medicina Article Syncope Time Frames for Adverse Events after Emergency Department Presentation: An Individual Patient Data Meta-Analysis Ludovico Furlan 1 , Lucia Trombetta 2 , Giovanni Casazza 3 , Franca Dipaola 4 , Raffaello Furlan 4 , Chiara Marta 1 , Filippo Numeroso 5 , Jordi Pérez-Rodon 6 , James V. Quinn 7 , Matthew J. Reed 8 , Robert S. Sheldon 9 , Win-Kuang Shen 10 , Benjamin C. Sun 11 , Venkatesh Thiruganasambandamoorthy 12 , Andrea Ungar 13 , Giorgio Costantino 1,3 and Monica Solbiati 1,3, * on behalf of the SYNERGI (SYNcope Expert Research Group International) 1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pronto Soccorso e Medicina d’Urgenza, 20122 Milan, Italy; furlan.ludovico@gmail.com (L.F.); chiara.marta@policlinico.mi.it (C.M.); giorgio.costantino@unimi.it (G.C.) 2 Scuola di Specializzazione in Medicina Interna, Università degli Studi di Milano, 20122 Milan, Italy; lucia.trombetta@unimi.it 3 Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, 20122 Milan, Italy; giovanni.casazza@unimi.it 4 Department of Biomedical Sciences, Humanitas University, Internal Medicine, Humanitas Clinical and  Research Center-IRCCS, 20089 Rozzano, Italy; franca.dipaola@humanitas.it (F.D.);  raffaello.furlan@hunimed.eu (R.F.) 5 Emergency Department, University Hospital of Parma, 43126 Parma, Italy; fnumeroso@gmail.com Citation: Furlan, L.; Trombetta, L.; 6 Arrhythmia Unit, Department of Cardiology, Hospital Universitari Vall d’Hebrón, Universitat Autònoma de Casazza, G.; Dipaola, F.; Furlan, R.; Marta, C.; Numeroso, F.; Barcelona, 08035 Barcelona, Spain; jordiperez@vhebron.net 7 Department of Emergency Medicine, Stanford University, Stanford, CA 94305, USA; quinnj@stanford.edu Pérez-Rodon, J.; Quinn, J.V.; Reed, 8 Emergency Medicine Research Group Edinburgh (EMERGE), Department of Emergency Medicine, Royal M.J.; et al. Syncope Time Frames for Infirmary of Edinburgh, Edinburgh EH16 4SA, UK; Matthew.Reed@nhslothian.scot.nhs.uk Adverse Events after Emergency 9 Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB T2N 4N1, Canada; Department Presentation: An Sheldon@ucalgary.ca Individual Patient Data 10 Mayo Clinic Arizona, Phoenix, AZ 85054, USA; wshen@mayo.edu Meta-Analysis. Medicina 2021, 57, 11 Department of Emergency Medicine, Leonard Davis Institute of Health Economics, University of 1235. https://doi.org/10.3390/ Pennsylvania, Philadelphia, PA 19104, USA; Benjamin.Sun@pennmedicine.upenn.edu 12 Department of Emergency Medicine, University of Ottawa, Ottawa, ON K1Y4E9, Canada; vthirug@ohri.ca medicina57111235 13 Intensive Care Unit, Department of Geriatrics, University of Florence, Azienda Ospedaliero Universitaria Academic Editor: Michael Christ Careggi, 50134 Firenze, Italy; andrea.ungar@unifi.it * Correspondence: monica.solbiati@gmail.com; Tel.: +39-0255036705 Received: 27 September 2021 Accepted: 10 November 2021 Abstract: Background and Objectives: Knowledge of the incidence and time frames of the adverse Published: 12 November 2021 events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time Publisher’s Note: MDPI stays neutral frames of adverse events of syncope patients. Materials and Methods: We combined individual patients’ with regard to jurisdictional claims in data from prospective observational studies including adult patients who presented syncope at the published maps and institutional affil- ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7–10 days, 1 month and 1 year after iations. ED evaluation. Results: We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7–10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled Copyright: © 2021 by the authors. death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI Licensee MDPI, Basel, Switzerland. 