampling for at least6 h. Moreover, patients with increased hs-cTnT and atypical presentation of ACS but without a relativechange 20% or an absolute concentration differenceof 5 ng/L were found to have UAP with hs-cTnTincreases due to underlying chronic cardiac damage orsevere renal failure. In addition, the diagnosis of UAPrequired the presence of typical symptoms togetherwith a history of coronary artery disease and previouscoronary interventionor detectionof a culprit lesion of 50% on coronary angiogram, or objective evidenceof myocardial ischemia on stress testing.

To discriminate procedure-related MI, we ex-cluded patients who underwent percutaneous coro-nary intervention (PCI) and developed subsequent hs-cTnT increases after PCI before a final diagnosis of unstable anginaor non-STEMI could be made. In con-trast, we did not exclude patients with increased base-line hs-cTnT and declining values after PCI.

In the absence of clinical variables suggestive of myocardial ischemia, increased hs-cTnT was inter-preted as unrelated to AMI, and the underlying reasonof myocardial damage was actively sought. Reasons forincreased hs-cTnT in the absence of ACS were catego-rizedinto cardiac, extracardiac, and uncertain.Cardiac

causes comprised acutely decompensated heart failure,decompensated valve disease, Tako-Tsubo cardiomy-opathy, myocarditis, pulmonary embolism, and atrialor ventricular tachyarrhythmias. Extracardiac causesincluded severe kidney dysfunction/end-stage renaldisease and sepsis.

Final diagnosis of ACS or non-ACS was based onall available clinical, laboratory, and imaging findingsadjudicated by an expert committee of 2 independentcardiologists blinded to the investigational biomarkerresults. A third cardiologist refereed in situations of disagreement.All medical decisions including the needand timing of coronary angiography, coronary inter-vention, or further diagnostic work-up were left to thediscretion of the attending cardiologist.

The study was performed according to the princi-ples of theDeclarationof Helsinki andapproved by thelocal ethics committee. Written informed consent wasobtained fromallparticipating patients.Follow-upwasaccomplishedvia telephonecontact or questionnaireatleast 6 months after discharge.

LABORATORY MEASUREMENTS

We measured cardiac troponin on COBAS E411 usingthe hs-cTnT assay (Roche Diagnostics), which is com-

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merciallyavailable in Germany (not yet available in theUS). The limit of the blank (3 ng/L) and limit of detec-tion (5ng/L) were determined in accordance with CLSIguidelineEP17-A. TheinterassayCVwas8% at 10 ng/Land 2.5% at 100 ng/L. The intraassay CV was 5% at 10ng/Land1%at100ng/L (12). Referenceintervalvalueswere established from a multicenter reference study and the 99th percentile value was determined at 14ng/L (13).

Along with admission values, several kinetic metricswere calculatedfromserialmeasurements including rela-tive change[(Cmax (3 h or 6h) Cbaseline) /Cbaseline 100,where C is hs-cTnT concentration] given as percent-age change in either direction (rise or fall) of hs-cTnT from baseline, absolute change betweenhighest hs-cTnT concentration from 3- or 6-h sam-ple and baseline [C max 3h or 6h Cbaseline ] expressed

as nanograms per liter, and peak hs-cTnT concen-tration within 6 h.

STATISTICAL ANALYSIS

Continuous variables were tested for normal distribu-tion and were presented either as mean (SD) or as me-dians with 25th and 75th percentiles. We comparedgroups by using the 2 test for categorical variablesandANOVA for continuous variables. We determined op-timal thresholds for relative and absolute changesfrom ROCcurveson thebasisof thecontinuouslymea-sured biomarker concentrations. We calculated diag-nostic sensitivities, diagnostic specificities, negative

predictive values (NPVs), and positive predictive val-ues (PPVs) for relative and absolute changes for clas-sification of finaldiagnosisofnon-STEMI. Tocompareareas under the curve (AUCs) we used the test of De-Long et al. (14). To demonstrate an added value of other kinetic changes compared to a 20% relativechange, we determinednet reclassification index(NRI)according to the method by Pencina et al. (15).

All analyses on performance were executed for theentire population and in 4 categories of incrementalbaseline hs-cTnT intervals to adjust for the effects of absolute baseline concentrations. The categories in-cluded baseline hs-cTnT concentrations of 14 ng/L,1449 ng/L, 5099 ng/L, and 100 ng/L.

