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Objective: Patients with suspected acute myocardial infarction (AMI) in the setting of left bundle branch block (LBBB) present an important diagnostic and therapeutic challenge to the clinician., Methods: We prospectively evaluated the incidence of AMI and diagnostic performance of specific ECG and high-sensitivity cardiac troponin (hs-cTn) criteria in patients presenting with chest discomfort to 26 emergency departments in three international, prospective, diagnostic studies. The final diagnosis of AMI was centrally adjudicated by two independent cardiologists according to the universal definition of myocardial infarction., Results: Among 8830 patients, LBBB was present in 247 (2.8%). AMI was the final diagnosis in 30% of patients with LBBB, with similar incidence in those with known LBBB versus those with presumably new LBBB (29% vs 35%, p=0.42). ECG criteria had low sensitivity (1%-12%) but high specificity (95%-100%) for AMI. The diagnostic accuracy as quantified by the receiver operating characteristics (ROC) curve of hs-cTnT and hs-cTnI concentrations at presentation (area under the ROC curve (AUC) 0.91, 95% CI 0.85 to 0.96 and AUC 0.89, 95% CI 0.83 to 0.95), as well as that of their 0/1-hour and 0/2-hour changes, was very high. A diagnostic algorithm combining ECG criteria with hs-cTnT/I concentrations and their absolute changes at 1 hour or 2 hours derived in cohort 1 (45 of 45(100%) patients with AMI correctly identified) showed high efficacy and accuracy when externally validated in cohorts 2 and 3 (28 of 29 patients, 97%)., Conclusion: Most patients presenting with suspected AMI and LBBB will be found to have diagnoses other than AMI. Combining ECG criteria with hs-cTnT/I testing at 0/1 hour or 0/2 hours allows early and accurate diagnosis of AMI in LBBB., Trial Registration Number: APACE: NCT00470587; ADAPT: ACTRN12611001069943; TRAPID-AMI: RD001107;Results., Competing Interests: Competing interests: CM has received research grants from the Swiss National Science Foundation and the Swiss Heart Foundation, the European Union, the Cardiovascular Research Foundation Basel, 8sense, Abbott, Alere, AstraZeneca, Beckman Coulter, bioMerieux, BRAHMS, Critical Diagnostics, Nanosphere, Roche, Siemens, Singulex and the University Hospital Basel, as well as speaker or consulting honoraria from Abbott, Alere, AstraZeneca, BG Medicine, bioMerieux, BMS, Boehringer Ingelheim, BRAHMS, Cardiorentis, Daiichi Sankyo, Novartis, Roche, Sanofi, Singulex and Siemens. LC reports grants from Roche and from Abbott, during the conduct of the study, grants from Roche, grants and personal fees from Abbott Diagnostics, grants from Siemens, grants from Radiometer, personal fees from AstraZeneca, and grants from Alere, outside the submitted work. BL has served as a consultant for Roche Diagnostics, Beckman Coulter, Siemens Healthcare Diagnostics, Radiometer Medical, bioMérieux Clinical Diagnostics, Philips Healthcare and Fiomi Diagnostics. TR has received research grants from the Swiss National Science Foundation (PASMP3-136995), the Swiss Heart Foundation, the University of Basel, the Professor Max Cloetta Foundation, and the Department of Internal Medicine, University Hospital Basel, as well as speaker’s honoraria from BRAHMS and Roche. EG has received honoraria for lectures from Roche Diagnostics, BRAHMS, Thermo Fisher and Mitsubishi Chemical Europe. MC has received research support and speaking honoraria from Roche, Thermo Fisher and Novartis. RT reports speaker honoraria from BRAHMS and Roche. WP reports grants from Roche and from Abbott, during the conduct of the study, and grants from Roche, grants and personal fees from Abbott Diagnostics, grants from Siemens, grants from Radiometer, personal fees from AstraZeneca, non-financial support from Bayer, personal fees from Hospira and grants from Alere, outside the submitted work. MRG has received speaking honoraria from Abbott and a research grant from the Swiss Heart Foundation. JB has received speaking honoria from Siemens. GB is an