Hrev_master [Emergency Care Journal 2013; 9:e14] [page 39] Proposal for the use in emergency departments of cardiac troponins measured with the latest generation methods in patients with suspected acute coronary syndrome without persistent ST-segment elevation Ivo Casagranda,1 Mario Cavazza,2 Aldo Clerico,3 Marcello Galvani,4 Filippo Ottani,2 Martina Zaninotto,5 Luigi M. Biasucci,6 Gianfranco Cervellin,7 Tiziano Lenzi,8 Giuseppe Lippi,9 Mario Plebani,10 Marco Tubaro11 1Emergency Department, Santi Antonio e Biagio e Cesare Arrigo Hospital, Alessandria; 2Emergency Department, S. Orsola-Malpighi Hospital, Bologna; 3Life Science Institution, S. Anna School, Pisa; 4Emergency Department, Morgagni- Pierantoni Hospital, Forlì; 5Department of Laboratory Medicine, University of Padua; 6Department of Cardiovascular Medicine, Sacro Cuore Catholic University, Rome; 7Emergency Department, University Hospital of Parma; 8Emergency Department, Santa Maria della Scaletta Civil Hospital, Imola; 9Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma; 10Department of Laboratory Medicine, Padua University Hospital; 11Cardiovascular Department, San Filippo Neri Hospital, Rome, Italy Abstract The purpose of this document is to develop recommendations on the use of the latest gen- eration of cardiac troponins in emergency room settings for the diagnosis of myocardial infarction in patients with suspected acute coronary syndrome without persistent ST-seg- ment elevation (NSTE-ACS). The main points which have been addressed reaching a consen- sus are: i) suitability and appropriateness of the terminology; ii) appropriateness of the request; iii) confirmation of the diagnosis of myocardial infarction (rule-in); iv) exclusion of the diagnosis of myocardial infarction (rule- out). Each point has been analyzed by taking into account the evidence presented in med- ical publications. Recommendations were developed using the criteria adopted by the European Society of Cardiology and the American Heart Association/American College of Cardiology. Each point of the recommenda- tion was submitted for validation to an exter- nal audit by a Group of Experts (named above). Suitability and appropriate- ness of the terminology Definition of high sensitivity cardiac troponin assay At the beginning of the new century, an international consensus document1,2 pointed out the prominent role of cardiac troponins I (cTnI) or T (cTnT) for the diagnosis of acute myocardial infarction (AMI). These sugges- tions have further developed in the subsequent decade,2,3 reaching the strength of a Universal Definition of Myocardial Infarction. According to these recommendations, the diagnosis of AMI is based on detecting the variation of cardiac troponin values with a typ- ical rise and falling pattern in patients with clinical suspicion of myocardial ischemia.2,3 This approach is also confirmed in the latest Universal Definition of Myocardial Infarction,2 which recommends, as a decision level for the diagnosis of AMI, that cTnI and cTnT eleva- tions are defined as concentrations greater than the 99th percentile of distribution values measured in a reference population consisting of apparently healthy individuals free from heart disease. The same guidelines recom- mend that such a decision level must be meas- ured with imprecision less than or equal to 10% [coefficient of variation (CV)]. These quality specifications for the determination of cardiac troponins were initially confirmed by a task force from the National Academy of Clinical Biochemistry (NACB) and the International Federation of Clinical Chemistry and laboratory Medicine (IFCC) committee for standardization of markers of cardiac damage laboratory medicine, and more recently by an interdisciplinary study group organized by the European Society of Cardiology (ESC).3,4 At the time of publication of the first con- sensus document,1 the recommended quality specifications were not satisfied by commer- cially available methods for the measurement of cTnI and cTnT.5,6 Only recently, in fact, some methods for cardiac troponin assay, character- ized by an improved analytical sensitivity (i.e. high-sensitivity assay), entered the market- place.6 It is noteworthy that only those immunometric techniques which are able to measure the 99th percentile of the distribution of proteins cTnI and cTnT in the reference pop- ulation with an error (expressed as CV) equal to or lower than 10% – as currently required by international guidelines – are defined as newer high-sensitivity methods for measuring cardiac troponins cTnI and cTnT.1-4 These assays should also be able to measure the lev- els of cTnI and cTnT in most (i.e. no less than 75%) adult subjects in apparent good health. In accordance with a recent article by Apple,7 one should classify the sensitivity of the latest gen- eration methods into four levels, depending on the proportion of apparently healthy subjects in which it is possible to measure the analyte concentrations (Table 1). As such, only meth- ods that measure cTnI and cTnT concentra- tions in most (i.e. >75%) healthy subjects should be defined as high-sensitivity. The denomination of ultra-sensitive methods should therefore be abandoned, because there is no reliable analytical basis to support the use of this term. The study group of the ESC4 has recently concluded that the reference population on which to calculate the 99th percentile of the dis- tribution of cTnI and cTnT values should con- sist of at least 300 apparently healthy subjects of both genders and distributed according to a broad age distribution. In addition, these sub- jects should result negative in a stress test and possess cardiac function within normal limits, as assessed by means of cardiac imaging. Unfortunately, these recommendations are difficult to implement at the local level by indi- vidual laboratories, principally because of the difficulty in recruiting a carefully selected wide target population. Individual laboratories may Emergency Care Journal; volume 9:e14 Correspondence: Ivo Casagranda, Emergency Department, Santi Antonio e Biagio e Cesare Arrigo Hospital, via Venezia 16, 15100 Alessandria, Italy. Tel./Fax: +39.0131.206224. E-mail: casagranda@libero.it Key words: acute coronary syndrome, cardiac tro- ponin, emergency department, high-sensitivity assays, non-ST- segment elevation. Note: this paper is also published in Clin Chem Lab Med 2013;51:1727-1737. DOI 10.1515/cclm- 2013-0423 with permission of Walter de Gruyter Publication. Contributions: the authors contributed equally. Conflict of interests: the authors declare no potential conflict of interests. Received for publication: 1 March 2013. Accepted for publication: 8 March 2013. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright I. Casagranda et al., 2013 Licensee PAGEPress, Italy Emergency Care Journal 2013; 9:e14 doi:10.4081/ecj.2013.e14 Non -co mmerc ial us e o nly [page 40] [Emergency Care Journal 2013; 9:e14] adopt as reference values those suggested by manufacturers or reported by recent scientific papers with the same technique, and which have been determined on a suitable number of healthy adults.6-14 However, it is well known that the concentrations of cTnI and cTnT are higher in males than in women of the same age, and tend to increase progressively over 60 years.6-14 It follows that the calculated value of the 99th percentile varies considerably depend- ing on the demographic characteristics of the reference population considered.6 It is also noteworthy that the average age of the refer- ence population on which the 99th percentile was calculated ranged from 37 to 59 years, according to some studies.12,14 By contrast, the average age of patients presenting to the emergency department with chest pain and suspected acute coronary syndrome can vary from 52 to 62 years, depending on the stud- ies,15-17 and in clinical practice, it may be even higher. A Canadian study investigated the age of 54,134 patients who presented to the emer- gency department with chest pain and/or sus- picion of acute coronary syndrome between 1998 and 2001. The study reported that patients with unstable angina or AMI had a higher average age of some 10-15 years com- pared to those without acute ischemic cardiac complications.18 Importantly, cTnI is measured by various methods, distributed by different manufactur- ers, and therefore the measured levels vary considerably (even more than 20 times) from method to method, as well as the reference val- ues.5 By contrast, cTnT is currently being measured by the same analytical procedure, and thereby presents practically the same val- ues and the same reference limits, even using different automated platforms. Table 2 shows some analytical characteristics and 99th per- centile values of the reference population of some cTnI and cTnT methods. Unfortunately, there are conflicting results in the literature concerning the analytical characteristics of cTnI methods.8-10 