CLINICAL RESEARCH
European Heart Journal (2014) 35, 2303–2311
doi:10.1093/eurheartj/ehu188
Acute coronary syndromes
Direct comparison of high-sensitivity-cardiac
troponin I vs. T for the early diagnosis
of acute myocardial infarction
1
Department of Cardiology, University Hospital Basel, Basel, Switzerland; 2Servicio de Urgencias y Pneumologia, CIBERES ISC III, Hospital del Mar – Institut Municipal D’Investigació
Mèdica, Barcelona, Spain; 3Universitäres Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; 4Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and
Harvard Medical School, Boston, MA, USA; and 5Laboratory Medicine, University Hospital Basel, Basel, Switzerland
Received 8 September 2013; revised 19 March 2014; accepted 15 April 2014; online publish-ahead-of-print 19 May 2014
See page 2273 for the editorial comment on this article (doi:10.1093/eurheartj/ehu201)
Aim
It is unknown whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the early diagnosis of acute
myocardial infarction without ST segment elevation (NSTEMI).
.....................................................................................................................................................................................
Methods
In a prospective multicentre study, we measured cTnI and cTnT using clinically available high-sensitivity assays (hs-cTnI
and results
Abbott and hs-cTnT Roche) and compared their diagnostic and prognostic accuracies in consecutive patients presenting
to the emergency department with acute chest pain. The final diagnosis was adjudicated by two independent cardiologists
using all information pertaining to the individual patient. The mean follow-up was 24 months. Among 2226 consecutive
patients, 18% had an adjudicated final diagnosis of NSTEMI. Diagnostic accuracy at presentation as quantified by the area
under the receiver-operating-characteristics curve (AUC) for NSTEMI was very high and similar for hs-cTnI [AUC: 0.93,
95% confidence interval (CI) 0.92– 0.94] and hs-cTnT (0.94, 95% CI: 0.92–0.94) P ¼ 0.62. In early presenters (,3 h since
chest pain onset) hs-cTnI showed a higher diagnostic accuracy (AUC: 0.92, 95% CI: 0.89–0.94) when compared with
hs-cTnT AUC (0.89, 95% CI: 0.86– 0.91) (P ¼ 0.019), while hs-cTnT was superior in late presenters [AUC hs-cTnT
0.96 (95% CI: 0.94– 0.96) vs. hs-cTnI 0.94 (95% CI: 0.93– 0.95); P ¼ 0.007]. The prognostic accuracy for all-cause
mortality, quantified by AUC, was significantly higher for hs-cTnT (AUC: 0.80; 95% CI: 0.78– 0.82) when compared
with hs-cTnI (AUC: 0.75; 95% CI: 0.73–0.77; P , 0.001).
.....................................................................................................................................................................................
Conclusion
Both hs-cTnI and hs-cTnT provided high diagnostic and prognostic accuracy. The direct comparison revealed small but
potentially important differences that might help to further improve the clinical use of hs-cTn.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Acute myocardial infarction † High-sensitive cardiac troponin
Introduction
Acute myocardial infarction (AMI) is a major cause of death and disability worldwide. Patients with symptoms suggestive of AMI account
for 10% of all emergency departments (ED) consultations, even
though only 10 –20% of them eventually suffer from AMI. Rapid
identification of AMI is of paramount clinical importance for early
treatment and management.1
* Corresponding author. Tel: +41 613286549, Fax: +41 61265353, Email: christian.mueller@usb.ch
†
M.R.G. and R.T. have contributed equally and should be considered first author.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: journals.permissions@oup.com.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on September 30, 2016
Maria Rubini Gimenez1,2†, Raphael Twerenbold 1,3†, Tobias Reichlin1,4, Karin Wildi 1,
Philip Haaf1, Miriam Schaefer 1, Christa Zellweger 1, Berit Moehring 1, Fabio Stallone 1,
Seoung Mann Sou 1, Mira Mueller 1, Kris Denhaerynck1, Tamina Mosimann 1,
Miriam Reiter 1, Bernadette Meller 1, Michael Freese 1, Claudia Stelzig 1,
Irina Klimmeck 1, Janine Voegele 1, Beate Hartmann 1, Katharina Rentsch 5,
Stefan Osswald 1, and Christian Mueller 1*
2304
Methods
Study design and population
Advantageous Predictors of Acute Coronary Syndrome Evaluation
(APACE) is an ongoing prospective international multicentre study (performed in nine different study centres in Switzerland, Spain, and Italy)
designed and coordinated by the University Hospital Basel Switzerland
to advance the early diagnosis of AMI.7,10 – 12 From April 2006 to
August 2012, consecutive patients older than 18 years presenting to
the ED with symptoms suggestive of AMI with an onset or peak within
the last 12 h were recruited, after informed consent was obtained.