0.3% to 0.9%) at 7–10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at This article is an open access article 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to distributed under the terms and 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7–10 days, 6.9% (95% conditions of the Creative Commons CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. Attribution (CC BY) license (https:// Conclusions: The risk of death or life-threatening adverse event is rare in patients presenting syncope creativecommons.org/licenses/by/ at the ED. The most common adverse events are brady and supraventricular arrhythmias, which 4.0/). Medicina 2021, 57, 1235. https://doi.org/10.3390/medicina57111235 https://www.mdpi.com/journal/medicina Medicina 2021, 57, 1235 2 of 9 occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial. Keywords: syncope; emergency department; outcomes; adverse events; arrhythmia; mortality; ECG monitoring; individual patient data; meta-analysis 1. Introduction Syncope is a frequent cause of emergency department (ED) visits and can be the final common presentation of numerous conditions, spanning from benign to life-threatening diseases [1]. Although numerous attempts have been made to develop consensus papers, risk prediction tools and clinical guidelines, the optimal management of patients with syncope in the ED is still uncertain [1–5]. Knowledge of the incidence and time frames of short-term outcomes after syncope is essential for informing effective management strategies and for supporting ED physicians in their decisions to discharge, admit or monitor patients [6]. Indeed, knowing the type and timing of short-term adverse events is essential in order to decide how long and in which setting we should observe patients [7]. Furthermore, it might aid decision making with respect to hospital admission and syncope units [8–10]. Moreover, assessing long-term outcomes after syncope might better inform differences between short and long-term risk factors and the possible role of different approaches (e.g., hospital admission and proper follow-up) for improving patients’ outcomes [10,11]. However, the relatively low incidence of adverse events and the heterogeneity in syncope definition, data collection and outcomes definition and assessment render it it difficult to assess the incidence and time interval between syncope and each adverse event [12–14]. The aim of the present study was to perform a meta-analysis of individual patients’ data in order to describe the incidence and time frames of short-term and long-term adverse events in patients presenting syncope at the ED. 2. Materials and Methods 2.1. Inclusion Criteria We aimed to combine individual-level patient data from prospective observational studies by recruiting consecutive adult (i.e., ≥18 years old) patients presenting syncope at the ED. We asked international syncope experts (members of the scientific committee and invited participants of the First and Second International Workshops on Syncope First Assessment) if they were willing to share data from their studies, and if they were aware of other possible studies to be included. In order to be included, studies had to report 7-day follow-up data. The syncope definition used in the original studies was accepted. Studies were excluded if they had the following factors: (1) only enrolled patients with a history of recurrent syncope; (2) only enrolled patients with a specific syncope etiology; and (3) only assessed treatment efficacy. 2.2. Outcomes and Definitions According to a previous consensus, we defined any of the following as serious out- comes [12]: (1) all-cause death; (2) ventricular arrhythmia (i.e., ventricular fibrillation, sustained ventricular tachycardia and symptomatic non-sustained ventricular tachycar- dia); (3) supraventricular arrhythmias; (4) sinus arrest with cardiac pause > 3 s; (5) sick sinus syndrome with alternating bradycardia and tachycardia; (6) second-degree type 2 or third-degree AV block; (7) permanent pacemaker (PM) or implantable cardioverter defibrillator (ICD) malfunction with cardiac pauses; (8) ischemic or structural heart dis- ease (defined as aortic stenosis with valve area ≤1 cm2 , hypertrophic cardiomyopathy with outflow tract obstruction and left atrial myxoma or thrombus with outflow tract obstruction); (9) pulmonary embolism; (10) aortic dissection; (11) occult hemorrhage or Medicina 2021, 57, 1235 3 of 9 anaemia requiring transfusion; (12) syncope resulting in major traumatic injury (trauma that requires admission or procedural/surgical intervention); (13) PM or ICD implantation; and (14) cardiopulmonary resuscitation. For the present study, we defined “arrhythmia” as any of the following: ventricular arrhythmia; supraventricular arrhythmias; sinus arrest with cardiac pause > 3 s; sick sinus syndrome with alternating bradycardia and tachycardia; and second-degree type 2 or