Author + information
- Received October 22, 2009
- Revision received December 17, 2009
- Accepted January 2, 2010
- Published online May 11, 2010.
- Till Keller, MD*,
- Stergios Tzikas, MD*,
- Tanja Zeller, PhD*,
- Ewa Czyz, MD*,
- Lars Lillpopp*,
- Francisco M. Ojeda, PhD*,
- Alexander Roth, PhD*,
- Christoph Bickel, MD‡,
- Stephan Baldus, MD§,
- Christoph R. Sinning, MD*,
- Philipp S. Wild, MD*,
- Edith Lubos, MD*,∥,
- Dirk Peetz, MD†,
- Jan Kunde, PhD¶,
- Oliver Hartmann, MSc¶,
- Andreas Bergmann, PhD¶,
- Felix Post, MD*,
- Karl J. Lackner, MD†,
- Sabine Genth-Zotz, MD*,
- Viviane Nicaud, MA#,
- Laurence Tiret, PhD#,
- Thomas F. Münzel, MD* and
- Stefan Blankenberg, MD*,* ()
- ↵*Reprint requests and correspondence:
Dr. Stefan Blankenberg, Department of Medicine II, Johannes Gutenberg-University, Langenbeckstrasse 1, 55101 Mainz, Germany
Objectives Early identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation.
Background The aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction.
Methods Between January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h.
Results Of 1,386 (66.4% male) enrolled patients, 299 (21.6%) had the discharge diagnosis of acute myocardial infarction, 184 (13.3%) presented with unstable angina, and in 903 (65.2%) an acute coronary syndrome could be excluded. Combined measurement of copeptin and TnT on admission improved the c-statistic from 0.84 for TnT alone to 0.93 in the overall population and from 0.77 to 0.9 in patients presenting within 3 h after chest pain onset (CPO) (p < 0.001). In this group the combination of copeptin with a conventional TnT provided a negative predictive value of 92.4%.
Conclusions In triage of chest pain patients, determination of copeptin in addition to troponin improves diagnostic performance, especially early after CPO. Combined determination of troponin and copeptin provides a remarkable negative predictive value virtually independent of CPO time and therefore aids in early and safe rule-out of myocardial infarction.
Early identification of myocardial infarction (MI) in chest pain patients is crucial to maintain a fast treatment initiation. Diagnosis of acute myocardial infarction (AMI) relies, besides clinical symptoms and electrocardiographic (ECG) findings, primarily on biomarker levels. Markers of myocardial necrosis such as cardiac troponin and creatine kinase-myocardial band (CK-MB) are the gold standard in detection of AMI, and their use is recommended by current guidelines (1). In particular, cardiac troponin provides excellent specificity (2,3).
The delayed release of necrosis markers after cell disintegration might explain the weakness in diagnostic performance of conventional troponin assays early after chest pain onset (CPO) (4). Therefore, markers with pathophysiologic background independent of cell necrosis might improve rapid diagnosis of AMI.
The antidiuretic hormone arginin-vasopressin (AVP) is secreted neurohypophyseal and controls osmotic homeostasis (5). Release of AVP is regulated by hyperosmolality, hypovolemia (6), hypotension, hypothalamic osmoreceptors and angiotensin II, reflecting individual stress level (7). The AVP-induced vasoconstriction is mediated by the V1areceptor on smooth muscle cells, the antidiuretic effect by the V2receptor on the distal kidney tubule, and the IP3 signal transduction pathway (8,9). Clinical relevance of AVP is given by its potential role in pathogenesis and its diagnostic value in congestive heart failure (10) and remodeling after AMI (11). As endocrine stress response, the AVP levels increase in shock and cardiac arrest (12–14). Routine measurement of AVP in clinical practice is prevented by various reasons, such as short half-life time (15), platelet binding (16), and assay variations. The glycosylated peptide copeptin is part of the uncleaved pro-AVP and emerges equimolar to AVP, because both are derived from the precursor prepro-AVP along with neurophysin II; therefore, it serves as an indirect marker for AVP. A recently developed assay for copeptin delivers the stability and reproducibility direct measurement of AVP is lacking (17).