SPSS 15.0 and MedCalc 11.1 statistical softwarepackages were used. All tests were 2-tailed, and a P value 0.05 was considered statistically significant.

Results

BASELINE

During a 6-month recruitment period a total of 863patients qualified for the kinetic study. Non-STEMIwas diagnosed in 165 patients (19.1%) and UAP in 177patients (20.5%). In 442 patients (51.2%) cardiac tro-

ponin increases were not due to ACS (non-ACS condi-tions). We excluded64 patients (7.4%)presenting withST-segment elevations or new left bundle-branchblockon electrocardiogram. Moreover,we excluded 15patients (1.7%)whounderwentPCI anddeveloped in-creasing hs-cTnT values after PCI but before the finaldiagnosis was made. Thus, the entire study populationconsisted of 784 patients, including patients with ACSand non-ACS conditions. The ACS study populationconsisted of 342 patients with non-STEMI and UAP.Reasons for cardiac troponin increases in non-ACSconditions comprised cardiac diseases in 152 (34.4%),extracardiac diseases in 159 (36.0%), and uncertaincauses in 131 patients (29.6%).

The baseline characteristics of the entire study pop-ulation (n 784) subdivided by final diagnosis are dis-played in Table 1. As expected, patientswith non-STEMIand patients with hs-cTnT increases not due to ACS dif-fered with respect to most baseline demographic charac-teristics and laboratory and angiographic findings. Inaddition, both groups within the ACS spectrumshowed significant differences, mainly in angiographicbaseline characteristics. More details on baseline char-acteristics are provided in the Data Supplement thataccompanies the online version of this article athttp://www.clinchem.org/content/vol58/issue1.

SERIAL CHANGES

Themediannumberof hs-cTnT measurementsper in-

dividual was 3 (25th to 75th percentile: 23). Table 2demonstrates hs-cTnT concentrations on presentationand during consecutive sampling, as well as maximalabsolute and relative changes. Fig. 1 shows the max-imal individual relative and absolute changes within6 h for patients with non-STEMI, UAP, or non-ACSconditions.

All 165 patients with non-STEMI and non-ACSconditions as well as 91 patients with UAP(51.4%) hadhs-cTnT concentrations 99th percentile in a least 1sample during the initial 6 h. Within this time frame,62.4% of patients with non-ACS conditions (n 276)

and 75.2% of patients with non-STEMI (n 124) ful-filled the 20% change criterion. Conversely,24.8% of patients with a final diagnosis of non-STEMI (n 41)didnot fulfill this diagnostic criterion within the initial6 h, but did spontaneously during subsequent sam-pling within 24 h. Compared to non-STEMI patientswith a relative change 20%, those patients with achange 20%presented later after onset of symptoms,at 20 h [interquartile range (IQR) 1248 h] vs 12 h(IQR 148 h) ( P 0.04), and showed higher hs-cTnTon presentation [306.4 ng/L (IQR 131.7589.2) vs 45.7ng/L (IQR 20.9201.4), P 0.001].

Kinetics in Non-STEMI and Non-ACS cTnT

Clinical Chemistry 58:1 (2012) 211
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PERFORMANCE OF SERIAL CHANGES FOR RULE-IN AND

RULE-OUT OF NON-STEMI

In the entire study population (n 784), AUCs weredetermined from ROC analysis for continuous values

including baseline hs-cTnT concentrations and maxi-mum hs-cTnT concentrations within 6 h as well as rel-ative and absolute changes. Comparison of AUC val-uesdemonstrateda significantly better performance of

Table 1. Baseline demographic, laboratory, and angiographic characteristics of hs-cTnT elevation in non-STEMI,unstable angina, and non-ACS patients.