third-degree AV block. We also defined as “bradyarrhythmia” any event with cardiac pause > 3 s; sick sinus syndrome with alternating bradycardia and tachycardia; and second-degree type 2 or third-degree AV block. In cases where more than one outcome occurred in a patient, we considered only the first outcome, except for diagnoses and procedures where we included both outcomes. For example, if a patient underwent pacemaker implantation after a diagnosis of sick sinus syndrome, both adverse events were counted. We also collected the number of patients with at least one serious adverse event. All the above outcomes were assessed 24 h, 72 h, 7–10 days, 1 month and 1 year after ED evaluation. We considered the cumulative incidence of outcomes (e.g., events happening at 7 days included both 24 h and 72 h events). 2.3. Statistical Analysis For each study, we collected data on patient characteristics (mean age, sex and admis- sion to hospital rate). The event rate with 95% confidence interval (CI) was calculated for every outcome at each pre-defined time frame. Due to expected clinical and methodological differences between the primary studies, all meta-analyses were performed by using the random effects model on the logit transformed rates. Pooled rates were calculated for each outcome at each time point. Statistical heterogeneity was quantified using the inconsistency index (I2) statistic, which ranges from 0% to 100% and is defined as the percentage of the observed between-trial variability that is due to heterogeneity rather than chance. All analyses were performed using SAS (release 9.4) statistical software. 3. Results 3.1. Study Selection and Characteristics Among the members of the scientific committee and invited participants of the First and Second International Workshops on Syncope First Assessment, the authors of nine studies agreed to share individual patients’ data [11,15–23]. The included studies enrolled 12,269 patients, and the number of patients enrolled in each study varied between 312 and 6454. The mean age of patients varied between 53 and 73 years, and 52% of them were females (range 42% to 57%). Hospital admission rate was 32% with high heterogeneity between studies (range 12% to 83%). The studies were published between 2007 and 2020. Most were conducted in Europe (four in Italy, one in Spain and one in the United Kingdom), and two were conducted in the USA and one in Canada. Table 1 describes the main characteristics of the included studies. Table 1. Characteristics of the included studies. Study N of Patients Mean Age (SD) (Years) N of Females (%) N of Admitted (%) Sun_2007 312 56 (24) 179 (57) 182 (58) Costantino_2008 689 64 (18) 386 (56) 236 (34) Ungar_2010 371 66 (21) 168 (45) 144 (39) Reed_2011 1100 63 (22) 587 (53) 538 (49) Pérez-Rodon_2014 616 57 (20) 259 (42) 154 (25) Numeroso_2016 347 73 (14) 162 (47) 157 (45) Thiruganasambandamoorthy_2016 6454 53 (23) 3526 (55) 789 (12) Solbiati_2020 345 65 (20) 171 (50) 102 (30) Probst_2020 2035 73 (9) 989 (49) 1682 (83) N: number; SD: standard deviation. Medicina 2021, 57, x FOR PEER REVIEW 4 of 9 Medicina 2021, 57, 1235 4 of 9 Solbiati_2020 345 65 (20) 171 (50) 102 (30) Probst_2020 2035 73 (9) 989 (49) 1682 (83) N: number; SD: standard deviation. 3.2. Data Synthesis 3.2. Data Synthesis The proportion of patients with adverse events varied between 2% and 13% at 24 h; The proportion of patients with adverse events varied between 2% and 13% at 24 h; 4% and 14% at 72 h; 4% and 16% at 7–10 days; 7% and 17% at 1 month; and 14% and 30% 4% and 14% at 72 h; 4% and 16% at 7–10 days; 7% and 17% at 1 month; and 14% and 30% at 1 year. The pooled rates of patients with adverse events ranged between 5.1% (95% CI at3.4% 1 year. The pooled to 7.7%; I2 94%;rates of patients 11,653 patients;with and adverse events 8 studies) at 24ranged between h and 21.3% 5.1% (95% CI (95% 15.8%CIto 3.4% 28.0%; I2 94%; 2917 patients; and 5 studies) at 1 year. Table 2 reports the pooled ratestoof to 7.7%; I2 94%; 11,653 patients; and 8 studies) at 24 h and 21.3% (95% CI 15.8% 28.0%; patientsI2 with 94%; adverse 2917 patients; eventsand 5 studies) at the differentattime 1 year. Table frames. 