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Event rates and risk factors in patients with Brugada syndrome and no prior cardiac arrest: A cumulative analysis of the largest available studies distinguishing ICD-recorded fast ventricular arrhythmias and sudden death

Open AccessPublished:October 28, 2013DOI:https://doi.org/10.1016/j.hrthm.2013.10.039

      Background

      All available studies that have addressed the issue of risk stratification in patients with type 1 Brugada electrocardiographic (ECG) pattern have considered a combined end point constituted by implantable cardioverter-defibrillator–recorded fast ventricular arrhythmias (ICD-FVA) and sudden death (SD) in patients without ICD.

      Objective

      As ICD-FVA are only a surrogate of SD, we tried to focus on the prognostic value of classical risk factors by separating patients with ICD-FVA from those without ICD who suffered SD.

      Methods

      We made a cumulative analysis of the largest available studies. Studies were selected in which the incidence of FVA and SD could be determined in patients with and without ICD separately. In addition, we tried to analyze the prognostic value of risk factors in patients with and without ICD separately.

      Results

      A total of 2176 patients were recruited from 5 studies, about one-third of whom had an ICD and two-thirds did not. Event rates per 1000 patient-years of follow-up were 31.3 (25–39) and 6.5 (4–10) in patients with and without ICD, respectively (P < .001). When considering FVA in patients with ICD, each single risk factor (spontaneous type 1 ECG pattern, familial juvenile SD, and +EPS) displayed limited clinical value, mainly owing to its low specificity (21%–61%) and low positive predictive value (9%–15%).

      Conclusions

      In patients with type 1 Brugada ECG pattern, most arrhythmic events occur in patients with an ICD while SD is rare in patients without an ICD. While we have an acceptable ability to predict ICD-FVA, we have insufficient data to predict SD.

      Abbreviations:

      ECG (electrocardiogram/electrocardiographic), +EPS (positive electrophysiologic study), −EPS (negative electrophysiologic study), ICD (implantable cardioverter-defibrillator), ICD-FVA (implantable cardioverter-defibrillator–recorded fast ventricular arrhythmias), PPV (positive predictive value), NPV (negative predictive value), SD (sudden death)

      Keywords

      Introduction

      Patients with type 1 Brugada electrocardiographic (ECG) pattern may suffer malignant arrhythmias and sudden death (SD). The real incidence of sudden SD in patients with type 1 Brugada ECG pattern is uncertain, as is risk stratification in these patients. Indeed, all published prospective studies
      • Brugada P.
      • Brugada J.
      Right bundle branch block, persistent ST-segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome.
      • Wilde A.A.
      • Antzelevitch C.
      • Borggrefe M.
      • et al.
      Proposed diagnostic criteria for the Brugada syndrome: Consensus report.
      • Priori S.G.
      • Napolitano C.
      • Gasparini M.
      • et al.
      Natural history of Brugada syndrome: insights for risk stratification and management.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Brugada P.
      • Brugada R.
      • Mont L.
      • Rivero M.
      • Geelen P.
      • Brugada J.
      Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      • Morita H.
      • Kusano K.F.
      • Miura D.
      • et al.
      Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome.
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      are registry-based population studies. There have been no randomized studies allocating patients with risk factors to an implantable cardioverter-defibrillator (ICD) or no-ICD groups. Furthermore, all studies have evaluated a combined end point constituted by implantable cardioverter-defibrillator–recorded fast ventricular arrhythmias (ICD-FVA) and SD in patients without ICD. Finally, as ICD-FVA and SD have a low incidence, most studies
      • Brugada P.
      • Brugada J.
      Right bundle branch block, persistent ST-segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome.
      • Wilde A.A.
      • Antzelevitch C.
      • Borggrefe M.
      • et al.
      Proposed diagnostic criteria for the Brugada syndrome: Consensus report.
      • Priori S.G.
      • Napolitano C.
      • Gasparini M.
      • et al.
      Natural history of Brugada syndrome: insights for risk stratification and management.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Brugada P.
      • Brugada R.
      • Mont L.
      • Rivero M.
      • Geelen P.
      • Brugada J.
      Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      • Morita H.
      • Kusano K.F.
      • Miura D.
      • et al.
      Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome.
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      have involved a relatively low number of cases.
      In order to collect a large population, we performed a cumulative analysis of the largest published studies in which patients with an ICD could be separated from those without an ICD. Our purpose was to establish the incidence of events in patients with and without an ICD, respectively. Furthermore, we tried to evaluate the prognostic value of classical risk factors with respect to ICD-FVA and to SD separately.