These differences are due both to different experimental protocols used for the calculation of the limit of detection (LOD) and limit of quantitation (LOQ) values, and to different versions of evaluated methods (for example prototype instead of commercial- ly available version).5,6,8-10,19 In Table 2, only the analytical characteristics of cTnI methods cur- rently most diffuse and commercially available in Italy are reported. Since cTnT and cTnI are different molecules, results are not inter- changeable, nor directly comparable.20 The high degree of analytical sensitivity of newer methods also allows the evaluation of the biological variation of circulating levels of cTnI and cTnT in healthy subjects21 or patients with cardiomyopathy.22 As a result, it is possi- ble to calculate the reference change value (RCV), which is related to both biological vari- ation and analytical imprecision. For many analytical methods, the RCV values vary in a range from 40-60% up to 86%. It is very likely that in presence of minor variations of cTnI and cTnT (e.g. 20% at concentration below the reference range), it is possible to rule out an acute event. In cases of strong clinical suspi- cion or high pre-test probability it is recom- mended, under these conditions that the test should be repeated after a few hours (typically between 3 and 4 h).4 Recommendations One should define as latest generation methods for determining troponins cTnI and cTnT only those immunometric assays that measure the 99th percentile of the distribution of proteins cTnI and cTnT in the reference pop- ulation with an error (expressed as CV) equal to or lower than 10%, as required by interna- tional guidelines.1-4 Latest generation methods showing an intermediate imprecision (10- 20%) should be considered clinically usable. One should define as latest generation methods of high sensitivity only those methods that measure the levels of cTnI and cTnT in the majority of apparently healthy adults who com- pose the population of normal reference range. The reference population on which the 99th percentile of the distribution of the values of cTnI and cTnT is calculated should consist of at least 300 apparently healthy subjects of both genders, and be based on a broad age distribu- tion.4 This reference population should also have demographic characteristics as similar as possible to patients who present to the emer- gency department with chest pain and suspect- ed acute coronary syndrome. Appropriateness of the troponin test request The advent of biomarkers assessment in the Opinion Report Table 1. Classification of methods with high sensitivity for the detection of cardiac tro- ponins I and T. Level score Measurable normal values below the 99th percentile (%) 1 (Contemporary) <50 2 (First generation, hs) 50 to <75 3 (Second generation, hs) 75 to <95 4 (Third generation, hs) ≥95 hs, high-sensitivity (according to Apple7). Table 2. Limit of detection, limit of quantitation at 10% coefficient of variation, and 99th percentile of widely diffuse cardiac troponins I and T methods commercially available in Italy. Methods LoD LoQ 99th Reference (ng/L) (ng/L) Percentile values (ng/L) cTnI Access AccuTnI Beckman 10 60 40 9 (Beckman Coulter, Brea, CA, USA) ADVIA TnI Ultra Siemens 6 57 72 8 (Siemens, Munich, Germany) AIA-PACK 3rd Gen Tosoh 8 100 33 10 (Tosoh Corp., Tokyo, Japan) ARCHITECT Abbott 9 32 28 9 (Abbott Laboratories, Abbott Park, IL, USA) Dimension RxL Siemens (Siemens) 40 140 70 9 Pathfast Mitsubishi 8 14 29 9 (Mitsubishi Chemical Medience Corp., Tokyo, Japan) Stratus CS Siemens (Siemens) 30 60 70 9 Vidas Ultra bioMérieux 10 110 20 9 (bioMérieux SA, Marcy l'Etoile, France) Dimension Vista Siemens (Siemens) 15 40 45 9 cTnT Roche Elecsys TnT hs (Roche Diagnostics, Basel, Switzerland) 5 13 14 9 LoD, limit of detection; LoQ, limit of quantitation (functional sensitivity) at 10% CV level; CV, coefficient of variation; cTnI, cardiac troponins I; cTnT, cardiac troponins T; hs, high-sensitivity. Non -co mmerc ial us e o nly [Emergency Care Journal 2013; 9:e14] [page 41] context of diagnosis of chest pain has provided emergency physicians with an important tool to quickly identify patients with suspected acute coronary syndrome. The recent introduc- tion of new methods for assessment of bio- markers of myocardial necrosis, in particular the latest generation of cardiac troponins, has allowed the identification of increasingly large areas of biochemistry positivity, that is not