2 reports Figure the pooled 1 shows rates the pooled of rates patients withwith of patients adverse events adverse at the events different over time. time frames. Figure 1 shows the pooled rates of patients with adverse events over time. Table 2. Pooled rates of patients with adverse events at the different time frames. Table 2. Pooled rates of patients with adverse events at the different time frames. N of Patients with N of Studies N of Studies N of Patients with Events N ofNPatients of PatientsPooledPooled Rate (%) Rate (%) 95% CI 95% (%) CI (%) I2 (%) I2 (%) Events 24 h 8 545 11,653 5.1 3.4–7.7 94 24 h 8 545 11,653 5.1 3.4–7.7 94 72 h 7 602 10,553 7.0 4.9–9.9 93 72 h 7 602 10,553 7.0 4.9–9.9 93 7–10 days 8 766 11,284 8.4 6.2–11.3 94 7–10 days 8 766 11,284 8.4 6.2–11.3 94 1 month 1 month 8 8 902 902 11,175 11,175 10.3 10.3 7.8–13.37.8–13.3 93 93 1 year 1 year 5 5 599 599 29172917 21.3 21.3 15.8–28.0 15.8–28.0 94 94 N: number; CI: confidence interval. N: number; CI: confidence interval. Figure 1. Pooled rates (with 95% CI) of patients with adverse events over time. Figure 1. Pooled rates (with 95% CI) of patients with adverse events over time. Death was reported as a primary outcome in all studies. The pooled death rate was 0.2% (95% was Death CI 0.1%reported as aatprimary to 0.5%) 24 h; 0.3% outcome (95% CI in0.1% all studies. to 0.7%) The pooled at 72 h; 0.5%death(95%rate CI was 0.3% 0.2% to 0.9%) at 7–10 days; 1% (95% CI 0.6% to 1.7%) at 1 month; and 5.9% (95% CI 4.5% to0.3% (95% CI 0.1% to 0.5%) at 24 h; 0.3% (95% CI 0.1% to 0.7%) at 72 h; 0.5% (95% CI 7.7%) toat0.9%) 1 yearat(Table 7–10 3days; 1% (95% and Figure CI 0.6% 2, panel A).to 1.7%) at 1 month; and 5.9% (95% CI 4.5% to 7.7%) Arrhythmia at 1 year (Table was3mostand common Figure 2, adverse panel A). event reported. The pooled rate of arrhythmia wasArrhythmia 3.1% (95% CIwas 2.0%most to 4.9%;common I2 91%;adverse event reported. 11,653 patients; The atpooled and 8 studies) 24 h; 4.8%rate(95% of arrhythmia CI 3.5% towas 6.7%; 3.1% (95% CI I2 88%; 2.0%patients; 10,553 to 4.9%; I2 and91%; 11,653 patients; 7 studies) at 72 h; and 5.8%8 studies) (95% CI at 24 h;to 4.2% 4.8% 7.9%;(95% CI 3.5% I2 91%; 11,284 to patients; 6.7%; I2 88%;and 810,553 studies)patients; at 7–10and 7 studies) days; 6.9% (95%at 72CIh;5.3% 5.8%to(95% 9.1%;CII2 4.2% 90%;to11,175 7.9%;patients; I2 91%; 11,284 patients;at and 8 studies) and 30 8days; studies) and at 9.9%7–10 days; (95% CI 6.9% 5.5% (95% to 17.1%;CI 5.3% to I2 96%; 9.1%; 2917 I2 90%; 11,175 patients; and 5patients; studies) at and 8 studies) 1 year (Tableat 30 days; 3 and Figure and2, 9.9% panel(95% B). CI 5.5% to 17.1%; I2 96%; The pooled 2917 ratesand patients; of PM or ICD implant 5 studies) at 1 yearranged (Tablefrom 3 and 0.6% (95%2,CI Figure 0.3%B). panel to 1.4%; I2 78%; 10,593 Thepatients; pooled and rates6 of studies) PM oratICD 24 himplant to 3.0% ranged (95% CIfrom 2.0% 0.6% to 4.5%; (95%I2 CI 89%; 10,804 0.3% patients; to 1.4%; I2 and 10,593 78%; 7 studies) at 1 month patients; and 6 and to 3.6% studies) at 24(95% h to CI3.0%2.5%(95%to 5.2%; CI 2.0%I2 73%; 2917 to 4.5%; I2patients; 89%; 10,804and 5 studies) patients; at 71 studies) and year (Tableat 1 3month and Figure and to2,3.6% panel C). CI 2.5% to 5.2%; I2 73%; 2917 patients; (95% Data on the pooled estimates of the and 5 studies) at 1 year (Table 3 and Figure 2, panel C). other outcomes at the different time frames are reported in Table S1. Table 3. Pooled rates of adverse outcomes at the different time frames. N of Studies N of Events N of Patients Pooled Rate (%) 95% CI (%) I2 (%) Medicina 2021, 57, 1235 5 of 9 Death 24 h 8 13 11,653 0.2 0.1–0.5 62 72 h 7 19 10,553 0.3 0.1–0.7 72 7–10 daysTable 3. Pooled 8 rates of adverse40outcomes at the different time frames. 11,284 0.5 0.3–0.9 69 1 month N of8 Studies 81 N of Events N of11,175 Patients 1.0(%) Pooled Rate 95% CI 0.6–1.7 (%) I2 (%) 80 Death 1 year 5 177 2917 5.9 4.5–7.7 66 Arrhythmia 24 h 8 13 11,653 0.2 0.1–0.5 62 24 72 hh 8 7 19 388 10,553 11,653 0.3 3.1 0.1–0.7 2.0–4.9 72 91 7–10 days 8 40 11,284 0.5 0.3–0.9 69 72 h 1 month 7 8 450 81 10,553 11,175 1.04.8 3.5–6.7 0.6–1.7 80 88 1 year 7–10 days 8 5 177 582 2917 11,284 5.95.8 4.5–7.7 4.2–7.9 66 91 Arrhythmia 1 month 8 676 11,175 6.9 5.3–9.1 90 24 h 8 388 11,653 3.1 2.0–4.9 91 1 year 72 h 5 7 282 450 2917 10,553 4.8 9.9 5.5–17.1 3.5–6.7 88 96 PM or ICD implant 7–10 days 8 582 11,284 5.8 4.2–7.9 91 1 month 8 676 11,175 6.9 5.3–9.1 90 24 h 6 86 10,593 0.6 