The release pattern of copeptin in patients with AMI with immediate rise after onset of chest pain and decrease toward physiologic levels within 5 days (18) as well as the potential use of copeptin in rule-out of AMI (19) was described recently. Thus, the role of copeptin as diagnostic marker in suspected acute coronary syndrome (ACS) needs to be evaluated in large prospective cohorts.
The aim of the current investigation is to prospectively test whether copeptin adds diagnostic information to that provided by troponin and whether the combination of copeptin and troponin is superior to the combination of myoglobin and troponin in early evaluation of patients with suspected AMI.
All patients with suspected ACS presenting consecutively at the chest pain units of the University Medical Center of the Johannes Gutenberg-University Mainz, the Federal Armed Hospital Koblenz, or the University Hospital Hamburg-Eppendorf between January 2007 and July 2008 were enrolled in this study, to reflect an unbiased real world population.
Patients older than 18 years and younger than 85 years of age with angina pectoris or equivalent symptoms were eligible to participate. Exclusion criteria were trauma or major surgery within the last 4 weeks, pregnancy, intravenous drug abuse, and anemia (hemoglobin <10 g/dl).
Patients treated with antihypertensive drugs at enrollment or who had previous diagnosis of hypertension were classified as hypertensive. Patients were categorized as currently smoking, former smoking (if stopped 4 weeks to 40 years prior), and nonsmoker (if stopped smoking >40 years ago). Patients receiving dietary treatment or medication for diabetes were considered to have diabetes mellitus. We considered patients with previously diagnosed hyperlipidemia or with total cholesterol >200 mg/dl at admission as hyperlipidemic.
Blood was drawn at admission and after 3 and 6 h. A 12-lead ECG was obtained at the same time points.
Diagnosis of AMI was established according to the universal definition of MI (1). Patients with symptoms of myocardial ischemia together with ECG changes and/or elevated biomarkers of myocardial necrosis were categorized as having an AMI. Relevant ECG changes were defined as follows: ST-segment elevation ≥0.2 mV in at least 2 contiguous leads in V2to V6or ST-segment elevation ≥0.1 mV in other leads or with new left bundle branch block documented in ECG at admission or in outpatient clinic ECG were classified as AMI with ST-segment elevation; and ST-segment depression and T- or Q-wave changes were classified as ECG signs representative for acute ischemia. Necrosis of myocardium was noted if at least 1 determination of in-house troponin exceeded the predefined upper reference limit of the corresponding assay and if a typical kinetic with rise or fall ≥20% within 6 h after admission could be observed.
Unstable angina pectoris (UAP) was diagnosed if ECG was nondiagnostic; in-house troponin was negative, but coronary angiography revealed a culprit lesion; or ischemia was proven in stress test with subsequent need of coronary intervention. All patients with excluded ACS were categorized as having noncoronary chest pain (NCCP). Final diagnosis was made by an expert committee of 2 cardiologists, blinded to copeptin values, on the basis of all available clinical, laboratory, and imaging findings.
The study was approved by the local ethics committees in Rheinland-Pfalz and Hamburg. Participation was voluntary; each patient gave written, informed consent.
Blood sampling and laboratory methods
Routine laboratory parameters, including C-reactive protein, creatinine, myoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), and CK-MB, were measured immediately after blood withdrawal by standardized methods. Additionally, ethylenediaminetetraacetic acid plasma, citrate plasma, and serum samples were collected at each time point, centrifuged, and frozen at −80°C.
Cardiac troponin T (TnT) (Roche Diagnostics, Mannheim, Germany) representing in-house troponin at 2 study centers was measured at each time point in all patients with the electrochemiluminescence immunoassay (ECLIA) technology on an Elecsys 2010 system with detection limit of 0.01 ng/ml and measuring range of 0.01 to 25 ng/ml. Reference limit based on the 99th percentile for a healthy population was 0.01 ng/ml, and 10% coefficient of variation (CV) was 0.03 ng/ml, which was used as diagnostic cutoff. In-house cardiac troponin I (Dimension RxL TnI, Siemens Healthcare Diagnostics, Erlangen, Germany) was used at 1 study center for adjudication of final diagnosis. The assay had a detection limit of 0.04 ng/ml with a measuring range of 0.04 to 40 ng/ml. The 99th percentile was 0.07 ng/ml, and the 10% CV used as diagnostic cutoff was 0.14 ng/ml. Additionally, sensitive cardiac troponin I with the TnI-Ultra assay (Siemens Healthcare Diagnostics) was determined on an ADVIA Centaur XP system. The assay detection limit was 0.006 ng/ml, measuring range was 0.006 to 50 ng/ml, 99th percentile was 0.04 ng/ml, and 10% CV was 0.03 ng/ml.