Patients with terminal kidney failure requiring regular dialysis were
excluded. For this analysis, patients were also excluded if (i) hs-cTnI
(Abbott) or hs-cTnT (Roche) levels were not available (n ¼ 661) or (ii)
the final diagnosis remained unclear after adjudication and at least one
cTn or hs-cTnT level was elevated (possibly indicating the presence of
AMI) (n ¼ 69) (iii) patients with a final diagnosis of ST segment myocardial infarction (STEMI) (n ¼ 75).
The study was carried out according to the principles of the Declaration of Helsinki and approved by the local Ethics Committees. The
authors designed the study, gathered, and analysed the data, vouch for
the data and analysis, wrote the paper, and decided to publish.
Routine clinical assessment
All the patients underwent a clinical assessment that included medical
history, physical examination, 12-lead ECG, continuous ECG monitoring,
pulse oximetry, standard blood test, and chest radiography. Levels of cTn
were measured at presentation and serially thereafter as long as clinically
indicated. Timing and treatment of patients were left to discretion of the
attending physician.
Adjudicated final diagnosis
Adjudication of the final diagnosis was performed centrally in the core lab
(University Hospital Basel) for all patients twice: Once according to conventional cTn levels used onsite (this method was used in the initial analyses to examine the performance of hs-cTn assays7,11 – 13 and once
including levels of Roche hs-cTnT in order to also take advantage of
the higher sensitivity and higher overall diagnostic accuracy offered by
hs-cTn assays,14,15 this allows the additional detection of small AMIs
that were missed by the adjudication based on conventional cTn
assays. Two independent cardiologists reviewed all available medical
records—patient history, physical examination, results of laboratory
testing, radiological testing, ECG, echocardiography, cardiac exercise
test, lesion severity, and morphology in coronary angiography—pertaining to the patient from the time of ED presentation to 90-day follow-up. In
situations of disagreement about the diagnosis, cases were reviewed and
adjudicated in conjunction with a third cardiologist.
Non-ST segment myocardial infarction was defined and cTn levels
interpreted as recommended in current guidelines.16,17 In brief,
NSTEMI was diagnosed when there was evidence of myocardial necrosis
in association with a clinical setting consistent with myocardial ischaemia.
Myocardial necrosis was diagnosed by at least one cTn value above the
99th percentile (or for the conventional cTn assays above the 10% imprecision value if not fulfilled at the 99th percentile) together with a significant rise and/or fall.9,18,19 The criteria used to define rise and/or fall in
conventional cTn and hs-cTnT are described in detail in the Supplementary material online, Methods.
All other patients were classified as ‘No NSTEMI’ for this analysis, including in this group the categories of unstable angina (UA), non-cardiac
chest pain (NCCP), cardiac but non-coronary disease (e.g. tachyarrhythmias, perimyocarditis), and symptoms of unknown origin with normal
levels of cTn and hs-cTnT (thereby ruling-out AMI).
Unstable angina was defined according to recent guidelines as follows:
(i) new onset (de novo) of severe angina, or recent destabilization of previously stable angina with at least severe (class III) angina characteristics
(crescendo angina), or post-MI angina, and (ii) either coronary artery
stenosis .70% on angiogram, or positive cardiac exercise testing, or in
ambiguous cases when AMI or sudden death occurred within 60 days,
and (iii) absence of alternative diagnosis.20
Measurement of high-sensitivity cardiac
troponin I and high-sensitivity cardiac
troponin T
Blood samples for determination of hs-cTnI (Abbott) and hs-cTnT
(Roche) were collected at presentation to the ED, in serum and EDTA
plasma tubes for hs-cTnT, and in serum for hs-cTnI. Additional samples
were collected at 1, 2, 3, and 6 h. When treatment required transferring
the patient to the catheter laboratory or coronary care unit, because the
diagnosis of AMI was certain, serial sampling was disrupted. After centrifugation, samples were frozen at 2808C until assayed in a blinded fashion
in a dedicated core laboratory. The Abbott hs-cTnI assay used was the
final pre-commercial release version of the ARCHITECT High Sensitive
STAT Troponin I assay (Abbott Laboratories, Abbott Park, IL, USA).
