Comparison of high sensitivity troponin T and I assays in the diagnosis of non-ST elevation acute myocardial infarction in emergency patients with chest pain

Clinical Biochemistry 47 (2014) 321–326

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Comparison of high sensitivity troponin T and I assays in the diagnosis of non-ST elevation acute myocardial infarction in emergency patients with chest pain☆,☆☆ Louise Cullen a,b,⁎,1, Sally Aldous c,1, Martin Than c, Jaimi H. Greenslade a,b,d, Jillian R. Tate a, Peter M. George c, Christopher J. Hammett a,d, A. Mark Richards e,f, Jacobus P.J. Ungerer a, Richard W. Troughton e, Anthony F.T. Brown a,d, Dylan F. Flaws d, Arvin Lamanna a,d, Christopher J. Pemberton e, Christopher Florkowski c, Carel J. Pretorius a, Kevin Chu a,d, William A. Parsonage a,d a

Royal Brisbane and Women's Hospital, Herston, QLD, Australia Queensland University of Technology, Brisbane, QLD, Australia Christchurch Hospital, Christchurch, New Zealand d The University of Queensland, Brisbane, QLD, Australia e Christchurch Heart Institute, University of Otago, Christchurch, New Zealand f Cardiovascular Research Institute, National University Heart Centre, Singapore b c

a r t i c l e

i n f o

Article history: Received 3 October 2013 Received in revised form 20 November 2013 Accepted 25 November 2013 Available online 5 December 2013 Keywords: High sensitivity troponin Acute myocardial infarction Chest pain Emergency Diagnostic accuracy

a b s t r a c t Objectives: Concentrations of troponin measured with high sensitivity troponin assays are raised in a number of emergency department (ED) patients; however many are not diagnosed with acute myocardial infarction (AMI). Clinical comparisons between the early use (2 h after presentation) of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) assays for the diagnosis of AMI have not been reported. Design and methods: Early (0 h and 2 h) hs-cTnT and hs-cTnI assay results in 1571 ED patients with potential acute coronary syndrome (ACS) without ST elevation on electrocardiograph (ECG) were evaluated. The primary outcome was diagnosis of index AMI adjudicated by cardiologists using the local cTnI assay results taken ≥6 h after presentation, ECGs and clinical information. Stored samples were later analysed with hs-cTnT and hs-cTnI assays. Results: The ROC analysis for AMI (204 patients; 13.0%) for hs-cTnT and hs-cTnI after 2 h was 0.95 (95% CI: 0.94– 0.97) and 0.98 (95% CI: 0.97–0.99) respectively. The sensitivity, specificity, PLR, and NLR of hs-cTnT and hs-cTnI for AMI after 2 h were 94.1% (95% CI: 90.0–96.6) and 95.6% (95% CI: 91.8–97.7), 79.0% (95% CI: 76.8–81.1) and 92.5% (95% CI: 90.9–93.7), 4.48 (95% CI: 4.02–5.00) and 12.86 (95% CI: 10.51–15.31), and 0.07 (95% CI: 0.04–0.13) and 0.05 (95% CI:0.03–0.09) respectively. Conclusions: Exclusion of AMI 2 h after presentation in emergency patients with possible ACS can be achieved using hs-cTnT or hs-cTnI assays. Significant differences in specificity of these assays are relevant and if using the hs-cTnT assay, further clinical assessment in a larger proportion of patients would be required. © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Abbreviations: ACS, acute coronary syndrome; AMI, acute myocardial infarction; cTn, cardiac troponin; ECG, electrocardiograph; ED, emergency department; hs, high sensitivity; NLR, negative likelihood ratio; NSTEMI, non-ST elevation myocardial infarction; PLR, positive likelihood ratio; UAP, unstable angina pectoris. ☆ Conflict of interest statements: Dr Cullen has received research grants from Alere (formerly Inverness Medical), Radiometer Pacific, Abbott Diagnostics, Roche and Siemens; consultancy fees from Abbott Diagnostics; and support to attend meetings/conferences from Abbott Diagnostics, Alere, Astra Zeneca, Novartis, Radiometer Pacific, Pfizer and Boehringer Ingelheim. Dr Than has received funds from Alere and Abbott Diagnostics to support research, for speaking commitments, and for travel expenses. Dr Greenslade and Dr Parsonage are co-investigators on research grants received from Roche, Abbott and Siemens. Dr Parsonage has also received research grants from Genzyme Corp. and Inverness Medical; consultancy fees from Abbott, Astra Zeneca, Pfizer and Hospira; and support to attend meetings/conferences from Abbott, Sanofi-Aventis and Astra Zeneca. Dr Tate has received speaking fees from Siemens Healthcare Germany. Dr Hammett and Dr Ungerer are co-investigators on a research grant from Roche. Dr Richards has received travel support and speaker's honoraria from Alere. Dr Brown has received funding from Astra Zeneca, Boehringer Ingelheim, Aventis, and Roche to attend educational meetings and honoraria from Boehringer Ingelheim and Roche for educational material. He is on the Board of the Queensland Emergency Medical Research Foundation and has received funding from this body as a co-investigator. He has been an Expert Medical Witness for the Queensland, Victorian and Northern Territory Coroners, and various legal companies. Dr Flaws received support from Alere to travel to meetings. The remaining authors report no conflicts. ☆☆ Financial support: This work was supported by research grants from Roche Diagnostics International Ltd (Rotkreuz, Switzerland), Abbott Laboratories (North Chicago, Illinois) and the Queensland Emergency Medical Research Foundation (Brisbane, Queensland, Australia) (QEMRF Proj-2008-002). Abbott Laboratories and Roche Diagnostics also supplied the reagents. The sponsors of this study had no role in the study design, data collection, data analysis, data interpretation, writing of the report or decision to submit the paper. ⁎ Corresponding author at: Department of Emergency Medicine, Ground Floor, James Mayne Building, Royal Brisbane and Women's Hospital, Herston QLD 4029, Australia. Fax: +61 7 3646 1643. 1 Both authors have contributed equally and should be considered first author. 0009-9120/$ – see front matter © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clinbiochem.2013.11.019

