Incremental Value of Copeptin for Rapid Rule Out of Acute Myocardial Infarction

Transcription

1 Journal of the American College of Cardiology Vol. 54, No. 1, by the American College of Cardiology Foundation ISSN /09/$36.00 Published by Elsevier Inc. doi: /j.jacc Biomarkers Incremental Value of for Rapid Rule Out of Acute Myocardial Infarction Tobias Reichlin, MD,* Willibald Hochholzer, MD,* Claudia Stelzig, MSC,* Kirsten Laule, MSC,* Heike Freidank, MD, Nils G. Morgenthaler, MD, Andreas Bergmann, PHD, Mihael Potocki, MD,* Markus Noveanu, MD,* Tobias Breidthardt, MD,* Andreas Christ, MD,* Tujana Boldanova, MD,* Ramona Merki, MD,* Nora Schaub, MD,* Roland Bingisser, MD,* Michael Christ, MD,* Christian Mueller, MD* Basel, Switzerland; and Henningsdorf, Germany Objectives Background Methods Results Conclusions The purpose of this study was to examine the incremental value of copeptin for rapid rule out of acute myocardial infarction (). The rapid and reliable exclusion of is a major unmet clinical need., the C-terminal part of the vasopressin prohormone, as a marker of acute endogenous stress may be useful in this setting. In 487 consecutive patients presenting to the emergency department with symptoms suggestive of, we measured levels of copeptin at presentation, using a novel sandwich immunoluminometric assay in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists using all available data. The adjudicated final diagnosis was in 81 patients (17%). levels were significantly higher in patients compared with those in patients having other diagnoses (median 20.8 pmol/l vs. 6.0 pmol/l, p 0.001). The combination of troponin T and copeptin at initial presentation resulted in an area under the receiver-operating characteristic curve of 0.97 (95% confidence interval: 0.95 to 0.98), which was significantly higher than the 0.86 (95% confidence interval: 0.80 to 0.92) for troponin T alone (p 0.001). A copeptin level 14 pmol/l in combination with a troponin T 0.01 g/l correctly ruled out with a sensitivity of 98.8% and a negative predictive value of 99.7%. The additional use of copeptin seems to allow a rapid and reliable rule out of already at presentation and may thereby obviate the need for prolonged monitoring and serial blood sampling in the majority of patients. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE]; NCT ) (J Am Coll Cardiol 2009;54: 60 8) 2009 by the American College of Cardiology Foundation Acute myocardial infarction () is the major cause of death and disability worldwide, with an ongoing increase in incidence. Approximately 15 million patients per year present to the emergency department (ED) with chest pain From the Departments of *Internal Medicine and Laboratory Medicine, University Hospital, Basel, Switzerland; and the Research Department, Brahms AG, Henningsdorf, Germany. This study was supported by research grants from the Swiss National Science Foundation (PP00B ), Brahms, Roche, the Department of Internal Medicine, University Hospital Basel, the Brandenburg Ministry of Economics, Germany, and the European Regional Development Fund. Dr. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the Novartis Foundation, the Krokus Foundation, Abbott, AstraZeneca, Biosite, Brahms, Roche, Siemens, and the Department of Internal Medicine, University Hospital Basel; as well as speakers honoraria from Abbott, Bayer, Biosite, Brahms, Roche, and Dade Behring. Dr. Morgenthaler is employed by Brahms. Dr. Bergmann is a member of the board of directors and a shareholder of Brahms and holds patent applications on the use of copeptin for diagnostics. Drs. Reichlin and Hochholzer contributed equally to this work. Manuscript received January 4, 2009, accepted January 28, or other symptoms suggestive of in the U.S. and Europe (1). Rapid assessment of these patients is critical to direct further diagnostic and therapeutic strategies. Electrocardiography (ECG) and cardiac troponin form the current diagnostic cornerstones and complement clinical assessment in current guidelines (2,3). They allow for a rule in of within the first 3 h after presentation in the majority of patients (4) and offer the opportunity to initiate appropriate, evidence-based treatment (5,6). The vast majority of patients presenting to the ED with suspected, however, finally prove not to have (7). Current rule out of is time-consuming and expensive (8). One-quarter to one-third of patients with present without significant ECG changes indicative of acute ischemia; therefore, ECG is of little help to rule out (7,9). The major limitation of current troponin assays is a sensitivity deficit at presentation due to a delayed increase of