0.3–1.4 78 1 year 5 282 2917 9.9 5.5–17.1 96 72 h 5 123 9493 1.4 0.8–2.3 79 PM or ICD implant 7–10 days 24 h 76 228 86 10,913 10,593 0.62.3 1.5–3.5 78 0.3–1.4 87 1 month72 h 75 123 273 9493 10,804 1.43.0 0.8–2.3 2.0–4.5 79 89 7–10 days 7 228 10,913 2.3 1.5–3.5 87 1 1year month 5 7 107 273 2917 10,804 3.0 3.6 2.5–5.2 2.0–4.5 89 73 N: number; CI: confidence 1 year interval; PM: 5 pacemaker; 107ICD: implantable 2917 cardioverter 3.6 defibrillator. Arrhythmia73included 2.5–5.2 ventricular arrhythmia N: number; CI: (ventricular confidence interval; fibrillation, PM: pacemaker; sustained ICD: implantable ventricular cardioverter tachycardia defibrillator. Arrhythmiaand symptomatic included non‐sustained ventricular arrhyth- mia (ventricular ventricular fibrillation, sustained tachycardia); ventricular tachycardia supraventricular and symptomatic arrhythmias; sinus arrestnon-sustained with cardiac ventricular pausetachycardia); >3 s; sick supraventricular sinus syndrome with arrhythmias; sinus arrest with cardiac pause >3 s; sick sinus syndrome with alternating bradycardia and tachycardia; second-degree type 2 alternating bradycardia and tachycardia; second‐degree type 2 or third‐degree AV block. or third-degree AV block. Figure 2. Pooled rates (with 95% CI) of mortality (A), arrhythmia (B) and PM or ICD implant (C) Figure 2. Pooled rates (with 95% CI) of mortality (A), arrhythmia (B) and PM or ICD implant (C) over time. over time. Medicina 2021, 57, 1235 6 of 9 4. Discussion In this study, we combined individual-level data from nine studies and 12,269 patients to describe the incidence and time frames of short-term and long-term adverse events in patients presenting syncope at the ED. This study confirms that syncope is potentially more benign than historically thought and that short-term mortality and life-threatening conditions (such as ventricular arrhythmias, pulmonary embolism and aortic dissection) are relatively rare. Adverse events mainly include arrhythmic (bradyarrhythmias and supraventricular arrhythmias), and these occur within the first 3 days after index syncope with incidence and does not increase much afterwards. Knowledge of the outcomes of syncope patients may prove useful for improving the management of these patients [6]. Indeed, knowing the type and timing of short-term adverse events is essential for deciding how long and in which setting we should observe patients [7]. Knowledge of short and medium-term outcomes might aid decision making with respect to hospital admission and syncope units [8–10]. Previous attempts have been made to describe the incidence of adverse events after syncope by using meta-analyses [14,24]. However, the heterogeneity of both syncope and outcome definitions and the lack of standardized follow-up durations made it difficult to combine data from different studies. We tried to overcome this problem by combining individual-level patients’ data and by using homogeneous definitions for syncope and adverse events in order to obtain data on each single adverse event at short, medium and long-term follow-up. The very low risk of short-term mortality, adverse outcome and high risk diagnosis supports data from previous studies [25], which have shown that these risks are low once patients with serious conditions already identified in the ED are excluded. The proportion of patients with adverse events does not increase significantly be- tween 72 h and 7–10 days after ED presentation. This suggests that most adverse events occur within the first 72 h and that extending observation beyond this time might not be worthwhile. A short period of observation in the ED or in a dedicated syncope observation unit could allow identification of most patients at risk of short-term adverse events. As most adverse events are arrhythmic, this study suggests that ECG monitoring during observation should be mandatory. Previous studies have suggested that ECG monitoring should last 12 or 24 h and that this duration could allow identification of most of the patients with adverse events [7,21,26,27]. Our study, having analyzed not only the proportion of patients with arrhythmia but also the trend over time, suggests that 3-day observation with ECG monitoring will identify a significant proportion of patients with adverse events and that a longer observation