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Introduction

Materials and methods

Elevated levels of circulating cardiac troponin (cTn) represent the biochemical component in the diagnosis of acute myocardial infarction (AMI), with current guidelines recommending that troponin assays ideally be precise (coefficient of variation b 10%) at the recommended decision cut-point of the 99th percentile of a healthy population [1]. This has prompted the development of high sensitivity cardiac troponin (hs-cTn) assays. In patients presenting with symptoms suggestive of acute coronary syndrome (ACS), these hs-cTn assays have been interpreted to be more sensitive for AMI than existing standard assays, identifying a larger number of patients with AMI (because low level cTn rises are detected), and also identifying patients with AMI earlier [2–4]. Based on early studies, guidelines suggest that a second hs-cTn assay result can reliably rule out AMI by 3 h following presentation if at least 6 h after symptom onset, compared to standard assays where sampling for measurement of a second cTn result is recommended at 6–9 h post presentation, or 8–12 h post-symptom onset [5,6]. Elevated hs-cTn has also been shown to provide more robust prognostic information compared with standard assays in patients with chest pain [7]. However, more widespread implementation of hs-cTn assays has also led to an increase in detection of elevated levels among patients diagnosed with non-coronary causes of chest pain such as structural cardiac diseases and arrhythmias [8], as well as non-cardiac conditions such as sepsis, pulmonary emboli, and renal failure [9]. Although elevations of cTn have prognostic value in some of these non-ACS presentations [10], there is no evidence that coronary revascularization improves outcome in this context. The interpretation of hs-cTn assay results can therefore be challenging, especially in patients with low level elevation. Most data come from studies investigating the first commercially available hs-cTn assay for troponin T (hs-cTnT), with less data available for the emerging high sensitivity troponin I (hs-cTnI) assays. Reports are emerging of significant differences between hs-cTnI and hs-cTnT assay performances, with wide dispersion of results for identical samples measuring both cTnI and cTnT, and in the clearance of these two biomarkers [11–13]. There are no studies comparing high sensitivity cTnT and cTnI assays within a clinical context. Thus the aim of this study was to compare performance of hscTnT and hs-cTnI assays and report sensitivity, specificity and predictive values for AMI in emergency department (ED) patients presenting with symptoms of possible ACS. We also assessed the prognostic utility of these high sensitivity assays for death within one year.