Copeptin was measured in ethylenediaminetetraacetic acid plasma by sandwich immunoluminometric assay (CT-proAVP LIA B.R.A.H.M.S AG, Hennigsdorf, Germany) as described in detail elsewhere (17,20). The assay has an analytical detection limit of 0.4 pmol/l and a functional assay sensitivity (lowest value with an interassay CV <20%) <1.0 pmol/l and allows precise measurement of copeptin in a range of 0.4 to 1,250 pmol/l.
To determine a diagnostic cutoff based on a reference population, copeptin was measured with the same assay as described in the preceding text in 5,000 individuals of the Gutenberg Heart Study. Characteristics of the participants are given in Online Table 1. On the basis of the distribution of copeptin, different potential cutoff values were considered (Fig. 1):the 99th percentile with 18.9 pmol/l as suggested for a biomarker in diagnosis of an AMI by the universal definition, the 97.5th percentile with 13 pmol/l as 95% of the measured values define the reference range of a biomarker, and the 95th percentile with 9.8 pmol/l as copeptin showed a skewed distribution and as only the upper reference limit is of interest in this context. Technical assistants measuring copeptin were blinded to the patients' characteristics.
To estimate glomerular filtration rate, the abbreviated Modification of Diet in Renal Disease equation was used (21).
Skewed variables were described by median and interquartile range. Symmetric variables were characterized by arithmetic mean and SD.
Association between copeptin and different continuous variables was assessed with Spearman rank correlation coefficient. The Mann-Whitney test was used to compare the median levels of copeptin among different groups defined by binary risk factors.
To describe changes over time, the Page L test for ordered alternatives was used in markers with continuous increase or decrease, and the Friedman 2-way analysis of variance by ranks test was used in markers without an obvious trend (22).
Receiver-operating characteristic (ROC) curves based on continuously measured biomarker levels dependent on time since chest-pain onset were calculated and graphed by using logistic regression according to diagnosis; all biomarkers entered these analyses after being log-transformed, due to their skewness. A nonparametric approach according to DeLong et al. (23) was used to test for difference between the areas under the curve (AUCs). Confidence intervals for the AUCs were constructed with the covariance matrix estimated by the DeLong et al. method.
Additionally, positive predictive values (PPVs), negative predictive values (NPVs), sensitivity, and specificity for the target markers were assessed by first applying a marker-specific cutoff value and consecutively calculating the corresponding values from a 2 × 2 table in the usual way that these quantities are defined. Because these numbers represent proportions, 95% confidence limits for binomial distributed variables are given additionally. All analyses were done with R 2.9.0 (R Foundation for Statistical Computing, Vienna, Austria).
Table 1provides the baseline characteristics of the overall study population at admission. Mean age was 61.5 years; 33.6% of the patients presented were women. In 903 of the 1,386 enrolled patients, an ACS could be excluded; these patients were classified as having NCCP, including patients with diagnosis of decompensated aortic valve stenosis (n = 2), aortic dissection (n = 5), myocarditis (n = 13), decompensated heart failure (n = 16), and pulmonary embolism (n = 17).
Discharge diagnosis of AMI was made in 299 patients (21.6%), including 93 patients (6.7%) having an ST-segment elevation MI. The diagnosis of UAP was made in 184 (13.3%) patients. The observed distribution of approximately 22% AMI and 35% ACS is in line with other European studies (24). Traditional risk factors were more common in ACS patients. As anticipated, biomarkers of myocardial necrosis as well as copeptin levels were highest in patients suffering AMI. The distribution of CPO time was comparable amongst all groups categorized according to diagnosis.
