Research

Original Investigation

Evaluation of High-Sensitivity Cardiac Troponin I Levels

in Patients With Suspected Acute Coronary Syndrome
Edward Carlton, PhD; Jaimi Greenslade, PhD; Louise Cullen, PhD; Richard Body, PhD; Martin Than, MBBS;
John W. Pickering, PhD; Sally Aldous, MBChB; Simon Carley, MD; Christopher Hammett, MBChB;
Jason Kendall, MD; Brian Keevil, MSc; Sarah Lord, MBBS; William Parsonage, MD; Kim Greaves, MD

Editorial page 379

IMPORTANCE Low concentrations of high-sensitivity cardiac troponin I determined on Author Audio Interview at
presentation to the emergency department (ED) have been shown to have an excellent jamacardiology.com
negative predictive value (NPV) for the identification of acute myocardial infarction. The
Supplemental content at
sensitivity, and therefore clinical applicability, of such testing strategies is unknown.
jamacardiology.com

OBJECTIVE To determine the diagnostic performance of low concentrations of

high-sensitivity cardiac troponin I in patients with suspected cardiac chest pain and an
electrocardiogram showing no ischemia as an indicator of acute myocardial infarction.

DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of 5 international (Australia, New

Zealand, and England) prospective, observational cohort studies with blinded outcome
assessment and 30-day follow-up was conducted. A total of 3155 patients presenting with
symptoms suggestive of cardiac ischemia were included in the analysis. Eligible patients had a
nonischemic electrocardiogram determined and high-sensitivity troponin I measured at
presentation. The lower limit of detection (1.2 ng/L) as well as cutoff concentrations rounded
to the nearest integer for a high-sensitivity troponin I assay were used in the analysis.
Recruitment was undertaken from November 1, 2007, to August 10, 2013.

MAIN OUTCOMES AND MEASURES The primary outcome was fatal or nonfatal acute
myocardial infarction occurring within 30 days of ED presentation, adjudicated with serial
troponin testing. The secondary outcome was the proportion of patients potentially suitable
for early discharge at each cutoff concentration.

RESULTS Of the 3155 eligible patients, 1771 were male (56.1%), and mean (SD) age was 57.4
(13.3) years. Acute myocardial infarction developed in 291 individuals (9.2%). The 1.2-ng/L
limit of detection gave a sensitivity of 99.0% (95% CI, 96.8%-99.7%) and an NPV of 99.5%
(95% CI, 98.4%-99.9%). This cutoff level would allow for early discharge of 594 patients
(18.8%). All higher rounded cutoff values had sensitivities less than 98.0%. Diagnostic
performance of the limit of detection was maintained when patients were stratified by age,
sex, risk factors, presence of coronary artery disease, and early presentation.

CONCLUSIONS AND RELEVANCE High-sensitivity troponin I concentrations determined at

presentation to the ED that were below the limit of detection identified 18.8% of patients
potentially suitable for discharge, with a high sensitivity for acute myocardial infarction.
Rounded cutoff values above the limit of detection may not have the required sensitivity for
clinical implementation.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Edward
Carlton, PhD, Emergency
Department, Southmead Hospital,
North Bristol National Health Service
Trust, Southmead Road, Bristol,
JAMA Cardiol. 2016;1(4):405-412. doi:10.1001/jamacardio.2016.1309 Avon BS10 5NB, England (eddcarlton
Published online June 1, 2016. @gmail.com).