Samples were thawed, mixed, and centrifuged (for 30 min at 3000 RCF
and 48C for serum samples or for 10 min, twice, at 3000 RCF for
plasma samples) prior to analysis and according to manufacturer’s
instructions. The hs-cTnI assay has a 99th percentile concentration of
26.2 ng/L with a corresponding coefficient of variation (CV) of ,5%
and a limit of detection (LoD) of 1.9 ng/L.21 The Roche hs-cTnT assay
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Cardiac troponins (cTn) I and T are proteins unique to heart and
specific and sensitive biomarkers of myocardial damage.2 – 4 Cardiac
troponin and 12-lead electrocardiogram (ECG) complement
patient history and physical examination in the evaluation of patients,
presenting with acute chest pain.5,6 A limitation of conventional cTn
assays is their low sensitivity at the time of patient presentation, owing
to a delayed increase in circulating levels requiring serial sampling for
6 –9 h in a significant number of patients.2 Recent studies found that
more sensitive cTn assays can improve the accuracy of the diagnosis
of AMI at the time of presentation to the ED.7,8
The cTn complex is immobilized on the thin filament of the
contractile apparatus and plays a critical role in the regulation of
excitation–contraction coupling in the heart.6 In AMI, cTnI and
cTnT are released from necrotic myocardium both as intact proteins
and degradation products.6 The clinical availability of fully developed
high-sensitivity assays for both cTnI (Abbott) and cTnT (Roche) in
Europe and other countries now for the first time provides the methodological requirement to appropriately test the hypothesis whether
the substantial biochemical differences including molecular weight
between cTnI (23 kDa) and cTnT (35 kDa) could result in different diagnostic and prognostic performances for both biomarkers.6,9
This hypothesis is based on preliminary findings from subgroup analyses as well as very recent observations with pre-commercial and still
experimental hs-cTnI assays.10 – 12
The aim of our large prospective multicentre study was to directly
compare the diagnostic accuracy of clinically available hs-cTnI and
hs-cTnT for NSTEMI, as well as their prognostic accuracy for allcause mortality during 24-month follow-up, in consecutive patients
presenting to the ED with acute chest pain.
M. Rubini Gimenez et al.
Comparison of hs-cTn I and T
2305
was measured on the Elecsys 2010 (Roche Diagnostics). The limit of blank
and LoD were determined to be 3 and 5 ng/L, respectively. The
99th-percentile of a healthy reference population was reported at
14 ng/L with an imprecision corresponding to 10% CV at 13 ng/L.22
This study does not include any measurements with hs-cTnT lots that
required the revision of the calibration curve.23 – 26 Calculation of the
glomerular filtration rate was performed using the abbreviated Modification of Diet in Renal disease formula.27
compared with the 1827 patients in the no-NSTEMI group [hs-cTnI
median 115.4 ng/L (IQR: 21.7–627.9) vs. 3.5 ng/L (IQR: 2.2– 7.2)
P , 0.001; hs-cTnT median 65.0 ng/L (IQR: 28.0– 152.5) vs. 7.0 ng/
L (IQR: 4.0 –12.4) P , 0.001]. Diagnostic accuracy of hs-cTn for
NSTEMI, as quantified by the AUC, was similar for hs-cTnI and
hs-cTnT (AUC hs-cTnI 0.93, 95% CI: 0.92–0.94; AUC hs-cTnT
0.94, 95% CI: 0.92– 0.94; P ¼ 0.619; Figure 2A).
Follow-up and prognostic endpoints
Diagnostic performance of high-sensitivity
cardiac troponin I and T in early presenters
Statistical methods
The data are expressed as medians + IQR for continuous variables,
and for categorical variables as numbers and percentages. Continuous variables were compared with the Mann–Whitney U test,
and categorical variables using the Pearson x2 test. Receiveroperating-characteristics (ROC) curves were constructed to assess
the sensitivity and specificity of both assays to compare their ability
to diagnose AMI and UA, as well as their prognostic accuracy. Prognostic accuracy was quantified by three complementary methods:
AUC using the dichotomy of survival, AUC using survival analysis
techniques and estimate the concordance index (Harrell’s c) using
the survival model, and a Cox proportional-hazard model. The comparison of areas under the ROC curves (AUC) was performed as
recommended by deLong et al.28 Pre-defined subgroups include
patients with recent onset of symptoms (,3 h).7
All hypothesis testing was two-tailed and P-value of ,0.05 was
considered statistically significant. All statistical analyses were performed using SPSS for Windows 21.0 (SPSS, Inc., Chicago, IL, USA)
and MedCalc 9.6.4.0 (MedCalc software, Mariakerke, Belgium).