employee of Roche Diagnostics. JWP is supported by a Senior Research Fellowship from the Canterbury Medical Research Foundation, Emergency Care Foundation and Canterbury District Health. All other authors declare that they have no conflict of interest with this study., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The clinical availability of high-sensitivity cardiac troponin (hs-cTn) has enabled the development of several innovative strategies for the rapid rule-out of acute myocardial infarction (AMI). Due to the lack of direct comparisons, selection of the best strategy for clinical practice is challenging., Methods: In a prospective international multicenter diagnostic study enrolling 3696 patients presenting with suspected AMI to the emergency department, we compared the safety and efficacy of 14 different hs-cTn-based strategies: hs-cTn concentrations below the limit of detection (LoD), dual-marker combining hs-cTn with copeptin, ESC 0 h/1 h-algorithm, 0 h/2 h-algorithm, 2 h-ADP-algorithm, NICE-algorithm, and ESC 0 h/3 h-algorithm, each using either hs-cTnT or hs-cTnI. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available clinical information including cardiac imaging and serial hs-cTn concentrations., Results: AMI was the final diagnosis in 16% of patients. Using hs-cTnT, safety quantified by the negative predictive value (NPV) and sensitivity was very high (99.8-100% and 99.5-100%) and comparable for all strategies, except the dual-marker approach (NPV 98.7%, sensitivity 96.7%). Similarly, using hs-cTnI, safety quantified by the NPV and sensitivity was very high (99.7-100% and 98.9-100%) and comparable for all strategies, except the dual-marker approach (NPV 96.9%, sensitivity 90.4%) and the NICE-algorithm (NPV 99.1%, sensitivity 94.7%). Efficacy, quantified by the percentage of patients eligible for rule-out, differed markedly, and was lowest for LoD-algorithm (15.7-26.8%)., Conclusion: All rapid rule-out algorithms, except the dual-marker strategy and the NICE-algorithm using hs-cTnI, favorably combine safety and efficacy, and can be considered for routine clinical practice., Clinical Trial Registration: NCT00470587, http://clinicaltrials.gov/show/NCT00470587., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We desired to determine cardiac troponin (cTn) concentrations necessary to achieve a positive predictive value (PPV) of ≥75% for acute myocardial infarction (AMI) to justify immediate admission of patients to a monitored unit and, in general, early coronary angiography., Methods: In a prospective multicenter diagnostic study enrolling patients presenting to the emergency department with symptoms suggestive of AMI, final diagnoses were adjudicated by 2 independent cardiologists based on clinical information including cardiac imaging. cTn concentrations were measured using 5 different sensitive and high-sensitivity cTn (hs-cTn) assays in a blinded fashion at presentation and serially thereafter. The diagnostic end point was PPV for rule-in of AMI of initial cTn concentrations alone and in combination with early changes., Results: Among 3828 patients, 616 (16%) had an AMI. At presentation, 7% to 14% of patients had cTnT/I concentrations associated with a PPV of ≥75%. Adding absolute or relative changes did not significantly further increase the PPV. PPVs increased from 46.5% (95% CI, 43.6-49.4) for hs-cTnT at presentation >14 ng/L to 78.9% (95% CI, 74.7-82.5) for >52 ng/L ( P < 0.001), whereas PPVs in higher hs-cTnT strata remained largely unchanged [e.g., 82.4% (95% CI, 77.5-86.7) for >80 ng/L vs 83.9% (95% CI, 76.0-90.1) for >200 ng/L ( P = 0.72)]. The addition of early changes in hs-cTnT further increased the PPV up to 60 ng/L, but not for higher concentrations., Conclusions: Serial sampling does not seem necessary for predicting AMI and concurrent decision-making in about 10% of patients, as it only marginally increases the PPV for AMI and not in a statistically or clinically significant way., Clinicaltrialsgov Identifier: NCT00470587., (© 2018 American Association for Clinical Chemistry.)