(Reprinted) 405

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 Research Original Investigation
P
atients with suspected cardiac chest pain account for
more than 6 million emergency department (ED) vis-
its annually across the United States.1 Current Ameri-
can Heart Association guidelines2 recommend serial measure-
ments of contemporary cardiac troponin at presentation and
3 to 6 hours after symptom onset. As a result, most patients
require prolonged assessment prior to safe discharge. This di-
agnostic approach leads to a large number of costly, poten-
tially avoidable hospital admissions.1,3 Strategies that could
safely identify a large proportion of patients suitable for dis-
charge after a single sample of blood is taken on arrival in the
ED would have major benefits to health care systems.
Low concentrations of high-sensitivity cardiac troponin
(hs-cTn) assays determined at presentation to the ED in com-
bination with nonischemic electrocardiogram (ECG) findings
demonstrate excellent prognostic ability in patients with sus-
pected acute coronary syndromes.4,5 It has therefore been
suggested5 that the clinical application of strategies that use
these low cutoff values could transform the assessment of chest
pain by identifying a large proportion of patients at low risk
for myocardial infarction (MI). These patients may be suit-
able for immediate discharge after a single sample of blood is
taken on arrival. However, large-scale cohort studies4,5 that re-
ported excellent negative predictive values (NPVs) (>99%) using
very low or undetectable cutoff strategies have not openly re-
ported the more important measure of diagnostic perfor-
mance: sensitivity. As practitioners may intuitively interpret
low cutoff hs-cTn strategies as diagnosticrather than prog-
nostictools, the provision of sensitivity values for informed
decision making in exclusion of acute coronary syndromes is
critical. In a meta-analysis6 of the diagnostic performance of
undetectable hs-cTnT levels in which sensitivity was pro-
vided, the point estimate was 97.4% (95% CI, 94.9%-98.7%).
This finding is below the minimum clinically acceptable thresh-
old of 99.0%.7
We aimed to evaluate the diagnostic performance of low
concentrations of hs-cTnI in patients with suspected cardiac
chest pain and a nonischemic ECG from 5 international ED co-
horts of prospectively recruited patients. We specifically in-
tended to report sensitivity for the diagnosis of fatal or non-
fatal acute MI (AMI).
Methods
Study Design and Participants
The study population consisted of eligible patients recruited
into 5 prospective ED cohort studies. The first 2 cohorts were
enrolled at 2 tertiary teaching hospitals (Royal Brisbane and
Womens Hospital, Brisbane, Australia, and Christchurch
Hospital, Christchurch, New Zealand) in the ADAPT (2-Hour
Accelerated Diagnostic Protocol to Assess Patients With Chest
Pain Symptoms Using Contemporary Troponins as the Only
Biomarker) study.8 The third cohort was enrolled at Poole
Hospital National Health Service Trust, Dorset, England, in
the TRUST (Triage Rule-Out Using High-Sensitivity Troponin)
study.9 The fourth cohort was enrolled at Central Manchester
University Hospitals National Health Service Trust, Man-
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Levels of Cardiac Troponin I in Patients With Suspected Acute Coronary Syndrome
Key Points
Question What is the diagnostic performance of low
concentrations of high-sensitivity troponin I (hs-cTnI) on
presentation to the emergency department?
Findings Pooled analysis of patients from prospectively recruited
emergency department cohort studies demonstrated that the
limit of detection has a high sensitivity and negative predictive
value for acute myocardial infarction, potentially allowing for early
discharge of some patients. Higher rounded cutoff values had
lower sensitivities.
Meaning In patients with symptoms suggestive of cardiac
ischemia, the limit of detection of hs-cTnI may have the required
diagnostic performance for clinical implementation, whereas
rounded cutoff values above this cutoff level do not.
chester, England, in the Novel Biomarkers of Acute Coronary
Syndromes With Metabolomics Study.10 The final cohort was
enrolled at Stockport National Health Service Trust, Stock-
port, England, in the Validation of the Manchester Acute
Coronary Syndromes decision rule study.11
Written informed consent was obtained from all patients,
and the study protocol was approved by the respective local
ethics committees (Human Research Ethics Committee,
Royal Brisbane and Women's Hospital [Australia], Upper
South A Regional Ethics Committee [New Zealand], Frenchay
Research Ethics Committee [Poole], and North West Cheshire
Research Ethics Committee [Manchester and Stockport]).
The present analysis, with waiver of informed consent and
use of deidentified data, was approved by those same ethics
committees. Recruitment was undertaken from November 1,
2007, to August 10, 2013.
All patients recruited in the trials were eligible for enroll-
ment if they presented with symptoms suggestive of cardiac
ischemia (acute chest, epigastric, neck, jaw, or arm pain, or dis-
comfort or pressure without an apparent noncardiac source).
For all cohorts, patients were excluded if any of the following
were present: ST-segment elevation MI or new left bundle-
branch block, new-onset ECG changes diagnostic of ischemia
(ST-segment depression 1 mm or T-wave inversion consis-
tent with ischemia), significant arrhythmias (sustained supra-
ventricular tachycardia, second-degree or complete heart
block, or sustained or recurrent ventricular arrhythmias), age
younger than 18 years, a clear cause of the symptoms other than
acute coronary syndromes, pregnancy, inappropriate recruit-
ment (eg, terminal illness), unwillingness to consent, and if fol-
low-up was considered impossible. Specific to the present
analysis, participants in whom hs-cTnI assay results deter-
mined on presentation to the ED were not available were
excluded. We selected patients in whom new-onset ECG
changes diagnostic of ischemia were absent to maximize clini-
cal applicability of the results and reflect clinical practice in
which patients with ECG changes are immediately defined as
high risk and therefore not suitable for discharge. All ECG
findings were adjudicated by blinded research staff (E.C., S.C.,
C.H., W.P., and K.G.).
jamacardiology.com
 Levels of Cardiac Troponin I in Patients With Suspected Acute Coronary Syndrome
All participants had laboratory troponin concentrations
