Prospective observational study of a consecutive patient cohort at a tertiary referral hospital (Hospital Universitari Vall D’Hebron, Barcelona, Spain). From January 2010 to October 2021, we included patients admitted for syncope with cBBB, in whom no definitive diagnosis was reached for the syncope in the initial assessment in the emergency department. We excluded patients younger than 18 years, those with pacemakers or implantable cardiac defibrillators in situ, patients with left ventricular ejection fraction<35% or with another direct indication for implantable cardiac defibrillator, those with severe comorbidities making it impracticable to undergo the study protocol (such us patients with less than 1 year of life expectancy or completely dependent for basic activities of daily living), and those who withheld informed consent for some of the tests included in the workup. In May 2022, we collected the final follow-up data of the patients. The patients’ clinical details, syncope characteristics, therapeutic management, and follow-up were recorded at the time of hospital admission. Some of the patients included in this article (n=443) had been previously included in a study intended to assess sex-related differences in this population.4

The study complies with the Declaration of Helsinki and was approved by the local ethics committee.

Patients were systematically managed according to the local clinical protocol,4 which is based on recommendations of the European Society of Cardiology (ESC) syncope guidelines.1,2 Briefly, the clinical diagnostic protocol applied in the study is based on 3 phases or steps. Step 1, prior to the patients’ inclusion in the study, consists of the initial assessment in the emergency department. Those cases with no certain or highly probable diagnosis are then considered as having unexplained syncope, and these patients are admitted to the hospital with continuous electrocardiogram (ECG) monitoring. Step 2 involves hospital admission with continuous ECG monitoring and an invasive EPS. Step 3 involves implanting an ICM with subsequent clinical monitoring (figure 1). The syncope was treated according to the clinical practice guidelines in line with the confirmed etiology.1 After hospital discharge, patients were followed up in the outpatient cardiology clinic, and those who had received a cardiac device were also followed up with the corresponding remote function.

Figure 1.

Central illustration. Diagnostic protocol schema and flow chart of patient inclusion in the study. CI, confidence interval, ECG, electrocardiogram; ED, emergency department; EPS, electrophysiological study; ICM, implantable cardiac monitor; p, patients; msec, milliseconds.

(2.16MB).

More detailed information on the diagnostic protocol, EPS, ICM monitoring, and treatment are provided in the supplementary data.

The main etiological mechanism of the syncope was established as certain or highly probable according to the definitions included in the ESC guidelines on syncope1 (table 1 of the supplementary data). Syncope due to aAVB or severe conduction disturbances (sCD), sinus node dysfunction, fast supraventricular tachycardia or ventricular tachycardia (VT) where considered an arrhythmic syncope. The patient details were analyzed by 2 cardiologists specialized in syncope to establish the definitive diagnosis according to the definitions. The etiology of syncopal recurrences was defined in the same manner.

The endpoints of the study were the risk of an arrhythmic syncope, test diagnostic yields, need for cardiac pacing related to syncope, and syncope recurrences after treatment and mortality.

Categorical variables are presented as absolute numbers (No.) and percentages. Continuous quantitative variables are presented as median and interquartile ranges [IQR]. The comparison of numerical variables was performed using the Student t test or Wilcoxon rank-sum test, depending on the distribution of the variables. The chi-square test or Fisher exact test was used to compare qualitative variables as appropriate. The Wald method was used to calculate the confidence interval for the population rates and proportions. Survival functions were estimated using the Kaplan-Meier method and their comparison was performed by the log-rank test. A Manten-Hazel test was used to evaluate the linear relation between the number of previous syncopal episodes and arrhythmic risk. A Cox proportional hazards multivariate model was developed to assess the association between previous syncopal episodes and arrhythmic syncope and to adjust for possible confounder variables. When we estimated the Cox proportional hazards model, we checked the different possible interactions between pairs of explanatory variables and found no statistically significant results. A saturated model including all clinically relevant covariates1,2,4,11–19 was estimated, and simplified models were evaluated. A relevant confounder effect was considered to be present when the hazard ratios (HRs) with and without the adjustment for the potential confounder differed by more than 10%. The most precise model with all relevant clinical covariates was finally selected. A P<.05 was considered statistically significant for all tests. All the statistical analyses were performed using Stata, version 15.1.0 (StataCorp LLC College Station, United States).

A total of 503 patients were included in the study, 265 (52.7%) with recurrent syncope (recurrent syncope group [RSG]) and 238 (47.3%) without previous syncopal episodes (single syncope group [SSG]) before the index event. Baseline characteristics are shown in table 1. Median age was 77.9 years [IQR: 71.0-83.2] and 36.8% where women. No relevant clinical differences were observed between the groups. In the RSG, 40.4% had had 1 previous syncope, while 16.6% reported 4 or more previous syncopal episodes.

Figure 1 summarizes the study flow chart. A definitive or highly probable diagnosis of the main cause of syncope was reached in 372 patients (74%) (73.1% in SSG and 74.3% in RSG, P=.754). In 281 (55.9%) patients, the diagnosis was reached in step 2 (in 252 patients after a positive EPS and in another 29 after showing symptoms with diagnostic criteria during the hospital stay). In step 3, a definitive diagnosis was reached in an additional 91 (18.1%) patients (80 due to the ICM findings and 11 due to clinical criteria). Figure 2A shows the diagnosis of the main causes of syncope. No significant differences were found between the 2 groups. Detailed information on the diagnosis in each step is provided in table 2 of the supplementary data.

Figure 2.