2 JACC Vol. 54, No. 1, 2009 June 30, 2009:60 8 Reichlin et al. for the Rapid Rule Out of 61 circulating levels (10). Exclusion of consequently requires prolonged monitoring over 6 to 9 h and serial blood sampling. This procedure contributes to overcrowding in the ED, and the associated costs probably exceed several billion U.S. dollars each year (11,12). The rapid and reliable rule out of, therefore, represents one of the large unmet needs in clinical medicine. The arginine-vasopressin system plays a crucial role in the regulation of the individual endogenous stress response (13). Levels of arginine-vasopressin have been shown to be elevated in heart failure (14) and in different states of shock (15), but investigation of the arginine-vasopressin system has been limited so far because arginine-vasopressin is unstable (half-life: 5 to 15 min) and largely attached to platelets (16,17)., the c-terminal part of the vasopressin prohormone, is secreted stoichiometrically with arginine-vasopressin from the neurohypophysis and is much more stable, thus overcoming the limitations and difficulties of assessing the arginine-vasopressin system (18). In a recent study, copeptin was markedly elevated in patients after and predicted adverse outcome (19); however, nothing is known about the diagnostic value of copeptin in. We hypothesized that the combination of a marker of cardiac necrosis, such as troponin, with a pathophysiologically different biomarker reflecting acute endogenous stress, such as copeptin, might allow for a rapid and accurate rule out of already at initial presentation without serial blood sampling. Methods Study design and population. From April 2006 to September 2007, a total of 492 consecutive patients presenting to the ED of the University Hospital Basel, Switzerland, with symptoms suggestive of such as chest pain and angina pectoris with onset or peak within the last 12 h were recruited in this prospective cohort study. Patients with terminal kidney failure requiring dialysis were excluded. The study was performed according to the principles of the Declaration of Helsinki and approved by the local ethics committee. Written informed consent was obtained from all participating patients. Routine clinical assessment. All patients underwent an initial clinical assessment that included clinical history, physical examination, 12-lead ECG, continuous ECG monitoring, pulse oximetry, standard blood tests, and chest radiography. Troponin T, the myocardial band (MB) fraction of creatine kinase and myoglobin, were measured at presentation and after 3 and 6 to 9 h, as long as clinically indicated. The timing and treatment of patients were left to the discretion of the attending physicians. Adjudicated final diagnosis. To determine the causal diagnosis at presentation for each patient, 2 independent cardiologists blinded to the results of copeptin reviewed all available medical records (including patient history, physical examination, results of laboratory and radiologic testing, Abbreviations and Acronyms acute myocardial infarction AUC area under the curve CI confidence interval ECG electrocardiography ED emergency department ROC receiver-operator characteristic ECG, echocardiography, cardiac exercise test, coronary angiography) pertaining to the patient from the time of ED presentation to 60-day follow-up. In diagnostic disagreement, cases were reviewed and adjudicated in conjunction with a third cardiologist. was defined as recommended in current guidelines (2,3). In brief, was diagnosed when there was evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Necrosis was diagnosed by a rising and/or falling pattern of troponin T with at least 1 value above the 99th percentile, with an imprecision of 10% (20). For the troponin T assay, the lower limit of detection is 0.01 g/l. Thus, to manifest a rising pattern, patients with normal initial values had to increase troponin T levels to the cutoff level of 0.04 g/l to fulfill criteria (21). Unstable angina was diagnosed in patients with normal troponin T levels and typical angina at rest, a sudden increase in episodes of a previously stable angina, in cases of positive cardiac exercise testing or cardiac catheterization with coronary arteries found to have stenosis of 70%, and in ambiguous cases in which follow-up information revealed or a sudden unexpected cardiac death within 60 days. Pre-defined further diagnostic categories included cardiac but not coronary symptoms (e.g., perimyocarditis, tachyarrhythmias) and noncardiac symptoms. If was excluded in the ED, but no sufficient further diagnostic procedures were performed for conclusive diagnosis, symptoms were classified as of unknown origin. Biochemical analysis. Troponin T was determined immediately using a 1-step enzyme immunoassay based on electrochemiluminescence technology. The MB fraction of