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ABSTRACT
OBJECTIVES: We tested the noninferiority of a fast-track rule-out protocol for the diagnosis of non-ST-
segment elevation myocardial infarction vs noncoronary chest pain based on the single-sampling combined
assessment of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin compared with the serial
assessment of medium-sensitivity cardiac troponin I.
METHODS: Ultra-sensitive copeptin and medium-sensitivity cardiac troponin I levels were measured at
presentation in 196 consecutive patients admitted to the emergency department for acute nontraumatic chest
pain within 6 hours from symptoms onset and without ST-segment elevation on a 12-lead electrocardio-
gram. The diagnostic performance for non-ST-segment elevation myocardial infarction diagnosis of the
dual-marker single-sampling strategy with medium-sensitivity cardiac troponin I and ultra-sensitive
copeptin on admission was compared with that of the serial 0- and 3-hour medium-sensitivity cardiac
troponin I sampling in reference to the adjudicated postdischarge diagnosis, using both the comparison of
area under the curve (AUC) receiver operating characteristic and the McNemar chi-square test.
RESULTS: The diagnosis of non-ST-segment elevation myocardial infarction was adjudicated in 29 patients
(14.8%). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin generated
an AUC of 0.87 (95% confidence interval, 0.82-0.91), which was noninferior with respect to the 3-hour
interval medium-sensitivity cardiac troponin I serial sampling (P ¼ .194 for AUC difference). The com-
bination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin also yielded a numerically
higher diagnostic sensitivity (100% vs 89.7%; P ¼ not significant).
CONCLUSIONS: A single-sampling strategy of combined ultra-sensitive copeptin and medium-sensitivity cardiac
troponin I is noninferior to a 0- and 3-hour serial medium-sensitivity cardiac troponin I sampling in ruling out
non-ST-segment elevation myocardial infarction and thus may allow an earlier discharge of patients who are
ruled out for non-ST-segment elevation myocardial infarction (ClinicalTrials.gov Identifier NCT01962506).
Ó 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The American Journal of Medicine (2016)
129, 105-114
KEYWORDS: Biomarkers; Cardiac troponin; Copeptin; Early discharge; Emergency department; Myocardial infarc-
tion; NoneST-segment elevation myocardial infarction
Funding: See last page of article. Requests for reprints should be addressed to Raffaele De Caterina, MD,
Conflict of Interest: See last page of article. PhD, Institute of Cardiology, “G. d’Annunzio” University e Chieti, C/o
Authorship: See last page of article. Ospedale SS. Annunziata, Via dei Vestini, 31 - 66013 Chieti, Italy.
E-mail address: rdecater@unich.it
0002-9343/Ó 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.amjmed.2015.06.033
106 The American Journal of Medicine, Vol 129, No 1, January 2016
The rapid and reliable ruling out of non-ST-elevation information of cardiac troponin. Copeptin, also known as C-
myocardial infarction in patients who are admitted to the terminal pro-arginine-vasopressin, is a 39 amino acid peptide
emergency department for acute chest pain is a major unmet derived from pre-pro-vasopressin and reflects arginine-
clinical need.1 In the absence of ST elevation at the stand- vasopressin release with a 1:1 stoichiometric generation
ard electrocardiogram (ECG), evaluation of cardiac tropo- ratio. Activation of the arginine-vasopressin system may mark
nins is currently the gold standard for the diagnosis of the individual’s response to acute endogenous stress, as
non-ST-segment elevation occurs in acute myocardial infarc-
myocardial infarction.2,3 However, tion.12 Two large cohort studies
a normal single value from a CLINICAL SIGNIFICANCE have demonstrated that levels of
contemporary cardiac troponin We tested the noninferiority of a fast- copeptin are increased during acute
assay—not exceeding the 99th track rule-out protocol for the diag- myocardial infarction,13,14 and that
percentile of a normal reference the combined determination of
nosis of non-ST-segment elevation
population—on admission does copeptin and medium-sensitivity
myocardial infarction vs noncoronary
not effectively rule out an evolving cardiac troponin in patients pre-
myocardial infarction because of chest pain based on the single-sampling senting early with myocardial
the delayed release kinetics of combined assessment of high-sensitivity infarction allows for a rapid and
cardiac troponin (the cardiac cardiac troponin I and ultra-sensitive safe ruling out of acute myocardial