Background: High-sensitivity cardiac troponin T (hs-cTnT) blood concentrations were shown to exhibit a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime and peak concentrations in the morning. We aimed to investigate whether this also applies to (h)s-cTnI assays and whether it would affect diagnostic accuracy for acute myocardial infarction (AMI)., Methods: Blood concentrations of cTnI were measured at presentation and after 1 h using four different cTnI assays: three commonly used sensitive (s-cTnI Architect, Ultra and Accu) and one experimental high-sensitivity assay (hs-cTnI Accu) in a prospective multicenter diagnostic study of patients presenting to the emergency department with suspected AMI. These concentrations and their diagnostic accuracy for AMI (quantified by the area under the curve (AUC)) were compared between morning (11 p.m. to 2 p.m.) and evening (2 p.m. to 11 p.m.) presenters., Results: Among 2601 patients, AMI was the final diagnosis in 17.6% of patients. Concentrations of (h)s-cTnI as measured using all four assays were comparable in patients presenting in the morning versus patients presenting in the evening. Diagnostic accuracy for AMI of all four (h)s-cTnI assays were high and comparable between patients presenting in the morning versus presenting in the evening (AUC at presentation: 0.90 vs 0.93 for s-cTnI Architect; 0.91 vs 0.94 for s-cTnI Ultra; 0.89 vs 0.94 for s-cTnI Accu; 0.91 vs 0.94 for hs-cTnI Accu)., Conclusions: Cardiac TnI does not seem to express a diurnal rhythm. Diagnostic accuracy for AMI is very high and does not differ with time of presentation., Clinical Trial Registration: NCT00470587, http://clinicaltrials.gov/show/NCT00470587., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Combining 2 signals of cardiomyocyte injury, cardiac troponin I (cTnI) and T (cTnT), might overcome some individual pathophysiological and analytical limitations and thereby increase diagnostic accuracy for acute myocardial infarction with a single blood draw. We aimed to evaluate the diagnostic performance of combinations of high-sensitivity (hs) cTnI and hs-cTnT for the early diagnosis of acute myocardial infarction., Methods: The diagnostic performance of combining hs-cTnI (Architect, Abbott) and hs-cTnT (Elecsys, Roche) concentrations (sum, product, ratio, and a combination algorithm) obtained at the time of presentation was evaluated in a large multicenter diagnostic study of patients with suspected acute myocardial infarction. The optimal rule-out and rule-in thresholds were externally validated in a second large multicenter diagnostic study. The proportion of patients eligible for early rule-out was compared with the European Society of Cardiology 0/1 and 0/3 hour algorithms., Results: Combining hs-cTnI and hs-cTnT concentrations did not consistently increase overall diagnostic accuracy as compared with the individual isoforms. However, the combination improved the proportion of patients meeting criteria for very early rule-out. With the European Society of Cardiology 2015 guideline recommended algorithms and cut-offs, the proportion meeting rule-out criteria after the baseline blood sampling was limited (6% to 24%) and assay dependent. Application of optimized cut-off values using the sum (9 ng/L) and product (18 ng 2 /L 2 ) of hs-cTnI and hs-cTnT concentrations led to an increase in the proportion ruled-out after a single blood draw to 34% to 41% in the original (sum: negative predictive value [NPV] 100% [95% confidence interval (CI), 99.5% to 100%]; product: NPV 100% [95% CI, 99.5% to 100%]) and in the validation cohort (sum: NPV 99.6% [95% CI, 99.0-99.9%]; product: NPV 99.4% [95% CI, 98.8-99.8%]). The use of a combination algorithm (hs-cTnI <4 ng/L and hs-cTnT <9 ng/L) showed comparable results for rule-out (40% to 43% ruled out; NPV original cohort 99.9% [95% CI, 99.2-100%]; NPV validation cohort 99.5% [95% CI, 98.9-99.8%]) and rule-in (positive predictive value [PPV] original cohort 74.4% [95% Cl, 69.6-78.8%]; PPV validation cohort 84.0% [95% Cl, 79.7-87.6%])., Conclusions: New strategies combining hs-cTnI and hs-cTnT concentrations may significantly increase the number of patients eligible for very early and safe rule-out, but do not seem helpful for the rule-in of acute myocardial infarction., Clinical Trial Registration: URL (APACE): https://www.clinicaltrial.gov . Unique identifier: NCT00470587. URL (ADAPT): www.anzctr.org.au . Unique identifier: ACTRN12611001069943.