measured at presentation and at least 6 hours after presenta-
tion (Brisbane, Christchurch, and Poole) or at least 12 hours af-
ter the development of peak symptoms (Manchester and Stock-
port) as part of clinical care. Electrocardiograms were recorded
on presentation. Treatment was managed according to local
protocols. All clinical management, including the decision to
perform stress testing or coronary angiography, was at the dis-
cretion of the attending physician.
Patient data were recorded according to standardized data
collection forms using a published data dictionary.12 Fol-
low-up events were monitored by dedicated research staff
through a combination of telephone contact, corroboration by
review of hospital online patient management systems, and
query to the national death registries at least 12 months after
index presentation.
Research samples obtained on presentation were centri-
fuged, and serum was stored frozen at 70C or below for later
analysis in a blinded fashion using an hs-cTnI assay (Archi-
tect Stat; Abbott Diagnostics) with a lower limit of detection
of 1.2 ng/L (to convert to nanograms per milliliter, divide by
1000; micrograms per liter, multiply by 106) (range, 1.2-1.9
ng/L) and a 10% coefficient of variation of 4.7 ng/L. Samples
were thawed, mixed, and centrifuged for 30 minutes at 3000g
and 4C for serum samples or twice for 10 minutes at 3000g
for plasma samples before analysis and according to the manu-
facturers instructions. Long-term stability of hs-cTnI has been
demonstrated.13
We determined a priori that primary cutoff concentra-
tions for analysis were the lower limit of detection of the
hs-cTnI assay (1.2 ng/L) and rounded cutoff concentrations
below 5 ng/L, the threshold previously identified5 as allow-
ing the maximal number of patients for potential discharge
with an NPV of greater than 99.5%. The analysis of rounded
concentrations was done because it is common practice for
clinical laboratories to round hs-cTnI results before reporting
them. Rounding occurred up or down to the nearest whole
number (eg, from 2.2 to 2 ng/L and from 2.6 to 3 ng/L).
Outcomes
The primary outcome was the presence of fatal or nonfatal AMI
occurring within 30 days of hospital attendance (including the
index ED visit). The secondary outcome was the proportion
of patients potentially suitable for early discharge at each cut-
off concentration.
The presence of AMI was defined according to the third uni-
versal definition of MI,14 which states that a rise and/or fall in
troponin, with at least 1 value above the 99th centile value in
the context of a patient with ischemic symptoms or signs (ECG
changes, such as new significant ST-segment T-wave changes
and pathologic Q waves, or imaging evidence, such as new re-
gional wall motion abnormality or intracoronary thrombus by
angiography) would satisfy the diagnosis. The diagnosis of AMI
was adjudicated using presentation and late troponin results,
according to assays in use at each institution at the time of re-
cruitment (eTable 1 in the Supplement). Blood samples ob-
tained 6 to 12 hours after patient presentation for clinical man-
agement were not available for hs-cTnI; therefore, it was not
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Original Investigation Research
possible to evaluate the outcome separately using this assay.
The end point was adjudicated by researchers (E.C., R.B., S.C.,
C.H., W.P., and K.G.) blinded to the presentation hs-cTnI re-
sults but with the knowledge of local troponin assay results.
Statistical Analysis
Baseline characteristics of the study population were ana-
lyzed with conventional group descriptive statistics accord-
ing to study cohort. Results were pooled for calculation of sen-
sitivity, specificity, NPV, and positive predictive value. To
illustrate the validity of each cutoff value as an exclusion tool,
a minimum clinically acceptable sensitivity threshold of 99%
was chosen, below which the missed-event rate becomes un-
acceptable to practitioners.7 Subgroup analysis for age, sex, car-
diac risk factor burden, history of coronary artery disease, and
time from symptom onset to ED presentation was under-
taken for the lower limit of detection cutoff concentration (1.2
ng/L). Data were analyzed using Stata, version 12 (StataCorp).
Results
Data were available for 3155 patients across 5 cohorts, includ-
ing 1164 (36.9%) from Australia, 810 (25.7%) from New Zea-
land, and 1181 (37.4%) from the United Kingdom (867 from
Poole, 134 from Manchester, and 180 from Stockport). Of these,
1771 (56.1%) individuals were male and the mean (SD) age was
57.4 (13.3) years. From the original cohorts, 626 patients were
excluded owing to the unavailability of hs-cTnI results; these
patients were not included in the 3155 individuals in the pres-
ent analysis.
Baseline characteristics of the study population, classi-
fied according to recruiting center, are summarized in the Table.
Of the 3155 patients included in the analysis, 291 developed a
fatal or nonfatal AMI within 30 days of the index presenta-
tion, resulting in a prevalence of 9.2%, ranging from 3.4% (Aus-
tralia) to 18.1% (New Zealand). Patients from New Zealand were
significantly older, had a higher cardiac risk factor burden (with
the exception of smoking), and were more likely to have a his-
tory of cardiac disease compared with the cohort with the low-
est prevalence of AMI (Australia) (P < .05 for all). Of the 291 pa-
tients adjudicated as having an AMI, 277 (95.2%) individuals
received the diagnosis at the index presentation and 14 (4.8%)
were identified during the following 30 days. Calculation of
diagnostic performance using 2 2 tables is available in eTable
2 in the Supplement.
Diagnostic Accuracy of the Limit of Detection
of hs-cTnI With Nonischemic ECG
Troponin concentrations were below the lower limit of detec-
tion (1.2 ng/L) in 594 (18.8%) of 3155 patients. This cutoff, to-
gether with a nonischemic ECG, would allow up to 18.8% of
patients to be discharged with a sensitivity of 99.0% (95% CI,
96.8%-99.7%) and an NPV of 99.5% (95% CI, 98.4%-99.9%)
(Figure 1A and B and eTable 3 in the Supplement). None of the
3 (0.5%) patients with false-negative results died within 30 days
of presentation. eTable 4 in the Supplement summarizes the
clinical characteristics of patients with a presentation hs-cTnI
(Reprinted) JAMA Cardiology July 2016 Volume 1, Number 4 407
 Research Original Investigation Levels of Cardiac Troponin I in Patients With Suspected Acute Coronary Syndrome