This was a pre-planned secondary analysis from an Australia–New Zealand collaborative study of the utility of early (0 h and 2 h) measurement of biomarkers and electrocardiography in ED patients with potential ACS. This secondary analysis compares the use of early hs-cTnT and hs-cTnI measurement in such patients. The study complies with the Declaration of Helsinki and was performed in accordance with ACTRN12611001076965. The research protocol was approved by the local hospital ethics committees. All participants gave informed consent. Patients presenting to a major metropolitan ED in Christchurch, New Zealand or Brisbane, Australia between November 2007 and February 2011 were recruited by research staff. The Australian site is an adult ED, with an annual attendance in Australia of 75,000. The New Zealand site is a mixed ED, with an annual attendance of 85,000. Patients with symptoms suggestive of cardiac ischemia (acute chest, epigastric, neck, jaw or arm pain, or discomfort or pressure without apparent non-cardiac source) were included. Patients were excluded if they were b18 years old, had ST elevation on electrocardiogram (ECG), were unable to provide informed consent, unwilling to participate or in whom follow-up was not possible. Research staff collected demographic and clinical data from patients, supervised ECG testing, and drew blood samples taken at presentation and 2 h after the first sample. Samples were stored to allow future analysis with hs-cTnT and hs-cTnI assays. At each institution patients underwent usual assessment including cTnI and ECGs taken on presentation and at least 6 h later. All management decisions were at the discretion of the attending clinician without knowledge of the hs-cTnT or hs-cTnI assay results. Patients were followed up after 30 days by telephone contact, review of hospital notes and a search of national registries for death up to one year from presentation. Patient data were recorded according to standardized data collection forms using a published data dictionary [14]. Patient diagnoses on admission and follow-up were independently adjudicated by cardiologists blinded to the hs-cTnT and hs-cTnI assay results, but with knowledge of the local cTnI assay results, ECGs and all other clinical information available up to 30 days after presentation. At both sites, two cardiologists independently reviewed all patients with ACS, with a third cardiologist available in cases of disagreement. This was not required. Outcome measures The primary outcome was the diagnosis of AMI within 24 h of presentation, defined as evidence of myocardial necrosis together with clinical evidence of myocardial ischemia (ischemic symptoms,

Fig. 1. STARD patient flow diagram with high sensitivity T and I assays. ADP, accelerated diagnostic pathway; AMI, acute myocardial infarction; STEMI, ST-elevation myocardial infarction; hs-TnT, high sensitivity troponin T; hs-TnI, high sensitivity troponin I.

L. Cullen et al. / Clinical Biochemistry 47 (2014) 321–326 Table 1 Patient characteristics at index admission. Characteristic

Australia (n = 771)

New Zealand (n = 800)

p

Age, median (interquartile range) Male Caucasian ethnicity Known ischemic heart disease Prior AMI Prior PCI Prior CABG Prior heart failure Prior stroke Peripheral vascular disease Hypertension Dyslipidemia Smoker Diabetes Family history ischemic heart disease Body mass index, median (interquartile range) Creatinine μmol/L, median (interquartile range) 2 h troponin positive TnI hsTnT hsTnI

54 (44.5–64) 456 (59.1) 670 (86.9) 162 (21) 126 (16.3) 79 (10.2) 49 (6.4) 38 (4.9) 70 (9.1) 14 (1.8) 338 (43.8) 327 (42.4) 179 (23.2) 102 (13.2) 356 (46.2) 28.0 (24.7–31.9)