troponin “blind period”).4,5 High- copeptin compared with the serial infarction.13,14 A recent controlled
sensitivity cardiac troponin as- assessment of high-sensitivity cardiac trial has shown that early discharge
says, the definition of which has troponin I. of low- to intermediate-risk pa-
changed over time,6 improve tients with suspected acute coro-
In this study, such single-sampling
sensitivity compared with most nary syndromes and both negative
contemporary cardiac troponin as- strategy, proving noninferior to a 0- copeptin and troponin at admission
says. Although it is not clear that and 3-hour serial high-sensitivity car- is safe, with the potential for
this improvement in performance diac troponin I sampling in ruling out reducing costs and shortening stay
would bring additional value in the non-ST-segment elevation myocardial in the emergency department.15
6
clinical setting, these assays now infarction, may thus allow an earlier However, the diagnostic accuracy
are considered to be preferable for discharge of patients ruled out for of a combination of both the newer
their ability to detect early minor non-ST-segment elevation myocardial ultra-sensitive copeptin assay and
increases in the analyte,7 but even infarction. the medium-sensitivity cardiac
with these assays there may be still troponin for the instant rule out of
a short “blind period” in cases of non-ST-segment elevation myo-
early admissions. Therefore, current European Society of cardial infarction has not been tested prospectively within the
Cardiology (ESC) guidelines for pain-free patients with a 6-hour time window of symptom onset.
Global Registry of Acute Cardiac Events score <140 Therefore, we designed the ultra-sensitive COPeptin in
recommend a “rapid” rule-out protocol for non-ST-segment addition to medium sensitivity cardiac troponin for the early
elevation acute coronary syndromes with serial sampling of diagnosis of non-ST-elevation Acute Coronary Syndromes
high-sensitivity cardiac troponin within 3 hours (class I (COPACS) study to test the hypothesis of a diagnostic non-
recommendation, level of evidence B).8 Both the ESC and inferiority for a dual-marker single-sampling strategy based
the American College of Cardiology/American Heart Asso- on the combination of ultra-sensitive copeptin and medium-
ciation guidelines8,9 highlight the importance of the time sensitivity cardiac troponin I compared with both single and
interval from chest pain onset to hospital admission. In rec- serial assessments (0 and 3 hours) of medium-sensitivity
ommending the use of high-sensitivity cardiac troponin, the cardiac troponin for the early diagnosis of non-ST-segment
ESC guidelines suggest retesting after 3 hours if patient elevation myocardial infarction in patients admitted within 6
presentation is within 6 hours from symptom onset or hours of chest pain onset.
in cases in which this information cannot be reliably ob-
tained. A dual sampling strategy is not needed with later
presentations.10 MATERIALS AND METHODS
The need for serial blood sampling in an emergency
department to rule out non-ST-segment elevation myocardial Study Design
infarction in patients presenting early is not ideal, because it The COPACS study was a prospective cohort single-center
does not allow an immediate diagnosis and a quick patient study carried out from July to December 2013, complying
triage on presentation. Therefore, a fast-track rule-out proto- with the Declaration of Helsinki and approved by the Ethics
col based on multi-marker single-sampling strategies has been Committee of the “G. d’Annunzio” University. The study
advocated.11 Among emerging biomarkers in myocardial was registered prospectively (ClinicalTrials.gov Identifier
infarction, copeptin has a virtually immediate increase and NCT01962506). Each patient gave written informed consent
rapid decrease,11 which complements the diagnostic before participation.
Ricci et al Ultra-sensitive Copeptin in Non-ST-Segment Elevation-Acute Coronary Syndrome 107
Figure 1 Flow chart of the recruitment and selection process, with biomarker results on admission and
adjudicated final diagnoses. The asterisk (*) indicates that in the subgroup of patients with non-ST-
segment elevation myocardial infarction presenting with a discordant ultra-sensitive copeptinþ/medium-
sensitivity cardiac troponin I pattern on admission, a third high-sensitivity cardiac troponin I sample at
>6 hours was required to confirm the diagnosis of non-ST-segment elevation myocardial infarction in 3
patients. Cop-cTnI ¼ copeptin cardiac troponin I; NCCP ¼ noncoronary chest pain; NSTEMI ¼ with
non-ST-segment elevation myocardial infarction.