Table. Characteristics of Patients With Presentation High-Sensitivity Troponin I Results

Brisbane, Christchurch, England

Australia New Zealand Poole Manchester Stockport
Variable (n = 1164) (n = 810) (n = 867) (n = 134) (n = 180)
Age, mean (SD), y 52.0 (13.2) 63.8 (13.1) 57.4 (13.0) 56.6 (14.8) 64.5 (15.2)
Male sex, No. (%) 630 (54.1) 461 (56.9) 515 (59.4) 91 (67.9) 74 (41.1)
hs-cTnI on presentation, 2 (1-4) 5 (3-15) 2 (1-4) 4 (2-7) 7 (5-18)
median, (IQR), ng/L
Fatal/nonfatal AMI 40 (3.4) 147 (18.1) 66 (7.6) 10 (7.5) 28 (15.6)
within 30 d, No. (%)
Risk factors, No. (%)
Dyslipidemia 462 (39.7) 455 (56.2) 583 (67.2) 44 (32.8) 75 (41.7)
Hypertension 432 (37.1) 478 (59.0) 566 (65.2) 54 (40.3) 70 (38.9)
Diabetes 147 (12.6) 133 (16.4) 145 (16.7) 19 (14.2) 32 (17.8)
Family history of CAD 499 (42.9) 497 (61.4) 327 (37.7) 21 (15.7) 60 (33.3)
Current smoking 312 (26.8) 121 (14.9) 210 (24.2) 35 (26.1) 29 (16.1)
Self-reported medical
history, No. (%)
Angina 184 (15.8) 381 (47.0) 223 (25.7) 33 (24.6) 78 (43.3)
MI 158 (13.6) 242 (29.9) 190 (21.9) 31 (23.1) 62 (34.4)
CABG 52 (4.5) 75 (9.3) 41 (4.7) 7 (5.2) 24 (13.3)
PCI 109 (9.4) 201 (24.8) 168 (19.4) 24 (17.9) 31 (17.2)
Investigations within
past 30 d, No. (%)
Stress ECG 674 (57.9) 292 (36.0) 248 (28.6) NR 35 (19.4)
Stress radionuclide 102 (8.8) 0 61 (7.0) NR 16 (8.9)
imaging
Abbreviations: AMI, acute myocardial
Stress echocardiogram 35 (3.0) 18 (2.2) 53 (6.1) NR 3 (1.7) infarction; CABG, coronary artery
Nonstress 204 (17.5) 152 (18.8) 214 (24.7) NR NR bypass graft; CAD, coronary artery
echocardiogram disease; CT, computed tomography;
CT coronary 36 (3.1) 0 84 (9.7) NR 0 ECG, electrocardiogram;
angiography ED, emergency department;
Angiography 152 (13.1) 216 (26.7) 147 (17.0) NR 18 (10.0) hs-cTnI, high-sensitivity cardiac
Symptom onset 3.8 (15.8) 5.3 (10.0) 2.3 (3.7) 3.2 (4.3) 3.1 (6.9) troponin I; IQR, interquartile range;
to presentation, MI, myocardial infarction; NR, not
median (IQR), h recorded; PCI, percutaneous
Time to hs-cTnI testing 0.4 (0.3) 0.6 (0.4) 0.6 (0.5) NR NR coronary intervention.
after arrival in ED, SI conversion factor: To convert
median (IQR), h
hs-cTnI to nanograms per milliliter,
Length of hospital stay, 11.6 (27.5) 45.4 (73.9) 18.6 (31.3) NR NR divide by 1000; micrograms per liter,
median (IQR), h multiply by 106.