65 (56–76) 482 (60.2%) 713 (89.1) 308 (38.5) 242 (30.2) 197 (24.6) 87 (10.9) 82 (10.2) 101 (12.6) 43 (5.4) 473 (59.1) 560 (70) 113 (14.1) 134 (16.8) 531 (66.4) 27.3 (24.4–30.8)

b0.01 0.66 0.17 b0.01 b0.01 b0.01 b0.01 b0.01 0.02 b0.01 b0.01 b0.01 b0.01 0.05 b0.01 0.01

88 (77–101)

b0.01

76 (64–88)

87 (11.3) 158 (20.5) 82 (10.6)

188 (23.6) 292 (36.5) 207 (25.9)

b0.01 b0.01 b0.01

Unless otherwise specified, data are number (% of total sample). AMI, acute myocardial infarction; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

ECG changes, or imaging evidence). AMI was diagnosed on the basis of a rising or a falling pattern of the laboratory cTnI concentrations, with at least one value above the 99th percentile. If the cTnI concentration was greater than the cut-off value but no rise or fall was detected, other causes of cTn elevation were considered. If no clear alternative cause for the cTn rise was apparent, and if the clinical presentation was suggestive of ACS, a diagnosis of AMI was made. The secondary outcome included all-cause mortality at one year. Reference tests Samples for clinical decision making (0 h and 6–12 h post presentation) were sent to the local central laboratory for measurement of cTnI. The assay used in Christchurch, New Zealand was the ARCHITECT STAT Troponin-I assay (Abbott Laboratories, Abbott Park, Illinois), limit

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of detection 10 ng/L, 99th percentile 28 ng/L, and 10% coefficient of variation 32 ng/L. The decision cut-point used was that recommended by the manufacturer at 30 ng/L. The assay used in Brisbane, Australia was the Beckman Coulter DxI Access Accu cTnI assay (Beckman Coulter, California), limit of detection 10 ng/L, 99th percentile 40 ng/L, and 10% coefficient of variation 60 ng/L. The decision cut-point used was that recommended by the manufacturer at 40 ng/L. Index tests Research samples taken 2 h apart from the presentation sample were collected, centrifuged and plasma and serum stored frozen at −80 °C for later analysis in a blinded fashion in batches for hs-cTnT and hs-cTnI. The hs-cTnT assay was the Elecsys Troponin T-high sensitive assay (Roche Diagnostics, Penzberg, DE), limit of detection 5 ng/L, 99th percentile 14 ng/L, and 10% coefficient of variation 13 ng/L. The decision cut-point as recommended by the manufacturer was 14 ng/L. The results were calculated using a standardized calibration curve specific for the reagent kit provided by the manufacturer in 2012 (Penzberg, DE). The hs-cTnI assay was the ARCHITECT High Sensitive STAT Troponin-I assay (Abbott Laboratories, Abbott Park, Illinois), limit of detection 1.2 ng/L, 99th percentile 26.2 ng/L with a corresponding co-efficient of variation b 5%. The overall decision cut-point used was that recommended by the manufacturer at 26.2 ng/L. Sex-specific cut-offs were not used for either assay. Statistical methods Continuous variables are presented as medians and interquartile ranges and categorical variables as numbers and percentages and are compared using the Chi squared test. Sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) for inpatient and 30 day events were calculated for hs-cTnT and hs-cTnI using the cut-points of the 99th percentile. Sensitivities and specificities were compared using the McNemar test. Receiver operating characteristic (ROC) curves were constructed for hs-cTnT and hs-cTnI for the diagnosis of non-ST elevation myocardial infarction (NSTEMI). Differences in one year survival were assessed by Kaplan–Meier survival curves. Hs-cTnT and hs-cTnI (normal versus elevated) were compared using the log rank test. All statistical analyses were performed with the use of SPSS for Windows software (IBM Version 19.0). Results

Fig. 2. ROC curves for index acute myocardial infarction using both 0 and 2 h results. X indicates the 99th percentile of each assay.