Background: Clinical performance of the novel high-sensitivity cardiac troponin I (Siemens-hs-cTnI-Centaur) assay is unknown. We aimed to clinically validate the Siemens-hs-cTnI-Centaur assay and develop 0/1-h and 0/2-h algorithms., Methods: We enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by 2 independent cardiologists including all clinical information twice: first, using serial hs-cTnT (Roche-Elecsys, primary analysis); second, using hs-cTnI (Abbott-Architect, secondary analysis) measurements in addition to the clinically applied (hs)-cTn. Siemens-hs-cTnI-Centaur was measured at presentation, 1 h, and 2 h. The primary objective was a direct comparison of diagnostic accuracy, quantified by the area under the ROC curve (AUC), of Siemens-hs-cTnI-Centaur vs the 2 established hs-cTn assays (Roche-hs-cTnT-Elecsys, Abbott-hs-cTnI-Architect). Secondary objectives included the development of Siemens-hs-cTnI-Centaur-specific 0/1-h and 0/2-h algorithms., Results: AMI was the final diagnosis in 318 of 1755 (18%) patients (using Roche-hs-cTnT-Elecsys for adjudication). The AUC at presentation for Siemens-hs-cTnI-Centaur was 0.94 (95% CI, 0.92-0.96) and comparable with 0.95 (95% CI, 0.93-0.97) for Roche-hs-cTnT-Elecsys and 0.93 (95% CI, 0.90-0.96) for Abbott-hs-cTnI-Architect. Applying the derived Siemens-hs-cTnI-Centaur 0/1-h algorithm to the validation cohort, 46% of patients were ruled out (sensitivity, 99.1%; 95% CI, 95.3-100), and 18% of patients were ruled in (specificity, 94.1%; 95% CI, 91.8-95.9). The Siemens-hs-cTnI-Centaur 0/2-h algorithm ruled out 55% of patients (sensitivity, 100%; 95% CI, 94.1-100), and ruled in 18% of patients (specificity, 96.0%; 95% CI, 93.1-97.9). Findings were confirmed in the secondary analyses using serial measurements of Abbott-hs-cTnI-Architect for adjudication., Conclusions: Diagnostic accuracy and clinical utility of the novel Siemens-hs-cTnI-Centaur assay are high and comparable with the established hs-cTn assays. ClinicalTrials.gov Identifier: NCT00470587., (© 2018 American Association for Clinical Chemistry.)

