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Background: The Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes not evident during emergency department (ED) evaluation., Objective: To externally validate the CSRS and compare it with another validated score, the Osservatorio Epidemiologico della Sincope nel Lazio (OESIL) score., Design: Prospective cohort study., Setting: Large, international, multicenter study recruiting patients in EDs in 8 countries on 3 continents., Participants: Patients with syncope aged 40 years or older presenting to the ED within 12 hours of syncope., Measurements: Composite outcome of serious clinical plus procedural events (primary outcome) and the primary composite outcome excluding procedural interventions (secondary outcome)., Results: Among 2283 patients with a mean age of 68 years, the primary composite outcome occurred in 7.2%, and the composite outcome excluding procedural interventions occurred in 3.1% at 30 days. Prognostic performance of the CSRS was good for both 30-day composite outcomes and better compared with the OESIL score (area under the receiver-operating characteristic curve [AUC], 0.85 [95% CI, 0.83 to 0.88] vs. 0.74 [CI, 0.71 to 0.78] and 0.80 [CI, 0.75 to 0.84] vs. 0.69 [CI, 0.64 to 0.75], respectively). Safety of triage, as measured by the frequency of the primary composite outcome in the low-risk group, was higher using the CSRS (19 of 1388 [0.6%]) versus the OESIL score (17 of 1104 [1.5%]). A simplified model including only the clinician classification of syncope (cardiac syncope, vasovagal syncope, or other) variable at ED discharge-a component of the CSRS-achieved similar discrimination as the CSRS (AUC, 0.83 [CI, 0.80 to 0.87] for the primary composite outcome)., Limitation: Unable to disentangle the influence of other CSRS components on clinician classification of syncope at ED discharge., Conclusion: This international external validation of the CSRS showed good performance in identifying patients at low risk for serious outcomes outside of Canada and superior performance compared with the OESIL score. However, clinician classification of syncope at ED discharge seems to explain much of the performance of the CSRS in this study. The clinical utility of the CSRS remains uncertain., Primary Funding Source: Swiss National Science Foundation & Swiss Heart Foundation.

Objective: To develop an ECG-based tool for rapid risk assessment of a cardiac cause of syncope in patients ≥40 years., Methods: In a prospective international multicentre study, 2007 patients ≥40 years presenting with syncope were recruited in the emergency department (ED) of participating centres ranging from large university hospitals to smaller rural hospitals in eight countries from May 2010 to July 2017. 12-Lead ECG recordings were obtained at ED presentation following the syncopal event. The primary diagnostic outcome, a cardiac cause of syncope, was centrally adjudicated by two independent cardiologists using all available clinical information including 12-month follow-up. ECG predictors for a cardiac cause of syncope were identified using penalised backward selection and a continuous-scale likelihood was calculated based on regression analysis coefficients. Findings were validated in an independent US multicentre cohort including 2269 patients., Results: In the derivation cohort, a cardiac cause of syncope was adjudicated in 267 patients (16%). Seven ECG criteria were identified as predictors for this outcome: heart rate and QTc-interval (continuous predictors), rhythm, atrioventricular block, ST-segment depression, bundle branch block and ventricular extrasystole/non-sustained ventricular tachycardia (categorical predictors). Diagnostic accuracy of these combined predictors for a cardiac cause of syncope was high (area under the curve 0.80, 95% CI 0.77 to 0.83). Overall, 138 patients (8%) were rapidly triaged towards rule-out and 181 patients (11%) towards rule-in of a cardiac cause of syncope. External validation showed similar performance., Conclusion: In patients ≥40 years with a syncopal event, a combination of seven ECG criteria enabled rapid assessment of the likelihood that syncope was due to a cardiac cause., Trial Registration Number: NCT01548352 (BASEL IX), NCT01802398 (SRS study)., Competing Interests: Competing interests: The authors designed the study, gathered and analysed the data, vouch for the data and analysis, wrote the paper and decided to publish. TZ, JD and CM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the manuscript. The sponsors had no role in designing or conducting the study and no role in gathering or analysing the data or writing the manuscript. The manuscript and its contents have not been published previously and are not being considered for publications elsewhere in whole or in part in any language, including publicly accessible websites or e-print servers. TZ has received research support from the Freiwillige Akademische Gesellschaft Basel (Switzerland). JEW reports a research grant from the Swiss Heart Foundation, the Swiss Academy of Medical Sciences and the Bangerter Foundation (YTCR 23/17). PB has received research funding from the University of Basel, the "Stiftung für Herzschrittmacher und Elektrophysiologie" and the Freiwillige Akademische Gesellschaft Basel. LC reports grants and personal fees from Abbott Diagnostics, grants and personal fees from Beckman Coulter, grants and personal fees from Siemens, outside the submitted work. MT reports grants and personal fees from Abbott, grants and personal fees from Alere, grants from Beckman, grants and personal fees