Patterns of Medium-Sensitivity Cardiac The delay from chest pain onset to emergency depart-
Troponin-I and Ultra-Sensitive Copeptin ment admission was significantly shorter among subjects
presenting with an ultra-sensitive copeptinþ/medium-sensi-
Measurements
tivity cardiac troponin I pattern (60 23 minutes) than in
Ultra-sensitive copeptin and medium-sensitivity cardiac
those with an ultra-sensitive copeptin/medium-sensitivity
troponin I were discordant in 57 cases (29%) on admission.
cardiac troponin Iþ pattern (300 42 minutes; P < .001).
Specifically, on admission, 47 patients presented with an ultra-
Diagnostic performances of the combined ultra-sensitive
sensitive copeptinþ/medium-sensitivity cardiac troponin
copeptin/medium-sensitivity cardiac troponin I on admis-
I pattern; 8 (17%) of these had a 3-hour positive medium-
sion vs the serial medium-sensitivity cardiac troponin I
sensitivity cardiac troponin, and 39 (82.9%) had a confirmed
sampling at 0 and 3 hours, and vs the single ms-cTnI sampling
negative medium-sensitivity cardiac troponin I on retesting.
on admission are summarized in Table 4. The dual-marker
Among those 8 patients with a positive medium-sensitivity
single-sampling strategy based on the ultra-sensitive copep-
cardiac troponin I retest, 3 patients were classified as having
tin/medium-sensitivity cardiac troponin I combination
a noneST-segment elevation myocardial infarction, and a
correctly ruled out non-ST-segment elevation myocardial
cardiac-related noncoronary chest pain diagnosis was estab-
infarction with 100% sensitivity and 100% negative predic-
lished in the other 5. Among those 39 patients with a second
tive value. The overall diagnostic performance of combined
medium-sensitivity cardiac troponin I negative test at 3 hours,
ultra-sensitive copeptin/medium-sensitivity cardiac troponin
in 3 patients a medium-sensitivity cardiac troponin I increase
I single-sampling strategy was noninferior to the serial
was detected beyond 6 hours, and a non-ST-segment elevation
assessment of medium-sensitivity cardiac troponin I within
myocardial infarction was finally diagnosed.
3 hours (AUC difference 0.068, P ¼ not significant).
An ultra-sensitive copeptin/medium-sensitivity cardiac
Sensitivity (100% vs 89.7%; P ¼ not significant) was also not
troponin Iþ pattern was documented on admission in 10
significantly different. Sensitivity of the single-sampling
patients: A final diagnosis of non-ST-segment elevation
strategy with ultra-sensitive copeptin/medium-sensiti-
myocardial infarction was adjudicated in 9 patients and of
vity cardiac troponin I for the rapid ruling out of non-ST-
noncoronary chest pain in 1 patient with a hypertensive
segment elevation myocardial infarction was higher than
emergency.
110 The American Journal of Medicine, Vol 129, No 1, January 2016
Table 3 Outcomes Related to Ultrasensitive Copeptin and Medium-Sensitivity Cardiac Troponin I Values at Admission to the Emergency
Department
us-Cop/ms-cTnIþ us-Copþ/ms-cTnI us-Copþ/ms-cTnIþ us-Cop/ms-cTnI
(n ¼ 10) (n ¼ 47) (n ¼ 15) (n ¼ 124)
Outcome during hospital stay
UA 0 (0) 0 (0) 0 (0) 0 (0)
NSTEMI 9 (90) 6 (12.8) 14 (93.3) 0 (0)
Coronary angiography 7 (70) 6 (12.8) 13 (86.7) 0 (0)
PCI 6 (70) 5 (10.6) 8 (53.3) 0 (0)
CABG 0 (0) 1 (2.1) 4 (26.7) 0 (0)
AHF 0 (0) 2 (4.3) 9 (60) 0 (0)
CV death 0 (0) 0 (0) 2 (13.3) 0 (0)
Non-CV death 0 (0) 0 (0) 0 (0) 0 (0)
Outcome at 90 d of follow-up
Readmission to ED for NCCP 1 (10) 6 (12.7) 2 (13.3) 12 (9.6)
UA 1 (10) 1 (2.1) 0 (0) 0 (0)
STEMI 0 (0) 0 (0) 0 (0) 0 (0)
NSTEMI 0 (0) 1 (2.1) 1 (6.7) 0 (0)
Coronary angiography 1 (10) 2 (4.3) 1 (6.7) 0 (0)
PCI 1 (10) 1 (2.1) 1 (6.7) 0 (0)
CABG 0 (0) 0 (0) 0 (0) 0 (0)
AHF 0 (0) 0 (0) 1 (6.7) 0 (0)
CV death 0 (0) 1 (2.1) 0 () 0 (0)
Non-CV death 0 (0) 0 (0) 0 (0) 0 (0)
Data are presented as n (%) of patients.