Results
Patient characteristics
The baseline characteristics of 2226 patients with suspected NSTEMI
are shown in Table 1. The adjudicated final diagnosis was NSTEMI in
18% of patients, UA in 10%, cardiac but non-coronary symptoms in
13%, non-cardiac cause in 54%, and symptoms of unknown origin
in 5%. Among the 399 NSTEMI patients, 85% had type I AMI and
15% had type II AMI.
Diagnostic performance of high-sensitivity
cardiac troponin I and T for acute
myocardial infarction
As shown in Figure 1, levels of the two hs-cTn at presentation were
significantly higher among the 399 patients who had NSTEMI
Among patients presenting to the ED with chest pain onset within 3 h
(representing 25% of the overall cohort), hs-cTnI showed a significantly higher diagnostic accuracy for NSTEMI compared with
hs-cTnT (Table 2). As shown in Figure 2B, among the early presenters
the AUC at presentation for hs-cTnI was 0.92, 95% CI: 0.89–0.94 vs.
hs-cTnT 0.89, 95% CI: 0.86–0.91 (P ¼ 0.019). In patients presenting
to the ED with chest pain onset of .3 h the AUC for hs-cTnI was significantly lower compared with hs-cTnT [0.94 (95% CI: 0.93–0.95)
vs. 0.96 (95% CI: 0.94–0.96)] (P ¼ 0.007).
Diagnostic performance of high-sensitivity
cardiac troponin I and T during serial
sampling
During serial sampling as well as when combining the level obtained at
presentation with changes within the first hours, diagnostic accuracy
for NSTEMI of both assays further increased (Table 3). While individual measurements performed at 1, 2, and 3 h showed similar accuracy, hs-cTnI showed a slightly lower diagnostic accuracy during
serial sampling compared with hs-cTnT when combining the level
obtained at presentation with changes within the first hours (AUC
hs-cTnI 0.95, 95% CI: 0.94–0.96 vs. hs-cTnT 0.96, 95% CI: 0.95–
0.97, P ¼ 0.004) (Figure 3). In early presenters, serial sampling provided similar accuracy with both assays.
Diagnostic performance of high-sensitivity
cardiac troponin I and high-sensitivity
cardiac troponin T for unstable angina
Among all consecutive patients, 9.7% had a final diagnosis of UA.
Levels at presentation of both hs-cTn assays were significantly
higher among patients whose final diagnosis was UA compared
with those with NCCP, hs-cTnI median 6.4 ng/L (IQR: 3.6 –12.1)
vs. 3.0 ng/L (IQR: 1.9 –5.1) P , 0.001; hs-cTnT median 10.7 ng/L
(IQR: 6.9– 15.9) vs. 6.0 ng/L (IQR: 3.9 –9.7) P , 0.001). Highsensitivity-cTnI had a slightly higher diagnostic accuracy for UA as
quantified by the AUC compared with hs-cTnT (0.74, 95% CI:
0.72 –0.77, vs. 0.72, 95% CI: 0.69– 0.74; P ¼ 0.07).
Correlation with angiographic findings
Among all patients in whom coronary angiography was performed
(n ¼ 530), 83% (n ¼ 441) had positive angiographic findings (one
vessel, two vessels or three vessels disease). The accuracy to
predict a positive angiographic finding as quantified by the AUC
was significantly higher for hs-cTnI when compared with hs-cTnT
(0.82, 95% CI: 0.78– 0.84, vs. 0.79, 95% CI: 0.76–0.81; P , 0.001).
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After hospital discharge, patients were contacted by telephone interview
or written form after 3, 12, and 24 months of follow-up. In case of
reported clinical events—in particular cardiovascular events—since
presentation to the ED, details were reviewed by asking the patients
and traced by establishing contact with the respective family physician
or treating institution. The primary prognostic endpoint was all-cause
mortality during 24-month follow-up; non-fatal AMI during the follow-up
was a secondary prognostic end-point. Information regarding death and
AMI was obtained from the national registry on mortality, the hospital’s
diagnosis registry or family physician’s records.
2306
Table 1
M. Rubini Gimenez et al.
Baseline characteristics of patients
Characteristic
All (n 5 2226)
NSTEMI (n 5 399)
No NSTEMI (n 5 1827)
P-valuea
62
50– 75
72
59– 72
60
48– 73
,0.001
1383 (62)
1111 (50)
319 (80)
273 (68)
1064 (58)
838 (46)
,0.001
,0.001
,0.001
...............................................................................................................................................................................