creatine kinase (by mass assay) and myoglobin were measured by immunoassays (all Elecsys 2010, Roche Diagnostics, Mannheim, Germany). Blood samples for determination of copeptin were collected at presentation to the ED in all patients, and as long as there was diagnostic uncertainty, after 1, 2, 3, and 6 h into tubes containing potassium ethylenediaminetetraacetic acid. After centrifugation, samples were frozen at 80 C until assayed in a blinded fashion in a single batch using a novel commercial sandwich immunoluminometric assay (B.R.A.H.M.S. LUMItest CT-proAVP, B.R.A.H.M.S AG, Hennigsdorf/Berlin, Germany), as described in detail elsewhere (18). Since this initial publication, the assay was modified as follows: the capture antibody was replaced by a murine monoclonal antibody directed to amino acids (GPAGAL) of proavp. This modification improved the sensitivity of the assay. The lower detection limit was 0.4 pmol/l, and the functional assay sensitivity ( 20% interassay CV) was 1 pmol/l. The

3 62 Reichlin et al. JACC Vol. 54, No. 1, 2009 for the Rapid Rule Out of June 30, 2009:60 8 median copeptin level in 200 healthy persons was 3.7 pmol/l and the 97.5 percentile was 16.4 pmol/l. Glomerular filtration rate was calculated using the abbreviated Modification of Diet in Renal Disease formula (22). ECG analysis. All 12-lead admission ECGs were assessed in a core laboratory by internal medicine specialists blinded to the clinical and biochemical patients details. The ECG manifestations indicative of were defined as recommended in current guidelines (2,3). Statistical analysis. Continuous variables are presented as mean SD or median (with interquartile range [IQR]), categorical variables as numbers and percentages. Continuous variables were compared with the Mann-Whitney U test and categorical variables using the Pearson chi-square test. Correlations among continuous variables were assessed with the use of the Spearman rank-correlation coefficient. Logistic regression was used to combine troponin T and copeptin in the diagnosis of and to adjust for other baseline variables. Receiver-operator characteristic (ROC) curves were constructed to assess the sensitivity and specificity throughout the concentrations of troponin T and copeptin and to compare the ability of troponin T, copeptin, and its combination to diagnose. Comparison of areas under the ROC curves was performed as recommended by Baseline Characteristics of the Patients Table 1 Baseline Characteristics of the Patients DeLong (23). All hypothesis testing was 2-tailed, and a p value of 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows 15.0 (SPSS Inc., Chicago, Illinois) and MedCalc (MedCalc Software, Mariakerke, Belgium). Results Characteristics of patients. Of the 492 consecutive patients enrolled in the study, 5 were excluded from the analysis because of missing copeptin or troponin T values. Baseline characteristics of the remaining 487 patients are shown in Table 1. The adjudicated final diagnosis was in 17% of patients, unstable angina in 17%, cardiac symptoms of origin other than coronary artery disease in 13%, noncardiac symptoms in 43%, and symptoms of unknown origin in 11%. Of the 81 patients with, 30 (37%) were diagnosed having ST-segment elevation MI and 51 (63%) as having non ST-segment elevation MI. Troponin T levels. Among patients with, troponin T at presentation was 0.01 g/l in 25% and below the decision limit of 0.04 g/l in 35% of patients. Of the 406 patients without, 5.9% had a troponin T at presenta- Acute Myocardial Infarction Characteristic All Patients (n 487) Yes (n 81) No (n 406) p Value Age, yrs Male 321 (66) 58 (72) 263 (65) 0.24 Risk factors Hypertension 282 (58) 54 (67) 228 (56) 0.08 Hyperlipidemia 192 (39) 35 (43) 157 (39) 0.45 Diabetes mellitus 77 (16) 13 (16) 64 (16) 0.95 Current smoking 127 (26) 26 (32) 101 (25) 0.18 History of smoking 154 (32) 24 (30) 130 (32) 0.67 History Coronary artery disease 166 (34) 27 (33) 139 (34) 0.88 Previous myocardial infarction 117 (24) 20 (25) 97 (24) 0.88 Previous revascularization 131 (27) 18 (22) 113 (28) 0.30 Peripheral artery disease 33 (7) 5 (6.2) 28 (6.9) 0.81 Previous stroke 36 (7) 8 (9.9) 28 (6.9) 0.35 Vital status Heart rate, beats/min Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Primary electrocardiographic findings Left bundle branch block 13 (2.7) 4 (4.9) 9 (2.2) 0.17 ST-segment elevation 39 (8.0) 29 (36) 10 (2.5) ST-segment depression 42 (8.6) 12 (15) 30 (7.4) 0.03 T-wave inversion 36 (7.4) 13 (16) 23 (5.7) No significant electrocardiographic abnormalities 357 (73) 23 (28) 334 (82) Laboratory assessment Estimated glomerular filtration rate, ml/min/1.73 m Management of patients Outpatients 229 (47) 2 (2.5) 227 (56) Values are presented as n (%) or mean SD.