      Methods

      Study selection

      We first conducted a literature search by means of the PubMed database in order to identify articles published between 2003 and 2012 that addressed the problem of the prognostic stratification of patients with type 1 Brugada ECG pattern without previous cardiac arrest. Study selection was first based on the possibility to compare event rates (incidence of ICD-FVA and SD) in patients with and without an ICD. Furthermore, articles were selected when they had a prospective design and included more than 150 patients. The arbitrary choice of a cutoff of 150 patients was made in order to exclude small studies, which could be affected by a selection bias.
      A further requirement was the possibility of establishing the prevalence of classical risk factors (spontaneous type 1 ECG pattern, familial juvenile SD, syncope, and +EPS) in patients with and without an ICD and their prognostic value with respect to the incidence of ICD-FVA and SD in patients with and without ICD, respectively.
      On the basis of this research, we selected 6 large studies (Table 1).
      • Brugada P.
      • Brugada J.
      Right bundle branch block, persistent ST-segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome.
      • Wilde A.A.
      • Antzelevitch C.
      • Borggrefe M.
      • et al.
      Proposed diagnostic criteria for the Brugada syndrome: Consensus report.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      Two other studies
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      that initially did not fulfill all inclusion criteria were added because authors send us their raw data that were not available in their original published articles.
      Table 1Features of the largest studies published between 2003 and 2012
      StudyNo. of patientsSex: malesType 1 ECG patternFamilial juvenile SDSyncope+EPSICD implantationMean follow-up (mo)Total eventsICD-FVASD (no ICD)
      Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      54740871%55%23%40%32%368.2%5.3%2.9%
      Eckardt et al
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      18813059%30%35%41%47%26–392.7%2.7%0%
      Takagi et al
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      15514586%10%37%79%*50%392.2%1.5%0.7%
      Kamakura et al
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      20019069%13%23%63%35%482%1.5%0.5%
      Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      16113836%34%31%303.7%3%0.7%
      Probst et al
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      96769045%32%41%40%32.53%2.3%0.7%
      Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      32025854%29%34%39%32%405.3%4.3%1%
      Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      30824756%21%41%45%364.6%4.6%0%
      Min-max (%)155–967130–69045–7110–5521–3734–7931–5026–402–8.21.5–5.30–2.9
      In the studies by Eckardt et al,
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      Probst et al,
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      and Giustetto et al,
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      we excluded those patients who had a history of previous cardiac arrest. Therefore, the no. of patient refer only to patients symptomatic for syncope or asymptomatic. The demographic characteristics and the prevalence of main risk factors, percentage of patients with an ICD, and the mean duration of follow-up are reported, as are the incidence of FVA interrupted by ICD, of SD and the sum of these events.
      ECG = electrocardiographic; +EPS = positive electropysiologic study; ICD = implantable cardioverter-defibrillator; ICD-FVA = fast ventricular arrhythmias recorded by implantable cardioverter-defibrillator; SD (no ICD) = sudden death in patients without implantable cardioverter-defibrillator.
      *Including nonsustained ventricular tachycardia.
      Finally, in order to gather more data on patients with ICD, 2 further studies by Sacher et al
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      and Sarkozy et al
      • Sarkozy A.
      • Boussy T.
      • Kourgiannides G.
      • et al.
      Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy in Brugada syndrome.
      were selected that analyzed only patients with ICD in detail (Table 2). The article by Sarkozy was admitted, although it referred to only 47 patients.
      Table 2Prevalence of risk factors in patients without previous cardiac arrest who underwent ICD implantation
      StudyNo. of patientsType 1 ECG patternFamilial SDSyncope+EPS/EPS performedFollow-up (mo)No. of events (ICD-FVA)
      The numbers in brackets refer to patients who had undergone EPS.
      Sarkozy et al
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      4762% (29)55% (26)55% (26)83% (38/46)Median 47 (IQR 4.5–156)7 (7)
      Sacher et al
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      20261% (124)42% (85)35% (70)82% (153/187)Mean 38 ± 2714 (14)
      Kamakura et al
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      7066% (44)23% (16)46% (32)87% (58/67)Mean 50 ± 133 (3)
      Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      11074% (82)38% (42)58% (64)85% (90/106)Median 40 (IQR 20–67)14 (10)
      Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      13772% (98/137)Mean 36 ± 813 (13)
      Total no. of cases566279/429 (65%)169/429 (39%)192/429 (45%)437/543 (80%)51 (44)
      ECG = electrocardiographic; +EPS = positive electropysiologic study; ICD = implantable cardioverter-defibrillator; ICD-FVA = implantable cardioverter-defibrillator–recorded fast ventricular arrhythmias; IQR = interquartile range; SD = sudden death.
      low asterisk The numbers in brackets refer to patients who had undergone EPS.
      The homogeneity of the available studies was tested by using a heterogeneity test. In addition, the Begg test was used to evaluate any predominant effect.