Background: There is concern that high-sensitivity cardiac troponin (hs-cTn) may have low diagnostic accuracy in patients with low acute coronary syndrome (ACS) probability., Methods: We prospectively stratified patients presenting with acute chest discomfort to the emergency department (ED) into 3 groups according to their probability for ACS as assessed by the treating ED physician using a visual analog scale: ≤10%, 11% to 79%, and ≥80%, reviewing all information available at 90 min. hs-cTnT and hs-cTnI concentrations were determined in a blinded fashion. Two independent cardiologists adjudicated the final diagnosis., Results: Among 3828 patients eligible for analysis, 1189 patients had low (≤10%) probability for ACS. The incidence of non-ST-segment elevation myocardial infarction (NSTEMI) increased from 1.3% to 12.2% and 54.8% in patients with low, intermediate, and high ACS probability, respectively. The positive predictive value of hs-cTnT and hs-cTnI was low in patients with low ACS probability and increased with the incidence of NSTEMI, whereas the diagnostic accuracy of hs-cTnT and hs-cTnI for NSTEMI as quantified by the area under the curve (AUC) was very high and comparable among all 3 strata, e.g., AUC hs-cTnI, 0.96 (95% CI, 0.94-0.97); 0.87 (95% CI, 0.85-0.89); and 0.89 (95% CI, 0.87-0.92), respectively. Findings were validated using bootstrap analysis as an alternative methodology to define ACS probability. Similarly, higher hs-cTnT/I concentrations independently predicted all-cause mortality within 2 years (e.g., hs-cTnT hazard ratio, 1.39; 95% CI, 1.27-1.52), irrespective of ACS probability., Conclusions: Diagnostic and prognostic accuracy and utility of hs-cTnT and hs-cTnI remain high in patients with acute chest discomfort and low ACS probability.ClinicalTrials.gov Identifier: NCT00470587., (© 2017 American Association for Clinical Chemistry.)

Background: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI., Methods: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality., Results: Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L, P <0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 ( P <0.0001) and 0.926 ( P =0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI ( P <0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both P <0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI ( P <0.05 for both) and similar to hs-cTnT at predicting death at 3 years., Conclusions: cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587., (© 2017 The Authors.)

Background: The early diagnosis of acute myocardial infarction (AMI) in patients with mild elevations of high-sensitivity cardiac troponin (hs-cTn) is a challenge. It is unclear whether copeptin, a marker of endogenous stress, or 1h-hs-cTn changes are better suited to address this important unmet clinical need., Methods: We prospectively enrolled patients presenting with symptoms suggestive of AMI to the emergency department (ED). Two independent cardiologists adjudicated the final diagnosis. Mild hs-cTn elevations were defined as 26.2 ng/L (99th percentile) to 75 ng/L for hs-cTnI, and 14 ng/L (99th percentile) to 50 ng/L (biological-equivalent to 75 ng/L for hs-cTnI) for hs-cTnT., Results: Among 1356 patients, 80 (6%) had mild hs-cTnI elevations at presentation. Within this group, AMI was the final diagnosis in 39 patients (49%). The diagnostic accuracy for the diagnosis of AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0.51 (95% CI 0.39-0.64) for hs-cTnI at presentation, 0.58 (95% CI 0.45-0.71) for copeptin at presentation, and 0.78 (95% CI 0.68-0.88) for 1h-hs-cTnI changes, which was significantly higher as compared to copeptin (p = 0.02) or hs-cTnI alone (p < 0.001). The additional use of 1h-hs-cTnI changes, but not of copeptin, improved diagnostic accuracy of hs-cTnI at presentation (AUC 0.80, 95% CI 0.70-0.90; p = 0.002 for comparison). Similar findings regarding copeptin and 1h-hs-cTnT/I changes were obtained for mild hs-cTnT elevations., Conclusions: About 6-22% of patients presenting with suggestive AMI to the ED have mild hs-cTnT/I elevations at presentation. In contrast to copeptin, the addition of 1h-hs-cTn changes substantially improves the early diagnosis of AMI.