Age, years
Median
IQR
Risk factors, n (%)
Hypertension
Hypercholesterolaemia
Diabetes
384 (17)
108 (27)
276 (15)
Current or previous smoking
Family history
1367 (61)
744 (33)
254 (64)
153 (38)
1113 (61)
591 (32)
Coronary artery disease
Previous AMI
777 (35)
514 (23)
203 (51)
137 (34)
574 (31)
377 (21)
,0.001
,0.001
Previous revascularization
612 (28)
147 (37)
465 (26)
,0.001
Peripheral artery disease
Previous stroke
142 (6)
122 (6)
57 (14)
39 (10)
85 (5)
83 (5)
,0.001
0.001
Left bundle branch block
ST-segment elevation
67 (3)
43 (2)
23 (6)
11 (3)
44 (2)
32 (2)
,0.001
,0.001
ST-segment depression
232 (10)
121 (30)
111 (6)
,0.001
T-wave inversion
No significant changes
296 (13)
1688 (76)
100 (25)
144 (36)
196 (11)
1464 (80)
,0.001
,0.001
26
24– 30
26
24– 29
27
24– 30
0.49
85
68– 101
74
57– 94
87
71– 103
,0.001
ASA
Vitamin K antagonists
809 (36)
191 (9)
200 (50)
41 (10)
609 (33)
150 (8)
,0.001
0.18
Beta-blockers
770 (35)
174 (44)
596 (33)
,0.001
Statins
ACEIs/ARBs
777 (35)
843 (38)
178 (45)
207 (52)
599 (33)
636 (35)
,0.001
,0.001
Calcium antagonists
321 (14)
82 (21)
239 (13)
,0.001
Nitrates
257 (12)
85 (21)
172 (9)
,0.001
0.31
0.021
History, n (%)
Body mass index (kg/m2)
Median
IQR
eGFR (mL/min/1.73 m2)
Median
IQR
Medication at presentation, n (%)
AMI, acute myocardial infarction; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ASA, acetyl salicylic acid; ACEI, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker.
Values are expressed in percentage or medians + IQR.
a
Comparisons between NSTEMI and no-NSTEMI patients.
Prognostic accuracy of high-sensitivity
cardiac troponin I and T for mortality
Patients were followed during a mean period of 24 months. During
this time a total of 153 patients died, 44% of them had a diagnosis
of NSTEMI and 56% had a different diagnosis than NSTEMI
(P , 0.001). Prognostic accuracy as quantified by the AUC was
high for both and significantly higher for hs-cTnT when compared
with hs-cTnI (0.80, 95% CI: 0.77–0.83, vs. 0.75, 95% CI: 0.73–0.79;
P , 0.001; Figure 4). The prognostic superiority of hs-cTnT was consistent in the NSTEMI group (P , 0.001) and in the non-NSTEMI
group (P ¼ 0.001).
Similar findings were obtained regarding cardiac death. Among all
patients 3% (n ¼ 69) suffered from a cardiac death during the followup. The accuracy to predict cardiac death as quantified by the AUC
was significantly higher for hs-cTnT when compared with hs-cTnI
(0.82, 95% CI: 0.80–0.84, vs. 0.79, 95% CI: 0.78–0.81; P ¼ 0.004.
Prediction of acute myocardial infarction
in the future
Among all patients in the no-NSTEMI group (n ¼ 1827), 3.6%
(n ¼ 65) suffered an AMI during the follow-up. The accuracy to
predict AMI among these patients as quantified by the AUC was
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ECG findings, n (%)
2307
Comparison of hs-cTn I and T
moderate for both and slightly higher for hs-cTnI when compared
with hs-cTnT (0.70, 95% CI: 0.68–0.72 vs. 0.66, 95% CI: 0.64–0.68;
P ¼ 0.07. Among all patients in the NSTEMI group (n ¼ 399),
14.8% (n ¼ 59) suffered an AMI during the follow-up. The accuracy
to predict AMI among these patients as quantified by the AUC was
very low for both (hs-cTnI 0.56, 95% CI: 0.51– 0.61 vs. hs-cTnT
0.54, 95% CI: 0.49–0.59; P ¼ 0.49).