1959 patients were recruited (Fig. 1), with exclusion of 388 patients in whom there was insufficient sample to measure hs-cTnT and hs-cTnI at both time points, leaving 1571 cases for analysis. Patient characteristics are shown in Table 1. The ED populations recruited in the two sites were different, with the cohort from New Zealand being older and more likely to have traditional risk factors for coronary artery disease. There was a significant difference (13.5%) in the proportions of patients with elevated values but without an adjudicated AMI. Hs-TnT was elevated in 287 (21.0%) patients and hs-cTnI elevated in 103 (7.5%) of the 1367 patients without an adjudicated AMI. The ROC curves for discrimination of index AMI (204 of 1571 patients; 13.0%) are shown in Fig. 2. The AUCs for hs-cTnT and hs-cTnI at 2 h were 0.95 (95% CI: 0.94–0.97) and 0.98 (95% CI: 0.97–0.99) respectively (p b 0.01). On presentation hs-cTnT was elevated in 185 (90.7%) and hs-cTnI in 181 (88.7%) of these patients. By 2 h, hs-cTnT was elevated in 191 (93.6%) and hs-cTnI in 195 (95.6%) of these patients. The sensitivity, specificity, PLR, and NLR of hs-cTnT and hs-cTnI for NSTEMI at 0 h and 2 h after presentation are shown in Table 2. The sensitivity of hs-cTnT and hs-cTnI for index AMI was not different at 0 h (p = 0.52), 2 h (p = 0.42) or combining 0 and 2 h results (p = 0.61).

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Table 2 Diagnostic accuracy of early measurements of hs-cTnT and hs-cTnI.

0h Sensitivity Specificity PLR NLR 2h Sensitivity Specificity PLR NLR 0 or 2 h Sensitivity Specificity PLR NLR

hs-cTnT % (95% CI)

hs-cTnI % (95% CI)

90.7 (85.9–94.0) 80.8 (78.6–82.8) 4.71 (4.19–5.30) 0.12 (0.08–0.18)

88.7 (83.7–92.4) 93.9 (92.5–95.0) 14.44 (11.67–17.86) 0.12 (0.08–0.18)

93.6 (89.4–96.2) 81.1 (78.9–83.0) 4.92 (4.40–5.55) 0.08 (0.05–0.13)

95.6 (91.8–97.7) 93.1 (91.7–94.3) 13.90 (11.41–16.93) 0.05 (0.03–0.09)

94.1 (90.0–96.6) 79.0 (76.8–81.1) 4.48 (4.02–5.00) 0.07 (0.04–0.13)

95.6 (91.8–97.7) 92.5 (90.9–93.7) 12.69 (10.51–15.31) 0.05 (0.03–0.09)

Hs-cTnI was more specific than hsTnT at both 0 h and 2 h (p b 0.001) and had a better PLR for AMI. Hs-cTnT was elevated by 2 h after presentation in 287 (21.0%) of the 1367 patients adjudicated as having a non-AMI diagnosis. 168 patients were diagnosed with other cardiac conditions such as arrhythmia, heart failure or valvular heart disease, and 18 patients had unstable angina pectoris (UAP) and 101