Analyses of serial blood sampling
In addition to blood sampling at admission, serial samples were obtained after 3 and 6 h. To prospectively assess the time course of the evaluated potential early biomarkers, patients with discharge diagnosis of AMI (n = 75) or NCCP (n = 213) presenting with CPO <2 h were selected. Figure 2illustrates the representative time courses of TnT, copeptin, myoglobin, and CK-MB in those patients during the first 6 h after admission. Median troponin T levels strongly increased within 6 h after admission (p < 0.001). By contrast, copeptin levels decreased during the first 6 h from its peak at admission (p < 0.001). Levels of myoglobin seemed to increase during the first 3 h and decline afterward (p = 0.397), whereas CK-MB concentration continuously increased within the observed 6 h (p < 0.001).
Biomarker concentration according to CPO
Table 2outlines the course of biomarker concentration at admission according to CPO time in the overall study population. The concentration of TnT continuously increased with CPO time in AMI patients, reaching a maximum later than 12 h after CPO. In AMI patients with CPO of <3 h, mean TnT was at the concentration of 10% CV with 0.03 ng/ml.
In contrast, median copeptin levels were highest in AMI patients with CPO below 3 h. In this time interval, patients with AMI had 5-fold higher copeptin levels (29.6 pmol/l) compared with NCCP (5.7 pmol/l) and UAP (5.45 pmol/l) patients. Median copeptin levels decreased over time, reaching values comparable to NCCP and UAP in patients presenting later than 12 h after CPO.
In patients with CPO below 3 h, NT-proBNP levels were elevated 2.5-fold in AMI patients compared with NCCP, increasing within 12 h after CPO. As expected, in AMI patients, myoglobin was already elevated 2-fold in patients presenting earlier than 3 h, peaking within 12 h after CPO. The time course of CK-MB showed a slower increase and later peak.
Correlates of copeptin
Association between classical risk factors and median copeptin levels according to diagnosis is displayed in Table 3.Men, obese patients, smokers, and patients with diabetes in the NCCP group and patients with diabetes in the UAP group had significantly higher copeptin levels. Female patients presenting with AMI had lower copeptin levels compared with male patients (13.55 pmol/l vs. 18.6 pmol/l; p = 0.25); this might be explained by the longer time interval between CPO and admission of female patients. Furthermore, prevalence of hypertension and hyperlipidemia tended to be related to copeptin levels.
Table 3also shows the correlation of continuous risk variables and of serum biomarkers and copeptin. Myoglobin as a marker of necrosis showed a mild correlation to copeptin in all diagnosis groups, TnT in NCCP and AMI patients, whereas CK-MB had no correlation with copeptin. Furthermore, creatinine and eGFR, showed a significant correlation with copeptin in all diagnostic groups.
Diagnostic value of copeptin
To compare the discriminatory ability of the continuous biomarkers troponin T, copeptin, myoglobin, and CK-MB in detecting MI, ROC curve analysis with AUC determination was performed according to different times after CPO (Table 4,upper section). The AUC for TnT increased over time, with highest value in the overall population (0.84) compared with patients presenting as early as 12, 6, and 3 h after CPO. CK-MB showed dynamics similar to troponin T with lower AUCs in all groups. In contrast, copeptin as well as myoglobin provided the highest discriminatory power in patients with CPO <3 h.
Adding the markers copeptin, myoglobin, and CK-MB individually to TnT improved the AUC significantly in all groups in comparison with troponin T alone. In patients presenting within <3 h after CPO, addition of copeptin to TnT revealed highest diagnostic power with AUC of 0.9 compared with addition of myoglobin to TnT. Combination of copeptin and TnT stayed superior with AUCs of 0.91, 0.92, and 0.93 in patients with CPO of <6 h and <12 h, and the overall population, respectively. Considering all patients at baseline, the combination of copeptin and TnT was superior to all single marker determinations or other marker combinations.
Using NT-proBNP as a diagnostic biomarker resulted in an AUC of 0.7 in the overall population; the combination of NT-proBNP and TnT was not significantly superior to troponin alone (AUC 0.87 vs. 0.84; p = 0.145).
The ROC curves of the single markers and their combination in serial samples at admission and after 3 and 6 h in the overall study population are graphed in Figure 3.
The lower section of Table 4shows sensitivities and specificities as well as PPV and NPV for TnT, copeptin, and myoglobin and combinations of these biomarkers for measured values above the respective cutoff.