4 JACC Vol. 54, No. 1, 2009 June 30, 2009:60 8 Reichlin et al. for the Rapid Rule Out of 63 tion 0.01 g/l and 2.2% above the decision limit for of 0.04 g/l. levels. As shown in Figure 1A, copeptin levels were significantly higher in patients with as compared with patients having other diagnoses (, median 20.8 pmol/l, IQR 7.9 to 60.6 pmol/l; unstable angina, median 7.4 pmol/l, IQR 4.0 to 12.3 pmol/l; cardiac symptoms of origin other than coronary artery disease, median 7.9 pmol/l, IQR 3.5 to 20.5 pmol/l, noncardiac symptoms, median 5.4 pmol/l, IQR 3.3 to 10.4 pmol/l; symptoms of unknown origin, median 7.8 pmol/l, IQR 4.2 to 13.0 pmol/l; p for all comparisons with patients). None of the other groups differed significantly from each other. levels differed significantly between patients with ST-segment elevation MI (median 45.5 pmol/l, IQR 21.0 to 123 pmol/l), non ST-segment elevation MI (median 11.7 pmol/l, IQR 6.2 to 50.8 pmol/l), and unstable angina (Fig. 1B). Among the 81 patients with, copeptin was significantly higher in patients with an initial troponin T level 0.01 g/l (median 75.9 pmol/l, IQR 26.0 to pmol/l) than in patients with a troponin T level 0.01 g/l (median 11.7 pmol/l, IQR 6.2 to 45.5 pmol/l; p 0.001). Furthermore, in patients with, there was a significant inverse correlation between copeptin and the time since onset of symptoms (r 0.44, p 0.001), whereas troponin T was positively correlated with the time since onset of symptoms (r 0.51, p 0.001). If patients with were divided into groups according to the time since onset of symptoms, copeptin levels at admission were highest in the group of patients presenting 0 to 4 h after onset of symptoms (median 52.5 pmol/l, IQR 13.6 to pmol/l) with a falling pattern thereafter (5 to 10 h, median 30.8 pmol/l, IQR 12.2 to 69.4 pmol/l; 10 h, median 9.9 pmol/l, IQR 5.4 to 25.5 pmol/l; p 0.001). Troponin T levels were lowest in patients presenting earliest and rising with increasing time since onset of symptoms (0 to 4 h, median 0.01 g/l, IQR 0.01 to 0.08 g/l; 5 to 10 h, median 0.11 g/l, IQR 0.02 to 0.38 g/l; 10 h, median 0.18 g/l, IQR 0.06 to 0.61 g/l; p 0.001) (Fig. 2). The distribution of several baseline characteristics across copeptin quartiles are shown in Table 2. Patients in the different quartiles of copeptin were comparable regarding most baseline characteristics, including history of coronary artery disease and history of MI. Patients in the highest quartile were older, more often male, and more often had hypertension, a higher body mass index, and a worse renal function. In a subgroup of 25 patients with diagnostic uncertainty until 6 h after presentation, serial sampling was performed. kinetics in the subgroup of 25 patients were analyzed and compared to a group of 83 patients with noncardiac symptoms, in whom samples were available at presentation, after 3 h, and after 6 h as well ( median copeptin values were 14.1 pmol/l at presentation, 7.7 pmol/l at 3 h, and 11.0 pmol/l at 6 h; vs. those of noncardiac patients: 5.6 pmol/l at presentation, 5.1 pmol/l at 3 h, and 5.4 pmol/l at 6 h). Figure 3 describes levels of copeptin according to ECG findings and troponin T status at presentation. If troponin T was 0.01 g/l at presentation, copeptin was significantly higher in patients with than in patients with other diagnoses, regardless of presence or absence and type A 200 B Unstable Angina Cardiac but not CAD 0 Non-cardiac unknown STEMI NSTEMI Unstable Angina Figure 1 Levels at Presentation levels at presentation to the emergency department (A) in all patients according to adjudicated final diagnosis and (B) in patients with acute coronary syndrome only. Boxes represent interquartile ranges and whiskers display ranges (without outliers further than 1.5 interquartile ranges from the end of the box). acute myocardial infarction; CAD coronary artery disease; NSTEMI non ST-segment elevation myocardial infarction; STEMI ST-segment elevation myocardial infarction.