Etiological diagnosis and diagnostic test yields. A: etiological diagnosis reached by the group. The dashed red line separates the overall arrhythmia diagnosis from the specific etiologies. B: electrophysiological study diagnostic yield by groups. C: ICM cumulative diagnostic yield according to time of follow-up (Kaplan-Meier failure estimates curve). aAVB/sCD, advanced atrioventricular block or severe conduction disturbances; AF, atrial fibrillation; CSH, carotid sinus hypersensitivity; EPS, electrophysiological study; ICM, implantable cardiac monitor; LCA, low cardiac output; OH, orthostatic hypotension; SND, sinus node dysfunction; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

(0.22MB).

The main findings in the EPS and in the ICM are shown in table 2. EPS had a similar diagnostic yield in both groups (49.6% in SSG vs 50.6% in RSG, P=.825) (figure 2B) and a similar negative predictive value for arrhythmic syncope (74.2% [95%CI, 65.7-81.2] in SSG vs 77.1% [95%CI, 69.2-83.5] in RSG). The diagnostic yield of ICM was also similar between the 2 groups (47.2% in SGG vs 50.0% in RSG, P=.724) (figure 2C).

A total of 295 (58.7%) patients required device implantation at the end of follow-up (table 3), (table 3 of the supplementary data shows the type of device implanted). In most patients (283 [56.3%] patients), the indication was bradycardia related to the syncope. Two implantable cardiac defibrillators and 2 cardiac resynchronization defibrillators were implanted due to VT. Three patients with VT were treated with antiarrhythmic drugs only due to their comorbidities. Additionally, 5 pacemakers were implanted due to postsurgical AV block and 3 additional pacemakers because of chronotropic insufficiency.

Arrhythmic syncope was identified in 291 (57.9%) patients, mostly secondary to bradycardia, especially aAVB/sCD (figure 3 and table 2 of the supplementary data). Table 4 of the supplementary data summarizes the differences in the baseline characteristics between of patients with and without an arrhythmic syncope. Figure 1 of the supplementary data shows the arrhythmic risk according to the type of cBBB.

Figure 3.

Risk of arrhythmic syncope by group and by number of previous syncopal episodes.

(0.16MB).

Arrhythmic risk was similar in patients with and without an SSE (58.8% [95%CI, 52.6%-65.1%]) vs 57.0% [95%CI, 51.0%-62.9%]), representing a risk ratio of 0.97 (95%CI 0.83-1.12) (figure 3). Furthermore, in the multivariate Cox model, after adjustment for possible confounding variables (including the type of cBBB), the presence of recurrent syncopal episodes was not associated with a higher risk of an arrhythmic syncope (HR, 1.06; 95%CI, 0.81-1.38; P=.674) (table 5 of the supplementary data and figure 1 of the supplementary data).

Although a linear trend between the number of previous syncopal episodes and the risk of arrhythmic syncope was observed in the RSG (MH test for linear trend: 3.9; P=.0487), no significant differences were found between the number of previous syncopes compared with an SSE (figure 3).

Patients were followed up for a median of 2.9 [IQR, 1.2-5.6] years. After hospital admission, 101 (20.1) patients had a recurrence of syncope (table 3). In most of them (66 patients), the recurrence occurred before the cause of syncope was established, and indeed it was used to reach the diagnosis in step 3. The recurrence was due to an arrhythmic cause in 74.4% of patients with SSG and in 58.1% of patients with RSG (P=.096). Importantly, once the etiological diagnosis was made and the appropriate treatment established, only 35 patients (7.0%) experienced another syncopal recurrence (13 [5.5%] patients in SSG and 22 [8.3%] in RSG, P=.211), most of them due to orthostatic or reflex mechanisms (table 6 of the supplementary data). The recurrence incidence rate in the SSG group was 1.7 per 100 person-years and 2.2 per 100 person-years in RSG (IRR, 0.76; 95%CI, 0.35-1.58).

A total of 116 (23.1%) patients died during the follow-up, 78.4% of them due to noncardiovascular causes (table 3). The mortality rate in the SSG and RSG was 6.6 per 100 person-years and 6.0 per 100 person-years respectively (IRR, 1.12; 95%CI 0.76-1.64). Figure 4 shows Kaplan-Meier survival curves according to the time of diagnosis and groups.

Figure 4.

Survival analysis. Kaplan-Meier survival curves according to the time of etiological diagnosis and by group. No significant differences are observed between SSG and RSG (Log-rank test P=.438) whether diagnosed in STEP 2 or otherwise (Log-rank test P=.081).

(0.12MB).

This study has some limitations. It is an observational study carried out at a single high-volume center with a dedicated syncope clinic. To minimize the potential biases inherent to the study design, the patients were included consecutively. In addition, possible confounding factors were analyzed, including those related to a possible temporal bias due to the relatively long inclusion period. The reasons why the patients had not consulted in previous episodes were not analyzed. Patients were included in the study after step 1, and so this series refers not to the global etiology of syncope in this population, but rather on those patients lacking an evident initial diagnosis. Patients with isolated/single right cBBB were not excluded. Even though the arrhythmic risk in this subgroup of patients is significantly lower than those with other types of cBBB,11 arrhythmic risk is still significant (around 1 in 4) and similar in the 2 groups (figure 1 of the supplementary data), and therefore the overall conclusion of this study should not be affected. Furthermore, the type of cBBB was included as a variable in the multivariate analysis. In addition, the tilt-test was not used in the workup protocol due to its low specificity in this population.1 However, in selected patients, the tilt-test could have revealed an indication for pacing.1 Moreover, the study was not designed to assess predictors of pacemaker implantation in the 2 groups.