Non-STEMI (n 165) UAP (n 177) Non-ACS (n 442)

Age, mean (range), years 70.4 (59.177.5) 71.4 (61.878.7) 74.1 (66.681.2)

Age 75 years, n (%) 52 (31.5%) 64 (39.0%) 205 (46.4%)

Male sex, n (%) 121 (73.3%) 106 (59.9%) 173 (39.1%)a

NT-proBNP,b mean (range), ng/L 559.5 (209.01294.0) 594.0 (2003629) 2943 (994.57982.5)a

eGFR, mean (SD) or (range) 73.2 (30.7) 69.1 (24.3) 63.0 (43.380.6)c

eGFR 60, n (%) 58 (35.2%) 58 (32.8%) 202 (45.7%)a

Leading symptom, n (%)

Angina pectoris 113 (68.5%) 133 (75.1%) 58 (13.1%)a

Dyspnea 13 (7.9%) 7 (4.0%) 149 (33.7%)d

Syncope 2 (1.2%) 0 29 (6.6%)c

Other 37 (22.4%) 37 (20.9%) 206 (46.6%)

History, n (%)CHF 28 (17.0%) 43 (24.3%) 88 (20.0%)

CAD 151 (91.5%) 149 (84.2%) 254 (57.5%)a

PCI 63 (38.2%) 99 (55.9%) 121 (27.4%)

CABG 21 (12.7%) 23 (13.0%) 44 (10.0%)

PAD 18 (10.9%) 24 (13.6%) 38 (8.6%)

Stroke 12 (7.3%) 13 (7.3%) 33 (7.5%)

COPD 19 (11.5%) 21 (11.9%) 81 (18.3%)

Risk factors, n (%)

Diabetes mellitus 58 (35.2%) 65 (36.7%) 133 (30.1%)

Cholesterolemia 105 (63.6%) 138 (78.0%) 228 (51.6%)

Hypertension 139 (84.2%) 166 (93.8%)d

351 (79.4%)Active smoking 33 (20.0%) 20 (11.3%)d 39 (8.8%)

Ex-smoker 54 (32.7%) 60 (33.9%) 146 (33.0%)

Family history 14 (8.5%) 14 (7.9%) 61 (13.9%)

GRACE score, mean (SD) 129.0 (33.8) 119.3 (31.0) 140.6 (32.7)c

Coronary angiography, n (%) 147 (89.1%) 127 (71.8%)c 129 (29.2%)a

Coronary artery disease, n (%) 146 (88.5%) 124 (70.1%)c 109 (24.7%)a

0 VD 2 (1.2%) 9 (5.1%) 55 (12.4%)

1 VD 23 (13.9%) 14 (7.9%) 13 (2.9%)

2 VD 22 (13.3%) 28 (19.4%) 16 (3.6%)

3 VD 94 (57.0%) 76 (42.9%)c 44 (10.0%)a

Left main trunk 5 (3.0%) 0 1 (0.2%)

PCI 105 (63.6%) 67 (37.9%)c 13 (2.9%)a

a P 0.0001 vs non-STEMI.b NT-proBNP, N-terminal pro-B type natriuretic peptide; eGFR, estimated glomerular filtration rate; CHF, chronic heart failure; CAD, coronary artery disease; CABG,

coronary artery bypass graft; PAD, peripheral artery disease; COPD, chronic obstructive pulmonary disease; VD, vessel disease.c P 0.01 vs non-STEMI.d P 0.05 vs non-STEMI.


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absolute changes (AUC 0.898) than relativechanges (AUC 0.752, P 0.0001), baseline hs-cTnT(AUC 0.731, P 0.0001), and maximum hs-cTnTconcentrations within 6 h (AUC 0.830, P 0.0001)(Fig. 2A).

The diagnostic sensitivities, diagnostic specifici-ties, PPVs andNPVs derived from ROC-based optimalcutoff values for relative and absolute changes as wellas for other relevant changes aredisplayed in Table 3.

TheROC-based optimal cutoffvalue of 9.2 ng/Lfor absolute changeshoweda diagnostic sensitivity of 89.7% (95% CI 84.093.9) with a NPV of 96.5% (95%CI 94.497.9). Diagnostic specificities were lower, yielding PPVs of 48.7% (95% CI 42.954.5) for theabsolute change of 9.2 ng/L. Compared to a 20%relative change, the absolute change of 5 ng/L(NRI 0.185, P 0.001), 20ng/L(NRI 0.272, P 0.001), and the ROC-optimized change of 9.2 ng/L(NRI 0.311, P 0.0001) demonstrated a significantadded value.