below the lower limit of detection and nonischemic ECG with
a diagnosis of fatal or nonfatal AMI. All 3 patients were men
and from a cohort (Poole) in which outcomes were adjudi-
cated using an alternative high-sensitivity troponin assay (Elec-
sys hs-cTnT; Roche Diagnostics). At the upper limit of detec-
tion for the hs-cTnI assay (<2 ng/L), 807 (25.6%) patients would
have been eligible for early discharge but with a sensitivity of
97.9% (95% CI, 95.4%-99.2%) and NPV of 99.3% (95% CI,
98.3%-99.7%).
Diagnostic Accuracy of Rounded Low Cutoff Concentrations
With Nonischemic ECG
The sensitivity decreased with increasing cutoff concentra-
tions (Figure 1A and eTable 3 in the Supplement). All rounded
cutoff values above 1.2 ng/L, up to and including 5 ng/L, had
sensitivities less than 98% (albeit with NPVs >99%). The cut-
off concentration of 5 ng/L had an excellent NPV (99.2% [95%
CI, 98.8%-99.5%]) but poor sensitivity (94.5% [95% CI, 91.1%-
96.7%]). The proportion of patients with an hs-cTnI value be-
low each cutoff concentration and the cumulative missed-
event rate are shown in Figure 2.
Stratified Subgroup Analysis at the Lower Limit of Detection
The sensitivity of an hs-cTnI concentration less than 1.2 ng/L
for AMI was similar in men and women and when stratified
by age, cardiac risk factor burden, and history of coronary ar-
tery disease (Figure 3 and eTable 5 in the Supplement). No pa-
tient aged 80 years or older (187 [5.9%]) had a presentation
hs-cTnI concentration below 1.2 ng/L. In a cohort with docu-
mented time from symptom onset to ED presentation, 1047
of 3124 patients (33.5%) were classified as early presenters (time
from symptom onset to ED presentation 2 hours). In these
patients, test sensitivity for AMI at 1.2 ng/L was maintained
at 98.6% (95% CI, 91.8%-99.9%) (Figure 3 and eTable 5 in the
Supplement). The reduction in diagnostic performance of
hs-cTnI cutoff concentrations above 1.2 ng/L to exclude AMI
cutoff was more marked in early presenters (eFigure in the
Supplement).

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 Levels of Cardiac Troponin I in Patients With Suspected Acute Coronary Syndrome Original Investigation Research

Figure 1. Diagnostic Accuracy of the Limit of Detection and Rounded Low Cutoff Concentrations
of High-Sensitivity Troponin I (hs-cTnI) With Nonischemic Electrocardiogram

A Sensitivity and specificity

100 100

95 80
Sensitivity, %

Specificity, %
90 60

85 40

80 Sensitivity 20
Specificity

75 0
<1.2 2 3 4 5 6 7 8 9 10 11 12 13 14
hs-cTnl Concentration at Presentation, ng/L

B Positive and negative predictive values A, Sensitivity and specificity for a

range of hs-cTnI concentrations at
100.0 60
presentation for the composite
outcome of index myocardial
99.5 infarction or cardiac death at 30 days.
Negative Predictive Value, %

Positive Predictive Value, %

The dashed line indicates the
99.0 40 minimum clinically acceptable
sensitivity threshold of 99%.7
B, Negative predictive value (NPV)
98.5
and positive predictive value (PPV)
findings for a range of hs-cTnI
98.0 20 concentrations at presentation for
the composite outcome of index
97.5 NPV myocardial infarction or cardiac death
PPV
at 30 days. The dashed line indicates
97.0 0 the minimum clinically acceptable
<1.2 2 3 4 5 6 7 8 9 10 11 12 13 14 negative predictive value threshold of
hs-cTnl Concentration at Presentation, ng/L 99.5%.5 1.2 ng/L represents the lower
limit of detection; error bars, 95% CI.