from Roche, outside the submitted work. FJM-S received speaker, advisory or consulting fees from Novartis, MSD, Bristol-Myers Squibb, Pfizer, The Medicine Company, Otsuka, Thermo Fisher, Cardiorentis, Sanofi, and research grants from the Spanish Ministry of Health and FEDER, Mapfre, Novartis, Bayer, MSD, Abbot and Orion-Pharma, outside the submitted work. WFP reports research grants from Abbott, Braincheck, Immunarray, Janssen, Roche and ZS Pharma, having served as a consultant for Abbott, AstraZeneca, Bayer, Beckman, Boehrhinger-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Ortho Clinical Diagnostics, Relypsa, Roche and Siemens, having provided expert testimony for Johnson and Johnson, and having ownership interests in Comprehensive Research Associates, and Emergencies in Medicine, Ischemia DX. MK reports personal fees from Bayer, personal fees from Daiichi-Sankyo, personal fees from Pfizer-BMS, personal fees from Böhringer-Ingelheim, outside the submitted work. TR has received research grants from the Goldschmidt-Jacobson Foundation, the Swiss National Science Foundation (PASMP3-136995), the Swiss Heart Foundation, the Professor Max Cloëtta Foundation, the University of Basel and the University Hospital Basel as well as speaker honoraria from Abbott, Bayer, Biosense, Brahms, Medtronic, Pfizer-BMS and Roche. BS has received consulting honoraria from Medtronic, outside the submitted work. CM has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the European Union, the KTI, the Cardiovascular Research Foundation Basel, the University Basel, the University Hospital Basel, Abbott, AstraZeneca, Beckman Coulter, BRAHMS, Critical Diagnostics, Idorsia, Novartis, Ortho Clinical Diagnostics, Roche, Sanofi, Siemens and Singulex, as well as speaker/consulting honoraria or travel support from Acon, Amgen, Bayer, BMS, Boehringer Ingelheim, Idorsia, Medtronic, Novartis, Osler, Roche, Sanofi, Siemens and Singulex., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021 Association for Publication of The Journal of Internal Medicine.)

Aims: The aim of this study is to characterize recurrent syncope, including sex-specific aspects, and its impact on death and major adverse cardiovascular events (MACE)., Methods and Results: We characterized recurrent syncope in a large international multicentre study, enrolling patients ≥40 years presenting to the emergency department (ED) with a syncopal event within the last 12 h. Syncope aetiology was centrally adjudicated by two independent cardiologists using all information becoming available during syncope work-up and long-term follow-up. Overall, 1790 patients were eligible for this analysis. Incidence of recurrent syncope was 20% [95% confidence interval (CI) 18-22%] within the first 24 months. Patients with an adjudicated final diagnosis of cardiac syncope (hazard ratio (HR) 1.50, 95% CI 1.11-2.01) or syncope with an unknown aetiology even after central adjudication (HR 2.11, 95% CI 1.54-2.89) had an increased risk for syncope recurrence. Least Absolute Shrinkage and Selection Operator regression fit on all patient information available early in the ED identified >3 previous episodes of syncope as the only independent predictor for recurrent syncope (HR 2.13, 95% CI 1.64-2.75). Recurrent syncope carried an increased risk for death (HR 1.87, 95% CI 1.26-2.77) and MACE (HR 2.69, 95% CI 2.02-3.59) over 24 months of follow-up, however, with a time-dependent effect. These findings were confirmed in a sensitivity analysis excluding patients with syncope recurrence or MACE before or during ED evaluation., Conclusion: Recurrence rates of syncope are substantial and vary depending on syncope aetiology. Importantly, recurrent syncope carries a time-dependent increased risk for death and MACE., Trial Registration: BAsel Syncope EvaLuation (BASEL IX, ClinicalTrials.gov registry number NCT01548352)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: The prevalence of pulmonary embolism (PE) in patients presenting with syncope to the emergency department (ED) is largely unknown. This information, however, is necessary to balance the potential medical benefit or harm of systematic PE screening in patients presenting with syncope to the ED., Objectives: This study sought to determine the prevalence of PE in patients with syncope., Methods: Unselected patients presenting with syncope to the ED were prospectively enrolled in a diagnostic multicenter study. Pre-test clinical probability for PE was assessed using the 2-level Wells score and the results of D-dimer testing using age-adapted cutoffs. Presence of PE was evaluated by imaging modalities, when ordered as part of the clinical assessment by the treating ED physician or by long-term follow-up data., Results: Long-term follow-up was complete in 1,380 patients (99%) at 360 days and 1,156 patients (83%) at 720 days. Among 1,397 patients presenting with syncope to the ED, PE was detected at presentation in 19 patients (1.4%; 95% confidence interval [CI]: 0.87% to 2.11%). The incidence of new PEs or cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.5% to 1.5%). In the subgroup of patients hospitalized (47%), PE was detected at presentation in 15 patients (2.3%; 95% CI: 1.4% to 3.7%). The incidence of new PEs or cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.4% to 2.0%)., Conclusions: PE seems to be a rather uncommon cause of syncope among patients presenting to the ED. Therefore, systematic PE-screening in all patients with syncope does not seem warranted. (BAsel Syncope EvaLuation Study [BASEL IX]; NCT01548352)., (Copyright © 2019. Published by Elsevier Inc.)