Analysis taking into consideration baseline hs-cTnT concentrations demonstrated a better perfor-mance of absolute changes than relative changes atbaseline hs-cTnT concentrations 14 ng/L (n 118

patients) with an ROC-based optimal cutoff for abso-lute changes of 4.7 ng/L (AUC 0.96 vs AUC 0.815,P 0.013) and baseline concentrations of 100 ng/L(n 155) with a cutoff value for absolute change of 47.6 ng/L (AUC 0.777 vs 0.695, P 0.0047). Atbaseline concentrations of 1449 ng/L (n 404) therelative change was significantly superior to absolute

change in identifying patients with non-STEMIusinga cutoff value of 43.5% for relative changes (AUC 0.928 vs 0.902, P 0.009). In the baseline concentra-tion range of 5099 ng/L (n 107) no significant dif-ference was found between absolute and relativechanges (AUC 0.81 vs 0.799, P 0.521) (Fig. 3). By comparing performance of relative and absolutechanges related to time from symptom onset to admis-sion, we observed an inferior performance of relativechanges among patients presenting later than 4 h afteronset of symptoms. In contrast, performance of abso-lute changes was superior to relative changes inde-pendent of time to symptom onset. Moreover, no sig-nificant difference was found for performance of absolute changes related to the time from symptomonset to admission (see online Supplemental Fig. 1).Thediagnosticperformanceof different changes with

Table 2. Baseline hs-cTnT, maximum absolute and relative changes.

Serial measurement Non-STEMI (n 165) UAP (n 177) Non-ACS (n 442)

No. of samples total 5 (46) 4 (34)a 3 (24)a

No. of samples 06 h 3 (23) 3 (33) 2 (23)

No. of samples 2472 h 1 (11) 1 (01) 0 (01)a

Sample at 3 h 133 (80.1%) 168 (94.9%)a 390 (88.2%)b

Sample at 6 h 143 (86.7%) 142 (80.2%) 365 (82.6%)

Any sample at 2472 h 145 (87.9%) 104 (58.8%)a 207 (46.8%)a

99th percentile 0 h 159 (96.4%) 89 (50.3%)a 418 (94.6%) 99th percentile 3 h 121 (92.4%) 79 (47.0%)a 344 (88.2%) 99th percentile 6 h 132 (92.3%) 68 (47.9%)a 233 (63.8%)a

99th percentile 06 h 165 (100%) 91 (51.4%)a 442 (100%)

hsTnT 0 h (baseline), ng/L 92.0 (27.3312.3) 14.0 (5.126.8)a 31.5 (19.560.4)a

hsTnT 3 h, ng/L 130.3 (46.4378.5) 11.6 (5.025.5)a 31.3 (19.462.1)a

hsTnT 6 h, ng/L 188.8 (62.4555.1) 10.8 (3.825.3)a 31.4 (19.363.6)a

hsTnT 24 h, ng/L 341.1 (114.1871.0) 18.3 (6.559.1)a 49.2 (27.691.6)a

hsTnT 48 h, ng/L 398.2 (116.1907.2) 54.0 (20.7134.6)a 61.8 (32.4184.9)a

hsTnT 72 h, ng/L 410.1 (152.71315.0) 68.7 (20.7197.1)a 92.0 (31.6258.6)a

Early peak (06 h), ng/L 245.5 (74.5642.0) 16.2 (6.231.4)a 35.1 (22.169.3)a

Late peak (2472 h), ng/L 381.0 (124.21148.2) 24.4 (11.583.5)a 52.3 (28.1101.9)a

Relative change, baseline to 6 h, % 53.9 (20.0200.3) 14.2 (7.922.4)a 15.6 (8.128.8)a

Absolute change, baseline to 6 h ng/L 56.5 (18.2250.0) 2.8 (1.15.6)a 5.1 (2.611.3)a

a P 0.0001 vs non-STEMI.b P 0.05 vs non-STEMI.



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addition of the99th percentile cutoffvalue forhs-cTnTare shown in online Supplemental Table 1.

In a specific ACS population (n 342), compari-son of AUC values demonstrated a significantly betterperformanceof absolute (AUC 0.941)than relativechanges (AUC 0.741, P 0.0001) as well as baseline(AUC 0.836, P 0.0001) andpeak hs-cTnT concen-trations (AUC 0.894, P 0.0001) (Fig. 2B). A valueof 6.9 ng/L was detected as the ROC-optimized abso-lute change. Theperformance of changes for rule-inand rule-out of non-STEMI in the specific ACS popu-lation is shown in online Supplemental Data Table 2.