Figure 2. Proportion of Patients With a High-Sensitivity Troponin I (hs-cTnI) Concentration Below Each Cutoff
Concentration and the Cumulative Missed Event Rate

100 Proportion with hs-cTnl below cutoff concentration, %

Cumulative missed events, No.
90

80

70

60
No., %

50

40

30

20

10

0
<1.2 2 3 4 5 6 7 8 9 10 11 12 13 14
hs-cTnl Concentration at Presentation, ng/L 1.2 ng/L represents the lower limit of
detection.

we demonstrate that hs-cTnI obtained at presentation to the

Discussion ED can, at a cutoff level of 1.2 ng/L in combination with a
nonischemic ECG, identify 18.8% of patients as being poten-
In more than 3000 patients with symptoms suggestive of car- tially suitable for immediate discharge, with a high diagnos-
diac ischemia obtained from 5 diverse international cohorts, tic performance in excluding AMI. To place these results in the

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 Research Original Investigation Levels of Cardiac Troponin I in Patients With Suspected Acute Coronary Syndrome

Although the proportion of patients potentially suitable

Figure 3. Sensitivity of High-Sensitivity Troponin I Concentrations
Less Than 1.2 ng/L (Lower Limit of Detection) at Presentation,
for discharge using the lower limit of detection is smaller
Stratified by Subgroups than the proportion determined using rounded cutoff val-
ues, such as 5 ng/L as proposed by Shah and colleagues,5 the
Suggested Sensitivity low sensitivity at concentrations above 1.2 ng/L brings into
Subgroup Total Cohort, % Threshold, 99%
Age question the safety of these cutoff values as an exclusion
<65 y 68.5 strategy within a clinical environment. Furthermore, it has
65 y 31.4 been demonstrated 5 that the diagnostic performance of
Sex higher rounded cutoff values, such as 5 ng/L, may be reduced
Male 58.9
in patients presenting within 2 hours of chest pain onset. Our
Female 41.1
data suggest that diagnostic performance is retained in early
Risk factor burden
1 39.8
presenters when the lower limit of detection cutoff value is
2 29.5 used.
3 30.8 We demonstrate the importance of presenting both sen-
Prior CAD sitivity and NPV to evaluate the diagnostic accuracy of early
Yes 35.3 strategies to exclude AMI. The NPV is directly related to the
No 64.7
prevalence of the target disease in the specific population un-
Time from chest pain onset
to ED presentationa der consideration and represents the posttest probability of a
2 h 33.5 negative test result. When clinical implementation of an ex-
>2 h 66.5 clusion strategy is considered, it is therefore important to es-
tablish the NPV for each hospital so that an attending physi-
90 92 94 96 98 100
Sensitivity, % cian can better interpret a negative test result. The NPV should
not be used to recommend generalization of a test across popu-
Summed risk factor burden included current smoking, hypertension, lations with varying disease prevalence. However, sensitivity
dyslipidemia, diabetes, family history of coronary artery disease (CAD), and age
is not affected by the disease prevalence, represents the true
less than 65 years (data missing in 4 cases). Prior CAD was defined as
patient-reported history of angina, myocardial infarction, percutaneous positive rate, and is therefore more useful to physicians in es-
coronary intervention, or coronary artery bypass graft. ED indicates emergency tablishing the validity of a diagnostic test at an individual pa-
department; error bars, 95% CI. tient level.
a
Data were missing in 31 cases. We chose a sensitivity threshold of 99%, below which the
miss-rate of AMI becomes unacceptable.7 When point esti-
context of absolute numbers of presenting patients, a number- mates are considered, the only hs-cTnI cutoff value that
needed-to-diagnose approach shows that, for the 1.2-ng/L cut- reached this sensitivity threshold was the lower limit of de-
off level, for every 10 630 patients assessed, 1990 would be cor- tection (1.2 ng/L). However, the lower limits of the 95% CI at
rectly reassured that they are not having an AMI, 10 would be these cutoff points fall below this 99% sensitivity threshold.
falsely reassured, and 8630 would undergo further investiga- Therefore, we suggest that implementation of limit of detec-
tion, of whom 990 would ultimately receive a diagnosis of AMI. tion exclusion strategies should undergo further evaluation in
We also demonstrate that cutoff values above the lower limit randomized clinical trials that test both clinical effect and cost-
of detection may not have the required diagnostic perfor- effectiveness in routine practice.
mance for clinical implementation. In particular, we identi- A key strength of our study is that all patients had out-
fied sensitivity of less than 95% for the cutoff value of 5 ng/L, comes adjudicated using serial troponin testing. This consis-
which has recently been recommended5 for implementation tent evaluation enabled the identification of any patients who
on the basis of an NPV greater than 99.5%. Although this high may subsequently have had an AMI and ensured accurate re-
NPV is maintained in our analysis, the possibility of missing 5 porting of event rates. This method is in contrast to previous
or more AMIs for every 100 AMIs presenting to the ED is un- work4,5 using registry or administrative data. More than one-
acceptable for most physicians.7 Regarding sensitivity, we were third of the patients in these studies were not assessed using
unable to determine whether our findings differed signifi- serial troponin test results; therefore, the number of missed
cantly from those reported by Shah et al5 since sufficient in- events may have been higher than reported. Our data demon-
formation to calculate a missed AMI rate in a comparable co- strate that this issue may be more relevant in the era of hs-cTn
hort was not provided in that study. assays. All 3 patients with an unidentified AMI according to the
Our analysis complements the work of studies and meta lower limit of detection of hs-cTnI were evaluated using se-
analyses4,6,15-17 demonstrating that the limit of detection of rial testing with an hs-cTnT assay, and no events were missed
hs-cTn assays (both I and T) show promise for excluding AMI when outcomes were evaluated with contemporary assays.
early in ED patients with suspected cardiac chest pain espe- When a high-sensitivity assay is used for outcome adjudica-
cially when used in combination with ECG findings. How- tion, the false-negative rate for AMI determined with a single
ever, to our knowledge, this analysis is the first to report full baseline test may have increased when compared with con-
diagnostic performance statistics for a range of low concen- temporary assays. The diagnostic sensitivity of the index test
trations of hs-cTnI across a range of international sites with may therefore be overestimated when an hs-cTn assay is used
varying degrees of disease prevalence. for outcome adjudication.