AHF ¼ acute heart failure; CABG ¼ coronary artery bypass graft; CV ¼ cardiovascular; ED ¼ emergency department; ms-cTnI ¼ medium-sensitivity
cardiac troponin I; NCCP ¼ noncoronary chest pain; NSTEMI ¼ non-ST-elevation myocardial infarction; PCI ¼ percutaneous coronary intervention;
STEMI ¼ ST-elevation myocardial infarction; UA ¼ unstable angina; us-Cop ¼ ultrasensitive copeptin.
measuring cardiac troponin with a 10% coefficient of vari- remains questionable, because increased diagnostic sensi-
ation at the 99th percentile of the reference population, is tivity of the cardiac troponin assay is likely to reduce, but
currently classified as “guideline acceptable,”30 and is in the not eliminate, the troponin-blind period after the onset of a
sensitivity range of tests currently approved for use in the myocardial infarction.
United States.6 Furthermore, a previous study by Keller
et al36 reported that among 1818 patients with suspected
acute myocardial infarction, a serial change in cardiac CONCLUSIONS
troponin I levels within 3 hours from admission (using the In patients presenting to the emergency department within
99th percentile diagnostic cutoff value) would have deter- 6 hours for acute chest pain, a strategy of single-sampling
mined a 99% negative predictive value and a 96% positive dual-marker ultra-sensitive copeptin/medium-sensitivity
predictive value for both high-sensitivity cardiac troponin I cardiac troponin I is noninferior to serial medium-sensitivity
and medium-sensitivity cardiac troponin I assays. However, cardiac troponin I sampling in allowing a rapid and reliable
whether the use of a higher sensitivity cardiac troponin ruling out of non-ST-segment elevation myocardial infarc-
assay would have changed the main message of this study tion, and may thus obviate the need for prolonged
Table 4 Comparison of the Diagnostic Performances of Various Biomarker Strategies for the Diagnosis of Non-ST-Elevation Myocardial
Infarction vs Noncoronary Chest Pain with Time Between Chest Pain Onset and Emergency Department Admission <6 Hours
Sensitivity AUC Difference
Biomarker Strategy (P value)* Specificity PPV NPV AUC (95% CI) (P Value)†
Serial ms-cTnI at 3 h 89.7% (.250) 98.2% 89.7% 98.2% 0.939 (0.896-0.968) -
ms-cTnI on admission 79.3% (.031) 98.8% 92% 96.5% 0.891 (0.838-0.931) 0.049 (.117)
us-Cop/ms-cTnI on admission 100% 74.2% 40.3% 100% 0.871 (0.816-0.915) 0.068 (.194)
Adjudicated final diagnosis by 2 independent cardiologists blinded to the results of copeptin.
AUC ¼ area under the curve; CI ¼ confidence interval; ms-cTnI ¼ medium-sensitivity cardiac troponin I; NPV ¼ negative predictive value;
PPV ¼ positive predictive value; us-Cop ¼ ultrasensitive copeptin.
*McNemar test comparing sensitivity of Cop-us/ms-cTnI.
†Hanley method comparing AUC of serial ms-cTnI.
Ricci et al Ultra-sensitive Copeptin in Non-ST-Segment Elevation-Acute Coronary Syndrome 113
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114 The American Journal of Medicine, Vol 129, No 1, January 2016
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2011;306:2684-2693. Conflict of Interest: ASJ has in the past consulted or presently consults
for most of the major biomarker diagnostic companies (Abbott Labora-
tories; Alere; Amgen Inc.; Beckman Coulter, Inc.; Critical Diagnostics;
Radiometer Medical ApS.).
Funding: The study was supported by institutional grants to the Insti- Authorship: All authors had access to the data and played a role in
tute of Cardiology, G. d’Annunzio University, Italy (to RDC). Copeptin writing this manuscript.