5 64 Reichlin et al. JACC Vol. 54, No. 1, 2009 for the Rapid Rule Out of June 30, 2009:60 8 Figure 2 and Troponin T Levels at Presentation in Relation to Time Since Onset of Symptoms Median levels of copeptin (blue bars) and troponin T (green bars) at presentation to the emergency department in patients with the adjudicated final diagnosis of acute myocardial infarction according to the time since onset of symptoms. of ECG abnormalities (p for groups with no significant ECG abnormalities and ST-segment elevation/ left bundle branch block not known to be old; p for group with ST-segment depression/t-wave inversion). However, if patients presented late after onset of symptoms and troponin T was 0.01 g/l already at presentation, no significant differences in copeptin levels were observed between patients with and without. Incremental diagnostic value of copeptin. The diagnostic accuracy of troponin T at presentation in the diagnosis of as quantified by the area under the ROC curve (AUC) was 0.86 (95% confidence interval [CI]: 0.80 to 0.92), which was significantly higher than the diagnostic accuracy of copeptin at presentation (AUC 0.75; 95% CI: 0.69 to 0.81; p 0.009) (Fig. 4). However, the combination of the 2 markers significantly increased the diagnostic accuracy provided by troponin T alone, with an AUC of 0.97 (95% CI: 0.95 to 0.98; p 0.001) for the combination of troponin T and copeptin. In contrast, the combination of troponin T with either the MB fraction of creatine kinase or myoglobin did not result in a significantly higher diagnostic accuracy as compared with troponin T alone. After adjusting for the variables with significant imbalances across copeptin quartiles, troponin T and copeptin invariably remained highly significant predictors of (for both biomarkers, p 0.001), whereas no other variable reached significance. If patients with ST-segment elevation MI who are in general triaged on the basis of symptoms and ECG rather than on initial biomarkers were excluded from the analysis, the combination of troponin T and copeptin yielded very similar diagnostic accuracy, as observed in the whole study population (AUC 0.96, 95% CI: 0.94 to 0.98). Rapid rule out of using troponin T and copeptin. Table 3 summarizes the diagnostic performance of various copeptin levels used in conjunction with a troponin T level 0.01 g/l at presentation. A copeptin level 14 pmol/l in combination with a troponin T level 0.01 g/l would have correctly ruled out at presentation with a sensitivity of 98.8%, a negative predictive value of 99.7%, a specificity of 77.1%, and a positive predictive value of 46.2%. In other Baseline Characteristics of the Patients in Relation to Quartiles Table 2 Baseline Characteristics of the Patients in Relation to Quartiles Characteristic Quartile 1 <3.8 pmol/l (n 122) Quartile pmol/l (n 122) Quartile pmol/l (n 122) Quartile 4 >14.9 pmol/l (n 121) p Value Age, yrs Male 61 (50) 83 (68) 96 (79) 81 (67) Risk factors Hypertension 65 (53) 61 (50) 70 (57) 86 (71) Hyperlipidemia 44 (36) 53 (43) 44 (36) 51 (42) Diabetes mellitus 15 (12) 18 (15) 18 (15) 26 (22) Current smoking 33 (27) 37 (30) 25 (21) 32 (26) History of smoking 29 (24) 39 (32) 48 (39) 38 (31) History Coronary artery disease 36 (30) 40 (33) 40 (33) 50 (41) Previous myocardial infarction 24 (20) 27 (22) 29 (24) 37 (31) Previous revascularization 29 (24) 33 (27) 33 (27) 36 (30) Peripheral artery disease 6 (5) 5 (4) 6 (5) 16 (13) Previous stroke 9 (7) 6 (5) 5 (4) 16 (13) Time from onset of symptoms (range) 10 (3 30) 11 (3 72) 12 (3 39) 7 (3 18) Body mass index, kg/m 2 (range) 24.7 ( ) 26.1 ( ) 26.5 ( ) 27.4 ( ) Estimated glomerular filtration rate, ml/min/1.73 m 2 (range) 104 (87 119) 100 (82 114) 96 (80 114) 73 (52 100) Values are presented as n (%) or mean SD unless otherwise indicated.