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 Levels of Cardiac Troponin I in Patients With Suspected Acute Coronary Syndrome Original Investigation Research

Our findings can be applied only to the assay tested
(hs-cTnI) and cannot be translated to other assays, even
high-sensitivity ones. The hs-cTnI assay is recommended
for clinical use as a high-sensitivity assay by consensus
guidelines.18 However, physicians should be aware that, at
low concentrations, test results are less reliable than at the
99th percentile19; therefore, any clinical implementation
should be a multidisciplinary decision between ED physi-
cians, cardiologists, and laboratory staff. No hs-cTn assay
is currently approved for use by the US Food and Drug
Administration, and whether the use of low concentrations
of hs-cTn in clinical practice will be approved remains
unknown.
Our analysis has several limitations. First, outcomes were
adjudicated using troponin assays, both sensitive and high-
sensitivity, in clinical use at the time of patient recruitment
rather than the hs-cTnI assay under evaluation. This
approach may lead to misclassification bias. Second, many
patients were excluded from the original cohorts as a result
of the unavailability of hs-cTnI results. This exclusion may
result in selection bias. Third, we selected patients in whom
new-onset ECG changes diagnostic of ischemia were absent
to reflect clinical practice. This method may serve to reduce
the outcome prevalence in the cohort as a whole and there-
fore raise the NPV of the index test. Furthermore, the popula-
tion selected for this analysis was likely to be of lower risk
compared with those of prior studies. 4,5,15-17 Finally, no
patient was discharged according to presentation hs-cTnI
assay results and the proportion of patients undergoing fur-
ther cardiac testing was high across all cohorts (Table).
Therefore, whether the strategies tested can be successfully
implemented into clinical practice and what further testing is
required remains unknown. The choice of outcome measure
for this analysis (fatal or nonfatal AMI occurring within 30
days) fails to incorporate the full spectrum of acute coronary
syndromes (eg, patients who may require urgent revascular-
ization). Therefore, a key concept in ensuring the safety of
this biomarker strategy is the availability of timely outpatient
testing to ensure early detection of such patients. Further
studies are required (ideally a randomized clinical trial) to
determine the clinical effectiveness of low cutoff concentra-
tions of high-sensitivity troponin.
Conclusions
High-sensitivity troponin I concentrations determined at pre-
sentation to the ED that were below the limit of detection iden-
tified 18.8% of patients potentially suitable for discharge with
a high sensitivity for AMI. Rounded cutoff values above the
limit of detection may not have the required sensitivity for clini-
cal implementation.