TnT showed a high specificity, independent of CPO (97.9%, 97.7%, and 97.7% with CPO <3 h, <6 h, and <12 h, respectively), as well as the highest PPV (88.1%, 87.9%, and 88.2%) compared with copeptin and myoglobin. The combination of TnT and myoglobin showed higher sensitivity (75.9%, 77.6%, and 77.6%) and higher NPV (89.9%, 91.1%, and 91.6%) than TnT alone with downside of lower specificity and PPV. Combining copeptin and TnT resulted in even higher sensitivity, and NPV with all 3 used cutoff values representing the 95th, 97.5th, and 99th percentiles of a general population. Highest sensitivity (85.1%, 87.4%, and 88.2%) and NPV (92.4%, 93.9%, and 94.6%) were achieved with 9.8 pmol/l as the cutoff representing the 95th percentile.
If patients with ST-segment elevation (n = 93) were excluded from the AMI group, single TnT determination at admission in the overall population showed an AUC of 0.87, which improved to 0.93 (p < 0.001) by adding copeptin. In patients with CPO <3 h, the AUC for TnT alone was 0.79; for the combination of troponin and copeptin, the AUC improved to 0.9 (p < 0.001). Sensitivity and NPV of TnT alone with 10% CV as cutoff was 64.7% and 92.4%, respectively, in the overall population and 46.7% and 89.0% in patients with CPO <3 h. Applying the 95th percentile cutoff of 9.8 pmol/l for copeptin in combination with TnT improved sensitivity and NPV to 89.3% and 96.5%, respectively, in the overall population and to 81.3% and 94.0% in patients with CPO <3 h.
Regarding rule-out of ACS including AMI and UAP, determination of TnT at admission with 10% CV as cutoff provided an NPV of 74.9%; in combination with copeptin with the 95th percentile as cutoff, an NPV of 80% was achieved. In patients with CPO <3 h, the NPV increased from 70.8% for TnT alone to 77.8% in combination with copeptin.
Early evaluation of AMI with a more sensitive troponin
Additional to conventional TnT, data are given in Table 5on a more sensitive troponin I representative for a new generation of commercially available troponin assays with 10% CV below the 99th percentile as recommended by the universal definition of MI. In identification of AMI patients presenting within 3 h after CPO, troponin I delivered an AUC of 0.96 (0.95 to 0.98); the combination with copeptin improved the AUC slightly to 0.97 (0.96 to 0.98) (p = 0.0397). Application of the 99th percentile cutoff of 0.04 ng/ml showed a high sensitivity of 86.7% and NPV of 95%; the combination with copeptin with the 95th percentile of 9.8 pmol/l was able to improve the sensitivity to 98.3% and NPV to 99%. The combination had a sensitivity of 79.3% and an NPV of 84.6%, in exclusion of an ACS.
Early identification of patients at risk in a population with undifferentiated chest pain is essential, because these patients benefit the most from an aggressive therapeutic regimen.
Cardiac TnT, the basis of the diagnostic work-up, had a low sensitivity of 43% in detecting AMI in patients presenting within 3 h. In this important group, copeptin had a sensitivity of 75.2%, being more sensitive than TnT as well as myoglobin (62.3%). The overall diagnostic performance of a single copeptin measurement reflected by ROC analysis could only challenge TnT within the first 6 h, due to lower specificity. Therefore, copeptin is not able to replace troponin in final rule-in of AMI but allows earlier decision-making in clinical practice.
Combination of cardiac troponin with markers of different origin or variant release kinetics should, in theory, add diagnostic information. Indeed, we showed that combining TnT and copeptin, which reflects a physiologic hemodynamic stress response to myocardial ischemia, significantly improved the ROC performance within 3 h after CPO. Myoglobin as a marker of myocardial necrosis added less to TnT compared with copeptin. The approach of adding copeptin to TnT provided stable diagnostic performance albeit time of presentation after CPO, which reflects both the early peak of copeptin with the following decrease and the slow increase of TnT levels over time.
The observed high sensitivity in the first hours after CPO makes copeptin an ideal candidate to complement troponin with its high specificity to accurately rule out AMI at admission. Our study supports this assumption, with an NPV of copeptin using the 95th percentile as cutoff combined with TnT using the 10% CV as cutoff of nearly 96% in the overall population and of already 92.4% in patients presenting within 3 h after CPO.
Regarding myoglobin, an established early marker of myocyte necrosis, our results are in line with previous studies (25). In the overall picture, we could show a clear superiority of copeptin over myoglobin in our setting.