patients were given an adjudicated diagnosis of undifferentiated chest pain. Elevated hs-cTnI was found in 103 (7.5%) patients without an adjudicated AMI. Sixty four patients were diagnosed as having other cardiac conditions, nine with UAP and 25 with undifferentiated chest pain. Thirteen patients were diagnosed with UAP but had elevated troponin results using either of the high sensitivity assays (Table 3). The sensitivity and specificity of hs-cTnT and hs-cTnI for NSTEMI at 0 h and 2 h after presentation were compared across sites. The sensitivity of hs-cTnT and hs-cTnI did not differ across sites (χ2 = 0.08, p = 0.93 and χ2 = 0.14, p = 0.71 respectively). The specificity of cTnI did not differ across sites (χ2 = 0.48, p = 0.49) but the specificity of cTnT was 6.5% (95% CI: 2.2–10.2%) lower in the New Zealand site compared to the Australian site (χ2 = 8.83, p = 0.03). Despite this difference, the substantial interpretation did not change; the specificity of cTnT was lower than cTnI for both the Australian and New Zealand sites (p b 0.01) (Table 4). Kaplan–Meier analysis for one year mortality shows that the combined 0 and 2 h results using hs-cTnT and hs-cTnI assays are predictive of 1 year death (Fig. 3). Discussion This study compared the diagnostic performance of an hs-cTnT assay with an hs-cTnI assay and demonstrated that they were equally

Table 3 Details of patients diagnosed with unstable angina and elevated troponin values using high sensitivity troponin assays. Patient details

sTnI results (0, 2, ≥6 h)

1. 64 year old male

50, 40, 40 (BC)

56.1, 56.0

2. 53 year old male

40, 50, 50 (BC)

30.5, 47.4

3. 80 year old male

200, 200, 200 116.6, 114.3 203.3, 196.4 Previous AMI, history of CHF, stroke and PAD, (BC) prior CABG and PCI, hypertension, diabetes, dyslipidemia and family history of CAD. 50, 70, 90 45.2, 44.6 44.2, 43.5 Prior angina, hypertension and diabetes. (AD) 30, 20, 30 26.8, 23.4 19.4, 19.2 Previous AMI, CABG and PCI. Hypertension, (AD) diabetes, dyslipidemia and family history of CAD. 20, 20, 20 28.4, 32.9 9.6, 11.1 Family history of CAD. (AD)

4. 82 year old female 5. 68 year old female

6. 49 year old male

hs-cTnI (0, 2 h)

hs-cTnT (0, 2 h)

Past medical history

Cardiac investigations and intervention

15.1, 13.6

Previous AMI, prior CABG, prior PCI, current smoker.

28.5, 30.4

Dyslipidemia and current smoker.

Angiography findings: 70% stenosis in the LAD, Alive 100% stenosis in the circumflex, 100% stenosis in the RCA EST positive at maximal workload. Alive Angiographic findings 90% stenosis in RCA. PCI performed. TTE with regional wall motion Alive abnormality indicative of AMI.

7. 68 year old male

0, 0, 0 (AD)

25.1, 26.5

6.2, 6.2

8. 50 year old male

40, 50, 40 (BC)

23.2, 24.4

23.9, 23.0

9. 67 year old male

10, 10, 10 (BC)

11.9, 10.9

14.3, 12.5

6.2, 5.4

14.1, 12.3

54.4, 50.7

29.9, 31.6

10.2, 9.1

46.1, 41.5

90.4, 86.7

35.1, 33.0

10. 92 year old female 30, 10, 40 (BC) 11. 51 year old male 30, 20, 30 (AD) 12. 79 year old male 20, 10, 10 (BC)

13. 45 year old male

10, 10, 10 (BC)

Prior angina, PAD, CABG and PCI. Hypertension, diabetes, dyslipidemia and family history of CAD. Previous AMI, CHF and CABG. Hypertension, diabetes and dyslipidemia.

Anaemia secondary to PR bleeding (haemoglobin 69). Transfused. Angiographic findings of 90% stenosis in LM, 100% stenosis in LAD, 90% stenosis in LCx and 30% stenosis in RCA EST which was positive at maximal workload. Angiogram showing 20% stenosis in LAD and 50% in LAD diagonal branch. Nil