Aims: It is unknown whether cardiac syncope, and possibly also other syncope aetiologies exhibit circadian, weekly, seasonal, and temperature-dependent patterns., Methods and Results: We prospectively recorded the exact time, date, and outside temperature of syncope of patients >40 years old presenting with syncope to the emergency department in a diagnostic multicentre study. Two independent cardiologists/emergency physicians adjudicated the final diagnosis based on all information becoming available during clinical work-up including 1-year follow-up. Among 1230 patients, the adjudicated aetiology was cardiac in 14.6%, reflex in 39.2%, orthostatic in 25.7%, other non-cardiac in 9.7%, and unknown in 10.8% of patients. All syncope aetiologies occurred much more frequently during the day when compared with the night (P < 0.01). While reflex and orthostatic syncope showed a broad peak of prevalence with 80.9% of these events occurring between 4 am and 4 pm, cardiac syncope showed a narrow peak of prevalence with 70.1% of all events occurring between 8 am and 2 pm. A weekly pattern was present for most syncope aetiologies, with events occurring mainly from Monday to Friday (P < 0.01). Reflex syncope displayed a seasonal rhythm and was more common in winter (P < 0.01), while cardiac syncope stayed constant over the year. Syncope occurred most often when the outside temperature was coldest. Overall the patterns observed for cardiac syncope were similar to the patterns observed for its differential diagnosis., Conclusion: Syncope aetiologies in patients >40 years old display circadian, weekly, seasonal, and temperature-dependent patterns. Unfortunately, these patterns do not allow to reliably differentiate cardiac syncope from other aetiologies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: Various scores have been derived for the assessment of syncope patients in the emergency department (ED) but stay inconsistently validated. We aim to compare their performance to the one of a common, easy-to-use CHADS 2 score., Methods: We prospectively enrolled patients ≥ 40 years old presenting with syncope to the ED in a multicenter study. Early clinical judgment (ECJ) of the treating ED-physician regarding the probability of cardiac syncope was quantified. Two independent physicians adjudicated the final diagnosis after 1-year follow-up. Major cardiovascular events (MACE) and death were recorded during 2 years of follow-up. Nine scores were compared by their area under the receiver-operator characteristics curve (AUC) for death, MACE or the diagnosis of cardiac syncope., Results: 1490 patients were available for score validation. The CHADS 2 -score presented a higher or equally high accuracy for death in the long- and short-term follow-up than other syncope-specific risk scores. This score also performed well for the prediction of MACE in the long- and short-term evaluation and stratified patients with accuracy comparative to OESIL, one of the best performing syncope-specific risk score. All scores performed poorly for diagnosing cardiac syncope when compared to the ECJ., Conclusions: The CHADS 2 -score performed comparably to more complicated syncope-specific risk scores in the prediction of death and MACE in ED syncope patients. While better tools incorporating biochemical and electrocardiographic markers are needed, this study suggests that the CHADS 2 -score is currently a good option to stratify risk in syncope patients in the ED., Trial Registration: NCT01548352., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional-pro-A-type natriuretic peptide (MRproANP), C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin., Methods and Results: We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1-year follow-up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes ( P <0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76-0.84), 0.69 (95% CI, 0.64-0.74), 0.58 (95% CI, 0.52-0.63), and 0.68 (95% CI, 0.63-0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82-0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87-0.93), which was significantly higher than for the ED probability alone ( P =0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of <77 pmol/L and an ED probability of <20% had a sensitivity and a negative predictive value of 99%., Conclusions: The use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01548352., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)