Discussion

Our findings demonstrate the superiority of absolutechanges in identification of non-STEMI within 36 hin a population ofconsecutive patientspresenting to anED with ACS and troponin increases due to non-ACSconditions. Concentration changes of hs-cTnT weresignificantly higher in non-STEMI than in other acutecardiac or extracardiac disease and there was a wideoverlap of values, particularly relative changes.

In direct comparisonof kinetic changes, absolutechanges outperformed relative changes (AUC

Fig. 1. Distribution of absolute (A) and relative (B) change in patients with a final diagnosis of non-STEMI (n165) 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, patients with non-STEMI showed significantly increased absolutechanges (P 0.0001, respectively) and relative changes (P 0.0001, respectively).

Fig. 2. Comparison of areas under the curve of baseline hs-cTnT, peak hs-cTnT within 6 hours, relative change andabsolute change for prediction of non-STEMI in the entire study population (A) and ACS population (B).


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0.898 vs 0.752, P 0.0001). Compared to a 20%relative change, the ROC-optimized absolutechange of 9.2 ng/L for the entire study population and6.9 ng/L for a specific ACS population demonstrated asignificant added value (NRI 0.331 and 0.499, P 0.0001, respectively). In addition, the performance of absolute changes was independent of time fromsymptom onset to admission, whereas the perfor-mance of relative changes declined 4 h after symptom

onset. Because 24.8% of all non-STEMI patients pre-sented with relative changes 20% within the initial6 h, and these patients were more likely to have in-creased baseline hs-cTnT concentrations with pro-longed time from symptom onset to admission, theconclusion canbe made that this group of patientsmay

already have reached a plateau of the cardiac troponinrelease curve. In contrast, only 10.3% of the non-STEMI patients using theabsolute change of 9.2 ng/Lwere below this cutoff in the initial 6 h. This result may indicate that absolute changes arealso more diagnos-tically sensitive in theplateau phaseof cardiac troponinrelease.

More importantly, we found that the ROC-optimized absolute change was useful to rule outnon-STEMI with a NPV of 96.5% in the entire study population and a NPV of 93.0% in patients with ACS.In comparison, the use of the ROC-optimized relative

changes for rule out yielded NPVs of 88.0% for theentire study population. However, with only weak PPVs for the ROC-optimized kinetic change values of 48.7% for absolute and 47.5% for relative change,rule-in of non-STEMI in a population consisting of ACS and non-ACS-related troponin increases is ex-tremely difficult. This finding can likely be explainedby the relative overlap of kinetic changes in this cohort,thus decreasing their usefulness to rule in non-STEMIin such a population. In contrast, implementation of dynamic changes only to patients with ACSallowsbothrule-in and rule-out of non-STEMI with a NPV of 93.0%, and a PPV of 82.8% for the ROC-optimized

Fig. 3. Performance of absolute and relative change related to 4 baseline hs-cTnT categories, i.e.< 14 ng/L, 1449 ng/L, 5099 ng/L and > 100 ng/L.

Table 3. Performance of kinetic changes in hs-cTnT within the initial 6 h for rule-in and rule-out of non-STEMIin the entire study population.

Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI) NRI a

Change 20% 75.2 (67.881.5) 58.1 (54.162.0) 32.4 (27.737.3) 89.8 (86.492.5)

Change 30% 63.6 (55.871.0) 75.1 (71.578.5) 40.5 (34.546.8) 88.6 (85.591.2) 0.055

Change 39.8%b 57.6 (49.765.2) 83.0 (79.885.9) 47.5 (40.454.6) 88.0 (85.190.5) 0.072

Change 50% 52.7 (44.860.5) 87.5 (84.790.0) 53.1 (45.160.9) 87.4 (84.589.9) 0.070

Change 100% 35.4 (28.143.2) 95.3 (93.396.8) 66.7 (55.876.4) 84.8 (81.987.3) 0.029

Change 250% 23.2 (17.030.4) 99.2 (98.199.7) 88.4 (74.996.1) 83.0 (80.085.6) 0.110

Change 5.0 ng/L 100 (97.8100) 55.4 (51.459.4) 37.4 (32.942.1) 98.3 (96.399.4) 0.185c

Change 9.2 ng/Lb 89.7 (84.093.9) 74.8 (71.278.2) 48.7 (42.954.5) 96.5 (94.497.9) 0.311c

Change 20 ng/L 72.7 (65.279.4) 87.7 (84.990.2) 61.2 (54.068.1) 92.4 (89.994.4) 0.272c

Change 50 ng/L 52.1 (44.260.0) 95.2 (93.296.7) 74.1 (65.281.8) 88.2 (85.590.5) 0.140

Change 100 ng/L 37.6 (30.245.4) 97.4 (95.898.5) 79.5 (68.887.8) 85.4 (82.687.9) 0.017

Change 200 ng/L 28.5 (21.736.0) 98.7 (97.599.4) 85.5 (73.393.5) 83.8 (80.986.4) 0.061a Vs relative change 20%.b ROC-based optimal cutoff for discrimination of non-STEMI.c P 0.001.