always securely attributable to the context of myocardial ischemia. The increased sensitivi- ty of the test, in fact, inevitably causes a lower specificity for ischemic damage. Therefore, it is increasingly common to detect a value exceeding the upper reference limit (99th percentile) of the latest generation troponins that is not necessarily ischemic in origin. These troponins have, in fact, a high specificity for myocardial injury but not for AMI (low positive predictive value). For this reason, it is essential that the emergency physician has broad awareness about the diag- nostic maze of chest pain, using the markers appropriately. The diagnosis of AMI in patients with nor- mal or non-diagnostic electrocardiogram (ECG) [generally referred to as non-ST eleva- tion myocardial infarction (NSTEMI)], should be based on the correct interpretation of the values of cTn, in particular its release kinetics, distinguishing myocardial damage caused by myocardial ischemia from myocardial injury caused by other factors. Evidence to support this possibility is still somewhat preliminary so far.23 The evaluation of chest pain patients with a non-diagnostic ECG in the emergency depart- ment is a dynamic and articulate process, where the use of marker should be targeted and guided especially as to the probability (i.e. likelihood) of disease.24 To avoid excessive use of this biomarker, it should be measured only in patients with chest pain who have a pre-test probability, even low, of suffering from myocar- dial infarction.25 It is necessary to systemati- cally correlate symptoms, clinical presentation and likelihood of disease.25-27 In particular, it is suggested to investigate all those patients with at least one risk factor of coronary artery dis- ease (CAD), even when associated with atypi- cal chest pain and those patients with no risk factors for CAD but with typical chest pain. Many patients, however, present with symp- toms other than chest pain (atypical presenta- tion), such as isolated dyspnea, transient pal- pitations, sudden fatigue, nausea/vomiting, diaphoresis, an acute confused state and syn- cope.28-32 In the study by Canto et al.,33 the vari- ables associated with a presentation charac- terized by the absence of chest pain were: his- tory of heart failure or stroke, older age (>75 years), diabetes mellitus, female gender and race other than white. In this study, only 17% of AMI patients without these risk factors had no chest pain at presentation; however, patients with at least three risk factors had a 50% or greater chance of not having chest pain at presentation. Patients with AMI and atypical presentation – with the exception of those with diaphoresis – are at high risk of death. The isolated dyspnea, particularly in diabetic patients and in the elderly, may be the only pre- senting symptom in the course of an acute coronary syndrome which is worsened by its high mortality rate.33,34 The appearance of pal- pitations, in particular from ventricular arrhythmia, has been linked by some authors with a manifestation of myocardial ischemia in the elderly population.35 Sudden fatigue can be a symptom that precedes or accompanies AMI in the absence of chest pain, particularly in diabetic patients.36-38 A syncope onset with- out prodromes should be considered suspect inasmuch as the cause may be the onset of ventricular arrhythmia following acute coro- nary ischemia.39 Due to the aforementioned reasons, a call to standardize symptom presen- tation in acute coronary syndromes has recent- ly been advocated. As such, rather than accept- ing descriptions as typical or atypical symp- toms, it is now considered imperative to eluci- date the entire ACS symptom complex.40 It is therefore appropriate to test troponin in patients presenting in the emergency depart- ment for ongoing or previous chest pain (regardless of the a priori probability of coro- nary heart disease), but also in those who report atypical symptoms in the presence of the high-risk conditions already mentioned (associated or not with electrocardiographic abnormalities). These patients are at high risk in cases where the diagnosis of myocardial infarction is confirmed. It is inevitable that this approach emphasizes the sensitivity of the diagnosis with respect to the specificity, with possible implications of increased workload and operating costs. Recommendations The measurement of cardiac troponins should be requested in patients presenting to the emergency