Disease entities of nonischemic etiology like myocarditis also might lead to elevated troponin levels and, therefore, result in lower specificity and PPV of troponin in evaluation of chest pain patients. Serial troponin determination can possibly exclude chronic diseases like renal impairment accompanied by troponin elevation (26). To distinguish other entities with acute onset and troponin rise like aortic dissection (27), early biomarkers of different origin than troponin like copeptin are amendatory, particularly in a real world population of patients with new-onset chest pain. Such biomarkers could also be helpful, due to the slow decrease of troponin, in detection of re-infarction with prolonged troponin elevation caused by initial necrosis.
In summary, we can state 3 major findings.
First, determination of copeptin as a single marker has diagnostic value comparable to that of myoglobin, being superior to a conventional TnT within the first 3 h after CPO. Neither single copeptin nor myoglobin determination is able, with regard to the overall population independent of CPO and need for high specificity, to displace or challenge a serial troponin T measurement to detect myocardial necrosis within a rule-in approach.
Second, combination of copeptin and TnT improves diagnostic performance for detection of AMI compared with single TnT measurement on admission, being clearly superior in patients presenting within 3 h after CPO. In contrast, combination of myoglobin and TnT adds less diagnostic information.
Third, combination of copeptin and conventional troponin T aids in early rule-out of AMI virtually independent of CPO with high NPV in patients presenting as early as 0 to 3 h after CPO.
The current universal definition of MI (1) asks for use of the 99th percentile as the troponin cutoff with CV of 10% at this concentration. This demand stimulated development of new troponin assays with high sensitivity in identification of AMI within the first hours after CPO where established troponins have shortcomings (2). Recently, we demonstrated that a more sensitive troponin I representative for this new troponin generation (28) provides a sensitivity of 84% in identification of AMI in patients presenting within 3 h after onset of chest pain (29). The present analysis shows comparable sensitivity of 85.1% for the combination of copeptin and conventional TnT in patients presenting as early as 3 h after CPO, compensating for the weakness of established troponins in the early phase. Combination of copeptin and more sensitive TnI could further improve sensitivity to 98.3% in patients presenting within 3 h, providing an excellent NPV of 99% with the downside of reduced specificity and PPV.
Therefore, combination of copeptin and troponin is useful in rapid evaluation of chest pain patients in many settings. Furthermore, in a point-of-care environment with inherent lower test sensitivity of troponin, copeptin could facilitate fast diagnosis and treatment initiation.
Using conventional cardiac troponin as a diagnostic criterion might favor the tested troponin compared with copeptin and myoglobin. The percentage of patients with AMI was rather high in this all-comers study. This distribution is in line with other European studies but might limit the use in populations with lower risk.
In triage of patients with suspected ACS, combined assessment of conventional troponin and copeptin improves diagnostic performance, specifically in the first hours after CPO, and thus might accelerate therapeutic decision-making. The addition of the classical early marker myoglobin to conventional troponin had, compared with copeptin, a less ameliorative effect.
Combined determination of troponin and copeptin on admission in patients early after onset of chest pain provides a high NPV. This combination might aid in early and safe rule-out of AMI and makes copeptin an ideal candidate to complement troponin in point-of-care testing.
For a supplementary table on the characteristics of 5,000 individuals of the Gutenberg Heart Study, please see the online version of this article.
The current study is funded through the research programs “Wissen schafft Zukunft”and “Schwerpunkt Vaskuläre Prävention”of the Johannes Gutenberg-University of Mainz and an unrestricted grant of the B.R.A.H.M.S. AG, Germany. Jan Kunde, Oliver Hartmann, and Andreas Bergmann are employed by B.R.A.H.M.S. AG, Germany.
- Abbreviations and Acronyms
- acute coronary syndrome
- acute myocardial infarction
- area under the curve
- creatine kinase-myocardial band
- chest pain onset
- coefficient of variation
- myocardial infarction
- noncoronary chest pain
- negative predictive value
- N-terminal pro-brain natriuretic peptide
- positive predictive value
- receiver operating characteristic
- troponin I
- troponin T
- unstable angina pectoris
- Received October 22, 2009.
- Revision received December 17, 2009.
- Accepted January 2, 2010.
- American College of Cardiology Foundation
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