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absolute change. Accordingly, it appears that the mostappropriate strategy to differentiate AMI in a cohortwith a high prevalence of acute hs-cTnT increases notdue to ACS is rule-out using absolute concentrationchanges, whereas rule-in of AMI may not be achievedadequately in this cohort.

In addition, our findings indicate a problem thatnot only the magnitude of rise and/or fall but also thetime interval in which the kinetic change should befulfilled is poorly defined. The data suggest that limit-ing the serial measurement to only 6 h would increasethe chance of misclassifying patients with hs-cTnT in-creases within the initial 6 h but without kineticchanges asnonACS related conditions instead of non-STEMI, particularly in situations with delayed presen-tation after onset of symptoms. This issue must be ad-dressed in forthcoming trials. However, this does not

affect patients without hs-cTnT increases in the first36 h since early rule-out can be accomplished reliably in these patients.

PREVIOUS FINDINGS

Previously, Apple et al. tested the utility of percentagechanges incTnI of 10, 20,and 30%, andreportedthat 30% change in cTnI should be used as the opti-mal change in addition to either the baseline orfollow-upconcentration to improvespecificity inpatientspresenting with symptoms of ACS (5). Our group dem-onstrated ROC-optimized relative -change values forhs-cTnT between 117% and 243% within 3 and 6 h,

respectively, for diagnosis of AMI in a selected smallcohort of patients with evolving AMI (6 ) . Conversely,Eggers et al. tested the impact of -change values of 20%, 50%, and 100% and found that a change 50% would have resulted in more frequent false-negative results in patients with an index diagnosis of AMI (7 ). Data on the impact of absolute changes ondiagnostic performance are sparse. Hitherto, only 1study has analyzed the diagnostic role of absolutechanges in the diagnosis of AMI. Reichlin et al. testedthe utility of absolute and relative changes for early diagnosis of AMI and also found that the performanceof absolute changes was significantly superior to theperformance of relative changes (16). The optimalcutoffvalue forabsolute changes from baseline to 2-hfollow-up sample was 7.0 ng/L, which is close to ourproposed cutoff value of 9.2 ng/L from baseline to 36h. However, in contrast to the study by Reichlin et al.(16), who evaluated kinetic changes among patientswith symptoms suggestive of AMI, we selected consec-utive patients presenting to an ED with ACS or tro-ponin increases in the absence of ACS. Therefore ourstudy population showed a higher prevalence of pa-tients with cardiac troponin increases at baseline (666of 784 patients, 84.9%), in contrast to 35% of patients

in the study by Reichlin et al. The high prevalence of patients with nonACS-related cardiac troponin in-creases in relation to AMI leads to increasing difficul-ties in diagnosing AMI without kinetic changes. More-over, in our study we showed a better diagnosticperformance of the ROC-optimized absolute changeof 9.2ng/L in directcomparison to theROC-optimizedrelative change of 39.8%. In contrast to Reichlin et al.(16) we could not demonstrate the diagnostic superi-ority of absolute changes independent of the under-lying baselineconcentration. Ourdata indicate that ab-solute changes were superior only in patients withlowand high baseline concentrations and in thecohortthat includes all baseline concentrations. However, inthe area of baseline concentrations slightly above the99thpercentile, relative changes showed a higher di-agnostic accuracy compared to absolute changes.

Therefore the use of relative change may be moreappropriate for baseline hs-cTnT concentrationsslightly above the 99thpercentile cutoff than in low orhigh hs-cTnT baseline concentrations because relative

changes tend to under- or overestimate kineticchanges in these concentration ranges.