6 JACC Vol. 54, No. 1, 2009 June 30, 2009:60 8 Reichlin et al. for the Rapid Rule Out of Patients with symptoms suggestive of No significant ECG abnormalities n=362 ECG Significant ECG abnormalities n=125 ST-Elevation/ LBBB not known to be old n=47 ST-Depression/ T-Inversion n=78 Troponin T Troponin T Troponin T > 0.01 µg/l n= µg/l n=329 > 0.01 µg/l n= µg/l n=23 > 0.01 µg/l n= µg/l n=50 n=18 9 (5-15) n=15 28 (8-64) n=5 61 (37-103) Minimum 20.8 n=324 6 (3-11) n=23 26 (11-57) n= n= (91-371) Minimum 15.7 n=13 7 (4-25) n=20 9 (4-33) n=8 34 (5-177) n=5 24 (12-43) Minimum 9.08 n=45 7 (3-14) P<0.001 P<0.001 P<0.016 Figure 3 Levels According to Admission ECG and Troponin T Status at Presentation values are presented, in pmol/l, as median (interquartile range). acute myocardial infarction; ECG electrocardiography; LBBB left bundle branch block. words, would have correctly been excluded at admission with only 1 laboratory assessment in 316 of 487 patients (65% of the entire study cohort). Of the remaining one-third of patients with positive results for either copeptin or troponin T or both, roughly one-half of patients finally received the diagnosis of. Discussion This prospective study involving unselected patients presenting to the ED with symptoms suggestive of examined the value of a dual marker strategy using troponin T, a marker of cardiac necrosis, and copeptin, a marker of endogenous stress, for rapid rule out of. We report 4 major findings: First, copeptin levels were significantly higher in patients with than in patients with other adjudicated diagnoses. Second, copeptin was significantly higher in patients with presenting early to the ED and still negative for troponin T. Conversely, copeptin provided no additional information in late presenters who were already positive for troponin T at admission. Third, the combination of troponin T and copeptin resulted in a very high diagnostic accuracy in the diagnosis of already at presentation (AUC 0.97). Fourth, an algorithm based on the combination of troponin T and copeptin ruled out at presentation with a sensitivity of 98.8% and a negative predictive value of 99.7%. Accordingly, continuous ECG monitoring and serial blood sampling, today needed in all patients to rule out, could be limited to the one-third of patients positive for either troponin T ( 0.01 g/l) or copeptin ( 14 pmol/l), whereas these resources would no longer be required for patients negative for both markers (nearly two-thirds of patients in our cohort). These findings have important clinical implications. The rapid and reliable exclusion of in patients presenting with chest pain is one of the large unmet needs in clinical medicine. Because of the delayed increase in troponins and normal or unspecific ECG findings, 10 million patients worldwide require prolonged monitoring and serial blood sampling each year before can safely be excluded. The additional costs associated with the remaining diagnostic uncertainty after the first troponin measurement are estimated to exceed several billion U.S. dollars each year (11,12). Thus, the improvement in the early rule out of offered by copeptin testing may have the potential to improve allocation of resources in the ED and to markedly reduce total treatment cost (24). Acute MI could be rapidly and reliably ruled out at admission in two-thirds of patients, and only the remaining one-third of patients (instead of all patients) would need monitoring and serial blood sampling, with roughly one-half of them (positive predictive value 46%) finally suffering from.