CTCA findings: Patent grafts, with distal LAD and LCx marginal not opacified well with contrast. Limited regional wall motion abnormality. Previous AMI and PCI. Hypertension, Angiographic findings: 70% stenosis in LAD, dyslipidemia and 70% stenosis in circumflex family history of CAD. and 10% stenosis in RCA Previous AMI, CHF and stroke. Hypertension. Further testing was deemed clinically inappropriate. Previous AMI, CHF and PCI. Hypertension, Angiographic findings of 70% in LAD, 99% stenosis in LCx and 50% stenosis in RCA. dyslipidemia and family history of CAD. Previous AMI, stroke, CABG and PCI. Hypertension, Stress radionuclide imaging positive dyslipidemia and family history of CAD. at maximal workload. Angiographic findings of 30% stenosis in the LAD, 100% in the circumflex and 100% in the RCA Previous AMI, prior PCI, diabetes, TTE with regional wall motion abnormality dyslipidemia and family history of CAD. indicative of AMI. Angiographic findings of stenosis of 95% in the circumflex. PCI performed.

1 yr vital status

Alive Alive

Alive

Alive

Alive

Alive

Alive Alive Alive

Alive

The decision cut-point for cases using the Beckman Coulter DxI Access Accu cTnI assay (Beckman Coulter, BC) assay was N40 ng/L. The decision cut-point for cases using the ARCHITECT STAT Troponin-I assay (Abbott Diagnostics, AD) assay was N30 ng/L. AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; CTCA, CT coronary angiography; EST, exercise stress test; LAD, left anterior descending artery; LCx, left circumflex artery; LM, left main coronary artery; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; RCA, right coronary artery; TTE, transthoracic echocardiography.

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Table 4 Sensitivity, specificity, PLR and NLR of Australian and New Zealand sites.

hs-cTnT Australia New Zealand hs-cTnI Australia New Zealand

Sensitivity % (95% CI)

Specificity % (95% CI)

94.4 (81.9–98.5) 94.0 (89.4–96.7)

82.0 (79.1–84.6) 75.5 (72.0–78.7)

5.26 (4.42–6.26) 3.84 (3.33–4.42)

0.07 (0.02–0.26) 0.08 (0.04–0.14)

94.4 (81.9–98.5) 95.8 (91.7–98.0)

92.9 (90.8–94.6) 91.9 (89.5–93.8)

13.35 (10.15–17.55) 11.88 (9.11–15.48)

0.06 (0.02–0.23) 0.05 (0.02–0.09)

sensitive for the diagnosis of AMI 2 h after presentation for ED patients presenting with possible cardiac chest discomfort. These findings support the early use of hs-cTn assays for the exclusion of AMI in this cohort [4,15,16]. The use of such sensitive assays should therefore reduce the rate of premature discharge in patients with unrecognised ACS, whilst having the potential to reduce ED and hospital overcrowding. This is supportive of rapid rule-out biomarker approaches used in combination with clinical risk stratification for AMI in ED patients [4,15,16], that may allow follow-on testing for coronary artery disease to occur early in an inpatient or outpatient setting. In keeping with other reports, no assay

PLR % (95% CI)

NLR % (95% CI)