period does not add much. After hospital discharge, ambulatory ECG monitoring and syncope units may help identify additional patients at risk of adverse outcomes. As for the 1-year risk of death, our 5.9% rate is in line with previous systematic reviews showing a mortality rate of 8.4% [14] and 7% [24]. Unlike the other endpoints that show little increase after day 3, long-term mortality continues to rise. This finding might be due to several reasons. As mortality is a strong endpoint and does not depend on how thoroughly patients are investigated, we may be observing an underestimation of the incidence of other adverse events. Indeed, patients might have died of undiagnosed conditions during follow-up. Moreover, syncope might be the epiphenomenon of frailty and other comorbidities, and the increase in mortality is not due to syncope per se and is, thus, not influenced by ED management. Unfortunately, it is impossible to reliably investigate the causes of death. Moreover, we did not compare our mortality rates to those of the general population to assess if they are higher than the expected mortality. Another limitation of the current study is that we adopted as adverse events what have previously been defined in international consensus documents [12,13]. However, some of them (such as arrhythmia) are dependent on how intensively patients are diagnosed; for others, the causal–effect relationship between syncope and the outcomes might be less certain [6]. Medicina 2021, 57, 1235 7 of 9 Finally, although we were able to homogenize outcome definitions and time frames by analyzing individual-level patients’ data, we observed high heterogeneity among the included studies. This finding could be due to the inclusion of populations with different ages and admission rates and, therefore, contains different risk profiles. However, we cannot exclude the possibility that heterogeneity might be the result of different strategies in management and follow-up of patients. Indeed, as most of the events are non-life- threatening arrhythmias, a more aggressive diagnostic strategy could result in finding a higher number of outcomes. Nevertheless, it could unpredictably impact prognosis. 5. Conclusions The findings of this study will help define the best approach for observing and ECG monitoring syncope patients in the ED, in short stay hospital facilities and as outpatients. In patients presenting syncope at the ED, mortality and life-threatening adverse events are rare and high-risk diagnoses are usually recognized in the ED. Most of the adverse events at follow-up are brady and supraventricular arrhythmias and occur within the first 3 days. Therefore, if patients are admitted for observation, they should undergo ECG monitoring. Considering the time frame of serious outcomes, ECG monitoring should occur during the patient’s ED stay during a short admission to a unit with ECG monitoring facilities. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/medicina57111235/s1, Table S1: Pooled rates of adverse outcomes at the different time frames. Author Contributions: Conceptualization, G.C. (Giovanni Casazza), R.F., M.J.R., R.S.S., G.C. (Giorgio Costantino) and M.S.; data curation, L.F., L.T., F.D., C.M., F.N., J.P.-R., J.V.Q., M.J.R., B.C.S., V.T., A.U., G.C. (Giorgio Costantino) and M.S.; formal analysis, G.C. (Giovanni Casazza) and M.S.; funding acquisition, F.D.; investigation, L.F., L.T., C.M., F.B., J.P.-R., J.V.Q., M.J.R., B.C.S., V.T., A.U., G.C. (Giorgio Costantino) and M.S.; methodology, G.C. (Giovanni Casazza), G.C. (Giorgio Costantino) and M.S.; project administration, L.F., L.T. and M.S.; resources, L.F., L.T. and G.C. (Giovanni Casazza); software, G.C. (Giovanni Casazza) and M.S.; supervision, G.C. (Giorgio Costantino) and M.S.; validation, G.C. (Giovanni Casazza) and G.C. (Giorgio Costantino); visualization, L.F., L.T., G.C. (Giovanni Casazza), M.J.R., G.C. (Giorgio Costantino) and M.S.; writing—original draft, L.T. and M.S.; writing—review and editing, L.F., G.C. (Giovanni Casazza), F.D., R.F., C.M., F.N., J.P.-R., J.V.Q., M.J.R., R.S.S., W.-K.S., B.C.S., V.T., A.U. and G.C. (Giorgio Costantino). All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Data sharing not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. 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