7 66 Reichlin et al. JACC Vol. 54, No. 1, 2009 for the Rapid Rule Out of June 30, 2009:60 8 Figure 4 ROC Curves at Presentation for the Diagnosis of Area under the receiver-operator characteristic (ROC) curves for troponin T (blue line) and copeptin (green line) at presentation, and the combination (red line) of both markers in the diagnosis of acute myocardial infarction (). Cardiac troponins currently are the biomarker of choice for the serologic diagnosis of (3,25). Our results confirm the delay of several hours between onset of symptoms and rise of troponin in observed in previous studies (4,10). In this study, 25% of patients with initially presented with a troponin T level 0.01 g/l. This rate was identical to that observed with a contemporary troponin I assay in a recent study (4). In addition, the AUC for at presentation was 0.86 in a prospective study using a novel sensitive troponin I assay, which is equal to the AUC of troponin T in our study (26). It is unknown whether the development of even more sensitive troponin assays will improve the utility of troponin to rapidly rule out, without resulting in a significant increase in false positive test results (27). Our data suggest that a dual marker strategy combining troponin T and copeptin benefits from the integration of complementary information provided by pathophysiologically different processes: troponin T for the detection and quantification of myocardial necrosis, and copeptin for the quantification of endogenous stress. It is important to note that despite extensive research with markers representing various pathophysiological pathways including inflammation, platelet activation, and ischemia, none of the markers previously assessed was able to consistently show incremental value in the early rule out of when used in combination with troponins (28 32). Clinical research of the arginine-vasopressin system was impaired until very recently by the instability of the active peptide. The introduction of a novel immunoassay measuring copeptin, the c-terminal part of the vasopressin prohormone, provided a unique window into the role of this system in common medical disorders (18). Research by our group and has suggested that copeptin and therefore the vasopressin system is a major determinant of outcome in patients with community-acquired pneumonia, exacerbated chronic obstructive pulmonary disease, sepsis, and (19,33 35). A recent study furthermore showed a correlation between copeptin and the individual stress level (36). Our findings suggest that endogenous stress occurring with the onset of results in a rapid release of vasopressin and copeptin. It is unknown whether vasopressin/copeptin secretion merely reflects the acute endogenous stress reaction associated with (13) or has additional pathophysiological beneficial effects, for example, on coronary artery blood flow (37). With increasing time after onset of symptoms, we observed decreasing levels of copeptin, in contrast to increasing levels of troponin T. The fall in copeptin levels may reflect a mechanism of adaptation by the endogenous stress system facing a continuous stress such as or may be the consequence of the resolution or at least reduction of chest pain after the onset of, or both. This extends and corroborates recent findings in 132 patients with and blood sampling for 5 days after diagnosis of, showing a copeptin peak with similar levels on day 1 and falling levels thereafter, until reaching a plateau by day 3 to 5 (19). In contrast to patients with, patients with unstable angina had similar copeptin levels as did patients with other causes of chest pain. These data suggest that induces a higher level of endogenous stress than unstable angina does, potentially related at least in part to the more prolonged course of chest pain in patients with. Ischemia, as long as not accompanied by necrosis (i.e., unstable angina), does not seem to be a stronger trigger of copeptin release than are other causes of chest pain. This finding is well in agreement with a recent study showing comparable increases in copeptin levels during exercise in patients with or without exercise-induced ischemia (38). at Presentation Value Used to Rule With OutTroponin Acute Myocardial T <0.01 g/l Infarction Value Used With Troponin T <0.01 g/l Table 3 at Presentation to Rule Out Acute Myocardial Infarction Cutoff Level (pmol/l) Sensitivity (%) Specificity (%) Positive Predictive Value (%) Negative Predictive Value (%)

8 JACC Vol. 54, No. 1, 2009 June 30, 2009:60 8 Reichlin et al. for the Rapid Rule Out of 67 therefore cannot discriminate patients with unstable angina from patients with nonischemic chest pain. Study limitations. First, this is a single-center study. However, as patient demographics were comparable to several recent studies including consecutive patients with symptoms suggestive of (28 30,39), we consider our results representative for unselected patient cohorts presenting to the ED with suspected. Second, 81 patients with is a small number for an rule out claim, and confirmation by larger studies is warranted before copeptin can be adopted into clinical practice. Furthermore, longterm follow-up data would be valuable in future studies. Third, as a prospective observational study, we cannot quantify exactly the benefit regarding the allocation of resources in the ED and treatment cost associated with the more rapid exclusion of provided by the additional use of copeptin. Our hypothesis regarding the economic impact needs to be confirmed (or rejected) in a randomized controlled trial with time to discharge and treatment cost as pre-defined end points (24). Fourth, further studies, specifically addressing the ability of copeptin to assist with guiding therapy (e.g., invasive therapy) will be important. Conclusions seems