in this study showed clear superiority in terms of clinical sensitivity for AMI [4]. A significant difference was found in the specificity for AMI between hs-cTnI and hs-cTnT assays 2 h after presentation. Variations in results when using different methods for analysing cTn have been shown to be greater than can be explained by analytical imprecision alone [17]. The biological variability of cTnT and cTnI in patients with stable coronary artery disease [18] and release of these molecules after myocardial injury [19,20] are significantly different [17]. Some of this may be explained by the differences in the sizes of the molecules (c-TnT, 37 kDa; cTnI, 24 kDa) which may influence their relative release times from necrotic tissue, and potential for degradation once released [21]. The description of the decreased specificity using a high sensitivity assay for AMI has only been using cTnT [9]. Within this study the diagnosis of AMI incorporated late (≥6 h) troponin values from sensitive cTnI assays. In practice the decreased specificity for AMI when using the hs-cTnT assay may result in a larger proportion of ED patients requiring further evaluation. We identified thirteen patients with a diagnosis of UAP, but with elevated troponin values assessed using the high sensitivity troponin assays. For some of these patients, the diagnosis was unlikely to have been changed by the use of high sensitivity cTn assays (Cases 1–4). For others, if a high sensitivity assay value had been incorporated in the original adjudication of the diagnoses, these patients may have been classified as NSTEMI rather than UAP (Cases 5–13). All of these patients had significant underlying coronary artery disease, and their investigations suggest that had a high sensitivity troponin assay been used in their clinical care, they would have been diagnosed with an AMI. It is recognised that the use of more precise assays has led to a greater proportion of patients meeting the universal definition of AMI [9], nevertheless the clinical entity of UAP is likely to continue to be a distinct diagnosis in the high sensitivity troponin assay era. The advantages of analytical methods with good specificity are also important. Troponin elevations can identify underlying cardiac conditions [22] however the disadvantage of high sensitivity cTn assays is that more patients with conditions other than AMI are also detected, in whom further evaluation and usually admission is required. A rise and/or fall in troponin values is essential to the diagnosis of AMI, and criteria for a significant change in troponin values are reported [23,24]. However in the acute setting, change criterion (deltas) may be found in conditions associated with non-type 1 AMI [25]. The use of change criteria was therefore not studied. Elevation of troponin detected by either the hs-cTnT or hs-cTnI assay was highly predictive of all-cause death. Overall, hs-cTnT was more predictive for adverse events, but hs-cTnI was more specific. Limitations

Fig. 3. Kaplan–Meier analysis for one year mortality for hs-cTnI and hs-cTnT.

Our study has limitations. Only patients presenting with a chest pain syndrome were enrolled. Our findings are not applicable to patients presenting with atypical symptoms with an eventual diagnosis of AMI. Some characteristics of the ED populations differed and the exact reason is unclear. Differences in the primary care models of the two countries, whereby troponin testing in general practice is common (personal communication M. Than, 2012), may have reduced some of the low

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risk patient presentations in New Zealand. We used sensitive (and not high sensitivity) troponin assays for the values incorporated in adjudication of diagnoses. This may influence the significance of our findings. If a cTnT assay (rather than a cTnI assay) was used for adjudication the final diagnoses may have differed for some individuals. This requires further investigation. Whilst there is an initiative to standardize cTn assays it is unlikely that this will occur in the short term [17]. Due to the lack of standardization of cTn assays, our findings are applicable only to the assays reported. The samples used for testing included both serum (Australia) and plasma (New Zealand); however it is unlikely that this affected the results. Good correlation between plasma and serum has been demonstrated for both hs-cTnI and hs-cTnT [26]. We used the sample taken soon after the time of presentation as the first sample, with the subsequent sample taken 2 h later, regardless of when the onset of symptoms occurred. The application of our findings in clinical practice would require the timing of samples to be based on time of presentation and not symptom onset. Conclusion Exclusion of NSTEMI two hours after presentation in emergency patients with symptoms of possible ACS can be achieved with equal high sensitivity using an hs-cTnT or an hs-cTnI assay. Both assays had modest specificity for AMI, with the hs-cTnI assay proving more specific for AMI than the hs-cTnT assay. The use of the hs-cTnI assay for evaluation may potentially lead to less misclassification and fewer consequent further investigations for ED patients with chest pain. Regardless of the underlying cause, elevated values are prognostically important with elevated levels using either hs-cTn assay being highly predictive of death over the next year. Acknowledgements We acknowledge the patients who participated in the study. We thank the research staff, emergency department staff and laboratory technicians of all participating sites for their invaluable efforts. References [1] Thygesen K, Alpert JS, White HD, Joint ESC/AACF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Circulation 2007;116:2634–53. [2] Aldous SJ, Richards AM, Cullen L, Than MP. Early dynamic change in high-sensitivity cardiac troponin T in the investigation of acute myocardial infarction. Clin Chem 2011;57:1154–60. [3] Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. 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. [4] Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858–67. [5] Chew DP, Aroney CN, Aylward PE, Kelly AM, White HD, Tideman PA, et al. 2011 addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes (ACS) 2006. Heart Lung Circ 2011;20:487–502.

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