While hs-cTn assays still await approval for clinical use in the USA,
two fully developed hs-cTn assays have become clinically available
in Europe and many other countries in 2010 (hs-cTnT, Roche) and
2013 (hs-cTnI, Abbott). This large prospective multicentre study
directly compared the diagnostic and prognostic accuracy of these
clinically available hs-cTn assays in consecutive patients presenting
to the ED with acute chest pain. We report six major findings.
First, in our analysis both hs-cTnI and hs-cTnT showed very high
diagnostic accuracy for NSTEMI (AUC 0.93 and 0.94) already at presentation, confirming and extending similar previous findings for both
clinically available as well as pre-commercial s-cTn and hs-cTn
assays.7,8,29 Secondly, in the overall group diagnostic accuracy at presentation for NSTEMI was similar with both assays. This finding is of
major clinical relevance for clinicians, laboratory experts, and hospital
administrators as it will help these decision-makers in planning the
future laboratory strategies of their institutions. However, our data
also suggested that time from symptom onset may impact on the respective diagnostic superiority of either test over the other: hs-cTnI
seemed to be superior in early presenters, while hs-cTnT seemed to
be superior in late presenters. It is important to highlight that the diagnostic superiority of hs-cTnI vs. T in early presenters methodologically is very sound, as our methodology introduced a small but
unavoidable bias in favour of hs-cTnT regarding diagnostic accuracy.
While local levels of both cTnI and cTnT were used for the adjudication, only hs-cTnT levels were available for the additional adjudication of small AMIs and more patients were enrolled in sites using
(hs-)cTnT rather than cTnI. In addition, the finding of diagnostic
superiority of hs-cTnI in early presenters is supported by similar
recent observations with s-cTnI in critical subgroups such as the
elderly and patients with pre-existing coronary artery disease11,12
Figure 2 Diagnostic performance of high-sensitivity cardiac troponins I and T. Receiver-operation-characteristic curves show the diagnostic accuracy of high-sensitivity cardiac troponins I and T for non-ST segment myocardial infarction at presentation to the emergency department with
acute chest pain in the overall cohort (A) and in the patients with a chest pain onset within 3 h (B).
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Figure 1 Levels of high-sensitivity cardiac troponin according to
final diagnoses. Troponins levels at the time of patients’ presentation to the emergency department. The boxes represent median
and inter-quartile ranges. hs-cTn, high-sensitivity cardiac troponin;
AMI, acute myocardial infarction; CAD, coronary artery disease.
Discussion
2308
M. Rubini Gimenez et al.
Table 2 Diagnostic accuracy of changes in
high-sensitivity cardiac troponin I vs. changes in
high-sensitivity cardiac troponin T in early presenters
AUC (95% CI)
hs-cTnI
AUC (95% CI)
hs-cTnT
P-valuea
0ha
1hb
0.92 (0.89– 0.94)
0.95 (0.92– 0.96)
0.89 (0.86–0.91)
0.95 (0.92–0.96)
0.019
0.97
0h+1hb
0.95 (0.92– 0.96)
0.94 (0.92–0.96)
0.74
1h+D0h21hb
2hc
0.95 (0.92– 0.97)
0.98 (0.95– 0.99)
0.95 (0.93–0.97)
0.97 (0.95–0.98)
0.44
0.88
0h+2hc
0.95 (0.92– 0.97)
0.96 (0.94–0.98)
0.05
2h+D0h22hc
3hd
0.96 (0.93– 0.98)
0.98 (0.94– 0.99)
0.96 (0.94–0.98)
0.98 (0.95–1.00)
0.42
0.60
0h+3hd
0.97 (0.94– 0.99)
0.99 (0.96–0.99)
0.18
3h+D0h23hd
0.98 (0.95– 0.99)
0.99 (0.96–0.99)
0.29
Time point
................................................................................
Figure 3 Diagnostic performance of high-sensitivity cardiac
troponin T and I within time. Receiver-operation-characteristic
curves displaying the diagnostic accuracy for non-ST segment myocardial infarction of serial sampling of high-sensitivity cardiac troponin I vs. high-sensitivity cardiac troponin T.