department with ongoing or previous chest pain. The measurement of troponins should be considered in patients without chest pain, but who have one of the following symptoms con- sidered equivalent to angina: sudden onset isolated dyspnoea, diaphoresis, palpitations, nausea/vomiting, sudden fatigue, an acute confused state or syncope. These symptoms arise the suspicion of acute coronary syn- drome. In case of the symptoms just listed, the measurement of troponins should be request- ed in patients with at least one of the following conditions: previous stroke, previous heart failure, advanced age (>75 years) diabetes mellitus, female gender. The assessment of troponins measured with the latest generation assay (characterized by improved diagnostic sensitivity) makes it inappropriate and virtually useless the contex- tual request of additional biochemical markers of myocardial ischemia and/or injury [e.g. myo- globin, creatine kinase MB (CK-MB), and oth- ers].41 Biochemical confirmation of the diagnosis of myocardial infarction (rule-in) The introduction in the market of new methods, with improved analytical sensitivity41 requires the redefinition of the diagnostic approach of suspected NSTE-ACS in terms of application of the biochemical algorithms used so far. Currently, we know that an increase above the cut-off in patients without typical ECG-changes, implies the same prognosis as overt STEMI. On the other hand, the optimal timing of coronary intervention for NSTEMI is still under debate. However, NSTEMI will change considerably with these new troponins assays and further interventions studies should be performed. The most discussed aspects in the applica- tion of these improved analytical methods in clinical practice mainly concern: i) the time of blood sampling; ii) the cut-off concentrations used for the diagnosis of AMI; iii) the amount of changes of troponin concentrations found in consecutive samples necessary to make the diagnosis of AMI. In this regard, some observations are need- ed. First, the improved analytical sensitivity allows accurate measurement of protein con- centrations nearly 5 to 20 times lower than those measured using previous generation methods. Accordingly, the concentrations measured upon admission may already be sug- gestive of myocardial infarction in a signifi- cantly larger percentage of patients. In addi- tion, it can be expected that troponin concen- trations change very rapidly within shorter time intervals.41,42 Second, the availability of methods able to measure the protein concentrations in a popu- lation of healthy subjects implies a decision making level (cut-off) corresponding to the 99th percentile. Third, there are several, not necessarily ischemic, clinical conditions (Table 3),43 asso- ciated with increased troponin concentrations, and which make it necessary a differential clinical and biochemical diagnosis, based on the evaluation of the kinetics of release and/or extent of increase. Opinion Report Non -co mmerc ial us e o nly [page 42] [Emergency Care Journal 2013; 9:e14] Recommendations Based on analytical considerations and tro- ponin concentration on admission (baseline sampling T0) in the clinical context of chest pain, the following diagnostic algorithms may be recommended44,45 (Figures 1 and 2). First, troponin on admission (T0) at or above the 99th percentile: serial sampling at intervals of 3 h (T1, high-sensitivity methods) or 6 h (T1, latest generation methods). The blood sample at the 6th h may be optionally con- sidered for high sensitivity methods. Interpretation: the kinetics are suggestive of acute myocardial necrosis if the increase of concentration in the blood samples after 3/6 h (T1) is greater than or equal to 50% of the baseline value (T0). Second, troponin on admission (T0) at or below the 99th percentile: serial sampling at intervals of 3 h (T1, high-sensitivity metods) or 6 h (T1, latest generation methods). The blood sample at the 6th h may be optionally con- sidered for high sensitivity methods. Interpretation: the kinetics are suggestive of acute myocardial necrosis if the concentration in the blood sample after 3/6 h (T1) is greater than or equal to 99% percentile and the extent of the increase is greater than or equal to 50% of the baseline value (T0). Acute myocardial infarction should be diagnosed in patients showing concentration changes as described above, when associated with clinical context of myocardial ischemia (based on the symptoms