to be an ideal partner for cardiac troponins for the rapid rule out of. The combination of copeptin and troponin significantly improved the diagnostic accuracy for at presentation as compared to troponin alone. Consequently, the additional use of copeptin may allow for a rapid and accurate rule out of and might obviate the need for prolonged monitoring and serial blood sampling in the ED for the majority of patients. This fundamental change in clinical practice may provide the opportunity to significantly improve patient management in the ED and to reduce treatment cost. Acknowledgments The authors are indebted to the patients who participated in the study, to the emergency department staff and the laboratory technicians for their most valuable efforts, and to Dr. Christian Schindler for expert statistical advice. Reprint requests and correspondence: Prof. Dr. Christian Mueller, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, Basel CH-4031, Switzerland. chmueller@uhbs.ch. REFERENCES 1. Nawar EW, Niska RW, Xu J. National Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. Adv Data 2007; 386: Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50: Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36: Macrae AR, Kavsak PA, Lustig V, et al. Assessing the requirement for the 6-hour interval between specimens in the American Heart Association classification of myocardial infarction in epidemiology and clinical research studies. Clin Chem 2006;52: Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/ non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/ Non ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2007;50:e Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2008;51: Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342: Peacock WF. Will SCUBE1 solve the ischemia marker deficit? J Am Coll Cardiol 2008;51: Speake D, Terry P. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. First ECG in chest pain. Emerg Med J 2001;18: Melanson SE, Morrow DA, Jarolim P. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol 2007;128: Polanczyk CA, Kuntz KM, Sacks DB, Johnson PA, Lee TH. Emergency department triage strategies for acute chest pain using creatine kinase-mb and troponin I assays: a cost-effectiveness analysis. Ann Intern Med 1999;131: Forberg JL, Henriksen LS, Edenbrandt L, Ekelund U. Direct hospital costs of chest pain patients attending the emergency department: a retrospective study. BMC Emerg Med 2006;6: Itoi K, Jiang YQ, Iwasaki Y, Watson SJ. Regulatory mechanisms of corticotropin-releasing hormone and vasopressin gene expression in the hypothalamus. J Neuroendocrinol 2004;16: Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005;46: Jochberger S, Mayr VD, Luckner G, et al. Serum vasopressin concentrations in critically ill patients. Crit Care Med 2006;34: Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973;52: Preibisz JJ, Sealey JE, Laragh JH, Cody RJ, Weksler BB. Plasma and platelet vasopressin in essential hypertension and congestive heart failure. Hypertension 1983;5:I Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 2006;52: Khan SQ, Dhillon OS, O Brien RJ, et al. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation 2007;115: Apple FS, Jesse RL, Newby LK, Wu AH, Christenson RH. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes. Circulation 2007;115:e Apple FS, Wu AH, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J 2002;144: Levey AS. Clinical practice. Nondiabetic kidney disease. N Engl J Med 2002;347: DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:

9 68 Reichlin et al. JACC Vol. 54, No. 1, 2009 for the Rapid Rule Out of June 30, 2009: Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350: Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116: Apple FS, Smith SW, Pearce LA, Ler R, Murakami MM. Use of the Centaur TnI-Ultra assay for detection of myocardial infarction and adverse events in patients presenting with symptoms suggestive of acute coronary syndrome. Clin Chem 2008;54: Jaffe AS. Chasing troponin: how low can you go if you can see the rise? J Am Coll Cardiol 2006;48: Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349: Heeschen C, Dimmeler S, Fichtlscherer S, et al. Prognostic value of placental growth factor in patients with acute chest pain. JAMA 2004;291: Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348: Anwaruddin S, Januzzi JL Jr., Baggish AL, Lewandrowski EL, Lewandrowski KB. Ischemia-modified albumin improves the usefulness of standard cardiac biomarkers for the diagnosis of myocardial ischemia in the emergency department setting. Am J Clin Pathol 2005;123: Staub D, Nusbaumer C, Zellweger MJ, et al. Use of B-type natriuretic peptide in the detection of myocardial ischemia. Am Heart J 2006; 151: Muller B, Morgenthaler N, Stolz D, et al. Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections. Eur J Clin Invest 2007;37: Stolz D, Christ-Crain M, Morgenthaler NG, et al., C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD. Chest 2007;131: Morgenthaler NG, Muller B, Struck J, Bergmann A, Redl H, Christ-Crain M., a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. Shock 2007; 28: Katan M, Morgenthaler N, Widmer I, et al., a stable peptide derived from the vasopressin precursor, correlates with the individual stress level. Neuro Endocrinol Lett 2008;29: Holmes CL, Landry DW, Granton JT. Science review: vasopressin and the cardiovascular system part 2: clinical physiology. Crit Care 2004;8: Staub D, Morgenthaler NG, Buser C, et al. Use of copeptin in the detection of myocardial ischemia. Clin Chim Acta 2009;399: Bassan R, Potsch A, Maisel A, et al. B-type natriuretic peptide: a novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation. Eur Heart J 2005;26: Key Words: copeptin y rule out y acute myocardial infarction y troponin.