Table 3 Diagnostic accuracy of changes in
high-sensitivity cardiac troponin I vs. changes in
high-sensitivity cardiac troponin T
AUC (95% CI)
hs-cTnI
AUC (95% CI)
hs-cTnT
P-valuea
0ha
0.93 (0.92– 0.94)
0.94 (0.92–0.94)
0.62
1hb
0.95 (0.94– 0.96)
0.95 (0.94–0.96)
0.48
0h+1hb
1h+D0h21hb
0.95 (0.94– 0.96)
0.95 (0.94– 0.96)
0.95 (0.94–0.96)
0.96 (0.95–0.97)
0.19
0.004
2hc
0.95 (0.94– 0.96)
0.95 (0.94–0.96)
0.92
0h+2hc
2h+D0h22hc
0.94 (0.92– 0.95)
0.96 (0.95– 0.97)
0.96 (0.95–0.97)
0.97 (0.96–0.98)
0.05
0.06
3hd
0.95 (0.93– 0.97)
0.96 (0.95–0.98)
0.07
0h+3hd
3h+D0h23hd
0.95 (0.93– 0.97)
0.96 (0.94– 0.97)
0.97 (0.95–0.98)
0.97 (0.96–0.98)
0.032
0.017
Time point
................................................................................
a ¼ 2226; b ¼ 1735; c ¼ 1374; d ¼ 642.
a
Comparisons between hs-cTnI vs. hs-cTnT.
and therefore quite certainly real. Although early presenters can be
assumed to derive the greatest benefit from early revascularization,
it remains uncertain whether the magnitude of the difference is sufficient to achieve clinical relevance. Even small differences in the diagnostic accuracy for AMI in early presenters may have sufficient effect
on the early management of patients. In addition, these differences
may impact also on, e.g. the negative predictive value of specific
rule-out algorithms.14 For their acceptance and adoption, clinicians
might see a difference between an algorithm that offers, e.g. a NPV
of 99.9% vs. an algorithm that offers an NPV of 99.5%. Thirdly,
during serial sampling, diagnostic accuracy of both hs-cTnI and
hs-cTnT further increased. While the direct comparisons of
hs-cTnI and hs-cTnT at the individual later time points showed
Figure 4 Prognostic performance of high-sensitivity cardiac
troponin T and I. Receiver-operation-characteristiccurves displaying the prognostic accuracy for all-cause mortality during the
24-month follow-up of high-sensitivity cardiac troponin I and highsensitivity cardiac troponin T.
similar accuracy for both, the comparison of the respective combinations of levels at presentation with serial measurements showed a
very small but statistically significant higher diagnostic accuracy of
hs-cTnT vs. hs-cTnI. Fourthly, comparing the diagnostic accuracy
of both assays to differentiate UA from NCCP, hs-cTnI was slightly
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on September 30, 2016
a ¼ 558; b ¼ 456; c ¼ 385; d ¼ 181.
a
Comparisons between hs-cTnI vs. hs-cTnT.
2309
Comparison of hs-cTn I and T
correlations close to 1,6,9 the use of two sample types might have
introduced a minor disadvantage for the hs-cTnT assay.
The observed differences should not distract from the enormous
amount of similarities between hs-cTnI and hs-cTnT, neither should
they be misinterpreted as a suggestion to use two hs-cTn assays in
parallel.5,29 In addition, it is important to highlight that hs-cTn must
always be used and interpreted in conjunction with all other clinical
information.
Some limitations of this study merit to be considered. First, we analysed the diagnostic and prognostic performance of cTnI and cTnT
using the two clinically available hs-cTn assays. Future studies will
need to evaluate whether our findings also apply to other hs-cTnI
assays once they will become clinically available. Secondly, since
our study was prospective and observational, we cannot determine
with precision the clinical benefit associated with the clinical use of
either hs-cTnI or hs-cTnT. Thirdly, as patients with terminal kidney
failure requiring dialysis were excluded from this study, we cannot
comment on the diagnostic and prognostic performance of cTnI or
cTnT in those patients. Fourth, our data set does not allow to
address the question whether and if to what extent the difference
in molecular weight (23 vs. 35 kDa) between cTnI and cTnT contributed to our findings.
In conclusion, both hs-cTnI and hs-cTnT provided high diagnostic
and prognostic accuracy. The direct comparison revealed small but
potentially important differences between the performance of the
cTnI molecule and the cTnT molecule that might help to further
improve the clinical use of hs-cTn in the management of patients
presenting with suspected AMI.
Supplementary material
Supplementary material is available at European Heart Journal online.
Acknowledgements
We thank the patients who participated in the study, the staff of
the EDs, the research coordinators, and the laboratory technicians
(particularly Esther Garrido, Melanie Wieland, Kathrin Meissner,
and Fausta Chiaverio) for their most valuable efforts. We also wish
to thank Stefanie von Felten for her help with the quantification of
the prognostic accuracy.