and/or ECG changes and/or the finding of imaging techniques). The percentage of increase recommended above takes into account current analytical performance of most methods commercially available, which measure the concentration at the 99th per- centile with an imprecision of about 20%. The use of the RCV calculated from studies of biological variability, needs further confir- mation, because the published data are con- flicted and only available for some meth- ods.21,46,47 It has been proposed that the signifi- cance of the percentage increase may vary according to the baseline concentration: 20% for values equal or above the 99th percentile, 50% for baseline values below 99th percentile, and 10% for values significantly increased at the presentation.42,48-50 The choice of the 50% Opinion Report Table 3. Clinical conditions associated with increased troponin concentrations (adapted from: Thygesen et al.43). Injury related to primary myocardial ischemia Plaque rupture Intraluminal coronary artery thrombus formation Injury related to supply/demand imbalance of myocardial ischemia Tachy-/brady-arrhythmias Aortic dissection or severe aortic valve disease Hypertrophic cardiomyopathy Cardiogenic, hypovolemic, or septic shock Severe respiratory failure Severe anemia Hypertension with or without LVH Coronary spasm Coronary embolism or vasculitis Coronary endothelial dysfunction without significant CAD Injury not related to myocardial ischemia Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks Rhabdomyolysis with cardiac involvement Myocarditis Cardiotonic agents, e.g. anthracyclines, herceptin Multifactorial or indeterminate myocardial injury Heart failure Stress (Takotsubo) cardiomyopathy Severe pulmonary embolism or pulmonary hypertension Sepsis and critically ill patients Renal failure Severe acute neurological diseases, e.g. stroke, subarachnoid Hemorrhage Infiltrative diseases, e.g. amyloidosis, sarcoidosis Strenuous exercise LVH, left ventricular hypertrophy; CAD, coronary artery disease. Figure 1. Latest generation methods diagnosing myocardial infarction. Figure 2. High sensitivity methods diagnosing myocardial infarc- tion. Non -co mmerc ial us e o nly [Emergency Care Journal 2013; 9:e14] [page 43] variation compared to basal value (recommen- dations of the first two sections; Figures 1 and 2) should be considered to be the best compro- mise taking into account both the biological variation of troponins and the imprecision of the major part of the methods at present time commercially available in Italy. Of course, the use of 50% variation increases test specificity, but also decreases test sensitivity in respect to the use of a lower percent variation (such as 20%).42 As a result, in some specific clinical setting, the choice of a lower percent variation may be preferable. Recent studies51-56 have shown that the vari- ation in absolute value of the concentration of troponin, allows a more accurate diagnosis than the percentage change, especially for val- ues close to the 99th percentile. Nevertheless, since this variation is method-dependent, it is not possible to provide a concentration value applicable to all methods available on the mar- ket and the former approach is thereby prefer- able also for purposes of harmonization. Biochemical exclusion of myocardial infarction (rule- out) It is essential for the emergency physician to rapidly rule out AMI and to discharge the patient with reasonable safety, particularly in those cases where he/she may have presented with chest pain and normal or non-diagnostic ECG. As for the rule-in, it is essential to estab- lish the timing of assessment of serum tro- ponin value. In cases where the value of tro- ponin is normal in the established time inter- vals, the patient may be discharged with rea- sonable confidence if the probability of acute coronary syndrome – at the end of the observa- tion period – is sufficiently low (Table 4).57 In case of troponin elevation and in the presence of conditions associated with persistently increased values (e.g. renal failure), it is nec- essary to establish the percentage increment below which it is reasonable to conclude that myocardial damage is caused by a chronic rather than an acute condition and, possibly, that the variation is not attributable to myocar- dial necrosis secondary to an acute ischemic event. We suggest an observational period of no less than 6 h before discharging patients Opinion Report Table 4. Probability of acute