More recently,data on biological variability ofcar-diac troponin in healthy individuals assessed by RCVsuggested that biological variation may be more im-portant for interpreting minor cardiac troponin con-centration increases at or just above the 99thpercentilelimit when assays of very high sensitivity are used (9 11). For concentrations above the 99thpercentile up to

49 ng/L our data support the usefulness of relativechanges of 43.5%, which is in the range of what hasrecently been reported for biological short-term vari-ability (9, 11). Moreover, we and Reichlin et al. provedthe feasibility of even small absolute changes duringserial sampling by showing very high diagnosticaccuracy.

However, an important obstacle with biologicalvariation is the fact that RCVs have to be calculated forevery cardiac troponin assay separately, and RCVsstrongly depend on the selection of the reference popu-lation. In addition, biological variation has not yet beenevaluated fordiscriminationof non-STEMI againstnonACS-relatedtroponinelevations. Thus, it appearsthatbi-ological variation may represent a useful metric to dis-criminate acute from chronic cardiac troponin increasesbut need further prospective validation.

LIMITATIONS

Because thereferencestandard inourstudy to diagnosenon-STEMIwas basedon the20% changewithin24hand not all non-STEMI patients fulfilled the 20%change within 6 h, we cannot exclude some bias whenevaluating the performance of different absolute andrelative changes. Moreover, not all patients in our


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study received angiography and had blood samplesavailable exceeding 6 h. This potentially may create abias for classification of non-STEMI and UAP. How-ever, sampling time was at least 24 h in two thirds of allpatients and the angiography rates are in compliancewith other ED population studies or contemporary clinical trials (3, 17). Given ambiguousclinical presen-tation, we also cannot exclude that some patientswhose illness would have qualified for type 2 MI wereclassified as non-ACS and vice versa. In addition,whenusing any absolute or relative changes, one has to beaware of the situation, that there may be some con-founding due to biological variation. Finally, differentprevalence of disease in different clinical settings may require other cutoff values for diagnosis of AMI inother populations. Therefore our results from a singleobservational study have to be confirmed by larger

clinical trials.Conclusions

The use of high-sensitivity cardiac troponin assays re-vealed that non-STEMI as well as other acute cardiacdiseases demonstrateda considerablerise and/or fall of cardiac troponin that may easily exceed 20% with asubstantial overlap in non-STEMI and other acutenon-ACS conditions. Theseresultsexplain whyrelative

changes fail to rule in non-STEMI in a populationconsisting of ACS patients and patients with acutenonACS-related troponin increases. Conversely,

-change criteria proved useful for rule-out of non-STEMI, both in the entire study population and in theACS cohort. Overall diagnostic performance of abso-lute changes was better than performance of relativechanges owing to a higher specificity of absolute

changes. With the use of absolute changes, a riseand/or fall of at least 9.2 ng/L for a population consist-ing of patients with ACS and non-ACS conditions, or6.9 ng/L for an ACS population seems to be more ade-quate than relative changes for ruling out AMI.

Author Contributions: All authors confirmed they have contributed tothe intellectual content of this paper and have met the following 3 re-quirements: (a) significant contributions to the conception and design,acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.Authors Disclosuresor PotentialConflictsof Interest: Uponman-uscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Employment or Leadership: S. Blankenberg, guest editor, Clinical

Chemistry , AACC.Consultant or Advisory Role: S. Blankenberg, Thermo Fisher; E.Giannitsis, Roche Diagnostics and BRAHMS.Stock Ownership: None declared.Honoraria S. Blankenberg, Roche Diagnostics, Abbott Diagnostics,Siemens, and Thermo Fisher; H.A. Katus, Novartis, Roche, andBayer; E. Giannitsis, Roche Diagnostics, Siemens Healthcare,BRAHMS Biomarkers, and Mitsubishi Chemicals.Research Funding: E. Giannitsis, Roche Diagnostics Ltd, Switzer-land; Mitsubishi Chemicals, Germany; Siemens Healthcare;BRAHMS Biomarkers, Clinical Diagnostics Division; and ThermoFisher Scientific, Germany.Expert Testimony: None declared.Other: H.A. Katus has developed the cardiac troponin T assay andholds a patent jointly with Roche Diagnostics.

Role of Sponsor: The funding organizations played no role in thedesignof study, choiceof enrolledpatients, reviewand interpretationof data, or preparation or approval of manuscript.

Acknowledgments: We would like to thank Francisco Ojeda-Echevarria for help with statistical analysis.

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