Funding
This study was supported by research grants from the Swiss National
Science Foundation, the Swiss Heart Foundation, the Cardiovascular
Research Foundation Basel, the University Hospital Basel, Abbott,
Roche, Nanosphere, Siemens, 8sense, Bühlmann and BRAHMS.
Conflict of interest: Prof. Mueller has received research grants from
the Swiss National Science Foundation and the Swiss Heart Foundation,
the Cardiovascular Research Foundation Basel, 8sense, Abbott, ALERE,
Brahms, Critical Diagnostics, Nanosphere, Roche, Siemens, and the University Hospital Basel, as well as speaker honoraria from Abbott, ALERE,
Brahms, Novartis, Roche, and Siemens. We disclose that T.R. has
received research grants from the Swiss National Science Foundation
(PASMP3-136995), the Swiss Heart Foundation, the University of
Basel, the Professor Max Cloetta Foundation and the Department of Internal Medicine, University Hospital Basel as well as speakers honoraria
from Brahms and Roche. All other authors declare that they have no
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on September 30, 2016
superior to hs-cTnT. However, it is important to highlight that overall
the diagnostic accuracy of hs-cTn for UA was only moderate, corroborating the data reported in earlier pilot studies in which the adjudication of the final diagnosis was based on conventional cTn assays
only.7 Further studies are needed to define the best possible clinical
use of hs-cTn in conjunction with all other clinical information in the
differentiation of UA from NCCP. Fifthly, prognostic accuracy for allcause mortality during 24-month FU was high for both hs-cTnI and
T. In fact, hs-cTnT was significantly superior compared with
hs-cTnI. Our data corroborate and extend recent studies in which
hs-cTnT was compared with a s-cTnI and pre-commercial hs-cTnI
assays and shown to be the better prognosticator.9,10,30 – 32 As
follow-up was performed blinded to levels of both hs-cTnT and
hs-cTnI and revealed a substantial number of deaths, and was consistent using three different statistical models to quantify prognostic accuracy, also the finding of prognostic superiority of hs-cTnT over
hs-cTnI methodologically seems very robust. The observed difference in prognostic accuracy (DAUC 0.05) was consistent in the
NSTEMI and non-NSTEMI group and clearly seems clinically meaningful.33 Sixthly, prognostic accuracy to predict non-fatal AMI
during 24-month FU among patients in the no-NSTEMI group was
low-to-moderate for both biomarkers, and slightly higher for
hs-cTnI compared with hs-cTnT. This finding is supported by a
similar observation in another chest pain cohort34 and highlights
the fact that different pathophysiological signals may be helpful in
the prediction of death vs. the prediction of acute plaque rupture
resulting in non-fatal AMI.
We can only speculate which pathophysiological differences
between cTnI and T or the specific hs-cTn assays used were the
major drivers for the observed differences. First, release of cTn
occurs first from the early appearing cytosol pool and subsequently
from the structural pool.6,35 – 37 Release from the latter is the reason
for the sustained elevations observed clinically in AMI and is a surrogate for irreversible break down of sarcomeric proteins.6 It is conceivable that the early appearing pool contains larger amounts of
cTnI than cTnT, which would explain that cTnI seems to be the superior signal in early presenters. On the other hand, if the cTnT signal
results to large extent from the irreversible break down of sarcomeric proteins, this more profound injury could then be well understood to be more closely linked to mortality when compared with a
signal that may be induced also from less severe injury. Recent observations from studies of exercise-induced myocardial ischaemia
support this hypothesis.38 Silent coronary plaque rupture with subsequent microembolization may be the possible mechanisms linking
hs-cTn with the risk of AMI in the future.39 – 41 As microembolization
represents a minor injury, it may result in a predominate release of
cTn from the early appearing cytosol pool and may therefore be
better reflected by levels of hs-cTnI. Patients experiencing silent
plaque rupture with microembolization may well be considered
at an increased risk of subsequent plaque ruptures that may not
heal spontaneously and that may result in clinically apparent AMI.
Secondly, we think it is unlikely that pre-analytical or analytical
issues of one of the assays played a relevant role as each assay
proved superior in at least one category. Measurements of hs-cTnT
were performed from two types of samples (serum and EDTA
plasma), while hs-cTnI was measured from only one type (serum).
While these sample types have been shown to reveal very high
2310
M. Rubini Gimenez et al.
conflict of interest with this study. The sponsors had no role in the design
of the study, the analysis of the data, the preparation of the manuscript, or
the decision to submit the manuscript for publication.
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