ARTICLE INFORMATION
Accepted for Publication: April 8, 2016.
Published Online: June 1, 2016.
doi:10.1001/jamacardio.2016.1309.
Open Access: This article is published under the
JAMA Cardiology open access model and is free to
read on the day of publication.
Author Affiliations: Emergency Department,
Southmead Hospital, North Bristol National Health
Service Trust, Bristol, England (Carlton, Kendall);
Emergency Medicine, Royal Brisbane and Womens
Hospital, Brisbane, Australia (Greenslade, Cullen,
Hammett, Parsonage); School of Medicine, The
University of Queensland, Brisbane, Australia
(Greenslade, Cullen); School of Public Health,
Queensland University of Technology, Brisbane,
Australia (Greenslade, Cullen); Central Manchester
University Hospitals, National Health Service
Foundation Trust, Manchester, England (Body,
Carley, Keevil); Department of Emergency
Medicine, Christchurch Hospital, Christchurch,
New Zealand (Than, Pickering, Aldous);
Department of Medicine, University of Otago,
Christchurch, New Zealand (Pickering); School of
Medicine, The University of Notre Dame, Sydney,
Australia (Lord); Sunshine Coast Hospital and
Health Services, University of the Sunshine Coast,
Nambour, Australia (Greaves).
Author Contributions: Dr Carlton had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Carlton, Cullen, Body,
Aldous, Lord, Greaves.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Carlton, Than, Pickering,
Carley, Greaves.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Carlton, Greenslade, Body,
Carley, Lord.
Obtained funding: Carlton, Greenslade, Cullen,
Than, Greaves.
Administrative, technical, or material support:
Kendall, Greaves.
Study supervision: Cullen, Than, Aldous, Greaves.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Carlton has undertaken research under
collaborative agreements with Abbott and Randox
Laboratories. Dr Cullen has received funding from
Abbott, Roche, Alere, Siemens, and Radiometer
Pacific for clinical trials and from Alere, Boehringer
Ingelheim, Pfizer, AstraZeneca, Abbott, Novartis,
and Radiometer Pacific for speaking and education.
Dr Body has undertaken research under
collaborative agreements with Roche, Siemens
Diagnostics, Alere, and Randox Laboratories and
has accepted travel and accommodation for
conferences from Roche Diagnostics and Randox
Laboratories. Dr Than has received funding from
Alere, Abbott, Beckman, and Roche for speaking
and support for other research. Dr Aldous received
funding from the National Heart Foundation (New
Zealand) for cardiac research. Dr Kendall has
received funding from Boehringer Ingelheim and
Novartis for speaking, education, and support for
other research. Dr Parsonage received funding from
the Queensland Emergency Medicine Research
Foundation, Abbott Diagnostics, Roche, Alere, and
Beckmann Coulter for research. He also has
received honoraria, travel expenses, and
consultancy fees from Abbott, AstraZeneca,
Hospira, and Aventis. Dr Greaves has received
funding from AstraZeneca for related research. No
other disclosures were reported.
Funding/Support: Australia/New Zealand cohorts:
Funding for the ADAPT study was predominantly
provided by the Christchurch Heart Institute and
the Queensland Emergency Medicine Research
Foundation with a small (20%) contribution from
industry (Abbott and Alere). Poole, England,
cohort: Funding was provided by the Royal College
of Emergency Medicine of the United Kingdom,
Bournemouth University. Manchester, England,
cohort: Funding was received from the Royal
College of Emergency Medicine of the United
Kingdom, as well as fellowship funding from the
United Kingdom National Institute for Health
Research (NIHR) and by the NIHR Clinical Research
Network (UK CRN 8376). Stockport, England,
cohort: Funding was received from the Royal
College of Emergency Medicine of the United
Kingdom as well as fellowship funding from the
NIHR and by the NIHR Clinical Research Network
(UK CRN 8376).
Role of the Funder/Sponsor: For all cohorts, no
commercial organization or sponsor was involved in
the design and conduct of the study; collection,
management, analysis and interpretation of the
data; and preparation, review or approval of the
manuscript; and decision to submit the manuscript
for publication.
Additional Contributions: We are indebted to the
patients who participated in the study. We thank
the research staff, emergency department staff,
and laboratory technicians of all participating
facilities for their valuable efforts.

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 Research Original Investigation
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