coronary syndrome secondary to coronary artery disease based on signs and symptoms at presentation (adapted from: Braunwald et al.57). Feature History Examination ECG Cardiac markers Likelihood Low Probable ischemic symptoms without Chest discomfort T-wave flattening or inversion Normal any medium likelihood characteristics; in leads with dominant R waves recent drug use Medium Main symptom: Extracardiac Fixed Q waves; Normal chest or left arm pain or discomfort; vascular disease abnormal ST segments or old age; male sex; diabetes mellitus T waves not documented as new High Main symptom: chest or left arm Transient mitral regurgitation, New transient ST-segment Elevated cardiac pain or discomfort reproducing hypotension, diaphoresis, deviation or T-wave inversion TnI, TnT, or CK-MB previously documented angina; pulmoary edema, rales with symptoms previously documented coronary artery disease, including myocardial infarction ECG, electrocardiogram; TnI, troponins I; TnT, troponins T; CK-MB, creatine kinase MB. Figure 3. Latest generation methods diagnosing unlikely myocar- dial infarction. Figure 4. High sensitivity methods diagnosing unlikely myocar- dial infarction.Non -co mmerc ial us e o nly [page 44] [Emergency Care Journal 2013; 9:e14] safely, considering the first assessment (T0) at the admission to the emergency department.41 Discharge can be considered only for patients with low or intermediate probability of ACS (Table 4).57 For troponins measured by using the latest generation methods – not high sen- sitivity – in patients admitted to the emer- gency department, the following schedule can be proposed (Figure 3): i) the first determina- tion is the time of arrival in the emergency department (considered as T0); ii) the second determination is obtained after 6 h. In case of patients with low or intermediate probability/risk of disease, if after 6 h the con- centration of serum troponin does not exceed the 99th percentile or does not show a signifi- cant kinetic increment (<50%), the diagnosis of AMI is highly unlikely and the patient is at low risk of adverse events in short-term; per- sistently negative troponin concentrations during observation identify a low-risk popula- tion for which it is possible to assume a fairly safe rule-out of AMI if non-coronary acute car- diac conditions can be excluded. These patients may be discharged with an outpatient indication stress test within the shortest time. If troponins are measured using high sensi- tivity methods, the following schedule of blood samples can be recommended58 (Figure 4): i) the first determination is the time of arrival in the emergency department (considered as T0); ii) the second determination after 3 h. If after 3 h the concentration of hs-Tn does not exceed the 99th percentile, the diagnosis of AMI is unlikely41,48,58 and it is highly unlikely if the concentration of high-sensitivity tro- ponins (hs-Tns) remains constantly below the limits of analytical sensitivity (4.5). In cases where the increase of the concentration is less than the percentage increment considered sig- nificant (≥50% variation from baseline) for myocardial infarction and concentrations do not exceed the 99th percentile, a second blood sample is indicated at the sixth hour.45,48,59,60 If at this time point the value does not exceed the 99th percentile, patients can be classified as at low risk of adverse events and may be dis- charged with an outpatient indication stress test within a short time. Recommendations To rule out AMI, the assessment of troponin measured by the latest generation methods should be performed at time 0 (arrival in the emergency department) and after 6 h, if all the values observed are ≤99th percentile or the variation concentration is <50% (below the 99th percentile), the patient can be discharged. When using high sensitivity methods, it is recommended to assess troponin values at time 0 and after 3 h. When both values are below the limit of analytical sensitivity, the patient may be discharged. When both values are <99th percentile and the patient is at low or intermediate probability of ACS, the patient can be discharged if different acute cardiac conditions can be ruled out. Patients with recurrent symptoms and high probability of coronary heart disease should be kept under observation over 3-6 h, or until a final diagno- sis has been reached. References 1. Alpert JS, Thygesen K, Antman E, Bassand JP. 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