Background: Four strategies for very early rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I (hs-cTnI) have been identified. It remains unclear which strategy is most attractive for clinical application., Methods: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnI levels were measured at presentation and after 1 hour in a blinded fashion. We directly compared all 4 hs-cTnI-based rule-out strategies: limit of detection (LOD, hs-cTnI<2 ng/L), single cutoff (hs-cTnI<5 ng/L), 1-hour algorithm (hs-cTnI<5 ng/L and 1-hour change<2 ng/L), and the 0/1-hour algorithm recommended in the European Society of Cardiology guideline combining LOD and 1-hour algorithm., Results: Among 2828 enrolled patients, acute myocardial infarction was the final diagnosis in 451 (16%) patients. The LOD approach ruled out 453 patients (16%) with a sensitivity of 100% (95% confidence interval [CI], 99.2%-100%), the single cutoff 1516 patients (54%) with a sensitivity of 97.1% (95% CI, 95.1%-98.3%), the 1-hour algorithm 1459 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%), and the 0/1-hour algorithm 1463 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%). Predefined subgroup analysis in early presenters (≤2 hours) revealed significantly lower sensitivity (94.2%, interaction P =0.03) of the single cutoff, but not the other strategies. Two-year survival was 100% with LOD and 98.1% with the other strategies ( P <0.01 for LOD versus each of the other strategies)., Conclusions: All 4 rule-out strategies balance effectiveness and safety equally well. The single cutoff should not be applied in early presenters, whereas the 3 other strategies seem to perform well in this challenging subgroup., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587., (© 2017 American Heart Association, Inc.)

Objective: The objective of the study is to evaluate the role of copeptin in the diagnosis of acute coronary syndrome (ACS) and its role in dual-cardiac marker diagnostic strategy with troponin., Design: A prospective cohort study was carried out from May 2012 to October 2012., Setting: The study was conducted at the emergency department (ED) of a public hospital in a cluster of Hong Kong., Methods: Patients aged at least 18 years presented with chest pain to ED who have intermediate or high likelihood of ACS were included. All patients had blood taken in the ED for copeptin and troponin I. The adjudicated diagnoses of ACS were made by 2 independent physicians based on the universal definition. Diagnostic characteristics were calculated. Receiver operating characteristic curves were created. Areas under the curves were compared for copeptin, troponin I, and dual-marker strategy with copeptin and troponin I., Results: A total of 637 patients were recruited. Seventy-eight had been diagnosed to be ACS. The negative predictive value of copeptin for ACS was 0.881 (0.849-0.907) compared with troponin I, 0.937 (0.913-0.956). The areas under the receiver operating characteristic curves of copeptin, troponin I, and dual-marker strategy were 0.68, 0.859, and 0.880, respectively., Conclusions: Addition of copeptin to troponin does not have significant improvement of the diagnostic accuracy of ACS in patients presented with chest pain., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The diagnosis of cardiac syncope remains a challenge in the emergency department (ED). Objective: Assessing the diagnostic accuracy of the early standardized clinical judgement (ESCJ) including a standardized syncope‐specific case report form (CRF) in comparison with a recommended multivariable diagnostic score. Methods: In a prospective international observational multicentre study, diagnostic accuracy for cardiac syncope of ESCJ by the ED physician amongst patients ≥ 40 years presenting with syncope to the ED was directly compared with that of the Evaluation of Guidelines in Syncope Study (EGSYS) diagnostic score. Cardiac syncope was centrally adjudicated independently of the ESCJ or conducted workup by two ED specialists based on all information available up to 1‐year follow‐up. Secondary aims included direct comparison with high‐sensitivity cardiac troponin I (hs‐cTnI) and B‐type natriuretic peptide (BNP) concentrations and a Lasso regression to identify variables contributing most to ESCJ. Results: Cardiac syncope was adjudicated in 252/1494 patients (15.2%). The diagnostic accuracy of ESCJ for cardiac syncope as quantified by the area under the curve (AUC) was 0.87 (95% CI: 0.84–0.89), and higher compared with the EGSYS diagnostic score (0.73 (95% CI: 0.70–0.76)), hs‐cTnI (0.77 (95% CI: 0.73–0.80)) and BNP (0.77 (95% CI: 0.74–0.80)), all P < 0.001. Both biomarkers (alone or in combination) on top of the ESCJ significantly improved diagnostic accuracy. Conclusion: ESCJ including a standardized syncope‐specific CRF has very high diagnostic accuracy and outperforms the EGSYS score, hs‐cTnI and BNP. [ABSTRACT FROM AUTHOR]