      Statistical analysis

      When performing cumulative analyses, we excluded any studies that also had been part of multicenter investigations in order to avoid the double counting of patients. Event rates (ICD-FVA and SD) were expressed per 1000 patient-years of follow-up, with 95% confidence intervals. Follow-up durations that were expressed as median values were changed to means and variances by using the method described by Hozo et al.
      • Hozo S.P.
      • Djulbergovic B.
      • Hozo I.
      Estimating the mean and variance from the median, range and the size of sample.
      The cumulative analysis of homogeneous studies was done by calculating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of risk factors, expressed as both percentages and proportions. When considering each risk factor (eg, spontaneous type 1 ECG pattern), we classified the presence and absence of this risk factor in patients with events as true positive and false negative, respectively. Conversely, in patients without events, the presence and absence of this risk factor was classified as false positive and true negative, respectively.
      All analyses were performed by means of the StataSE 12.0 statistical software (StataCorp, College Station, TX). Two sample-proportion tests were used to calculate statistical differences between group percentages. Event rates were compared between groups by means of incidence rate (incidence density or person-time) data. In all statistical tests, a value of P < .05 was considered statistically significant (when not specified, the P value should be considered 2-tailed).

      Published data and original databases

      We asked all authors of the included studies to check their respective data in our text and tables and, if possible, to provide further data. The authors found only minimal errors in our analysis of data pooled from their original articles. All errors were corrected.
      The original articles by Eckardt et al,
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      Takagi et al,
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      Kamakura et al,
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      Giustetto et al,
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      and Probst et al,
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      also included patients with previous cardiac arrest. In all these studies, our analysis was limited to patients who were symptomatic for syncope or asymptomatic.
      In the original study by Sacher et al,
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      18 of 514 patients had a history of previous cardiac arrest. These 18 patients could not be excluded from the analysis of sensitivity, specificity, PPV, and NPV of classical risk factors because, in the original article, data from patients with previous cardiac arrest were pooled with those of patients who only had syncope or were asymptomatic. This problem was solved by the authors, who sent us original data that excluded patients with previous cardiac arrest.
      In the original article by Brugada et al,
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      the mean follow-up reported was 24 ± 32 months. When these authors sent us their original data, they reported an updated follow-up of 36 ± 31 months.
      In the multicenter study published by our group in 2011,
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      a number of cases provided by Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      had previously been included in the article by Probst et al.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      Therefore, when we performed a cumulative analysis of both our article
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      and that of Probst et al
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      (Table 2) to avoid double counting of patients, patients from the study of Giustetto et al who had been included in the article by Probst et al were excluded from our original database. Therefore, in Table 2, the total numbers of patients and events are lower than those in our original article.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.

      Results

      Preliminary analysis of the largest studies

      The 8 selected large studies and the characteristics of their patients are listed in Table 3. The number of patients in these 8 studies
      • Brugada P.
      • Brugada J.
      Right bundle branch block, persistent ST-segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome.
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      ranged between 155 and 967. All studies included patients with both spontaneous and drug-induced type 1 ECG patterns. The composition of the various populations was similar in terms of the prevalence of spontaneous type 1 ECG pattern (with the exception of the study by Brugada et al, Takagi et al, and Kamakura et al that had a 71%–86% prevalence vs 45%–59% in other studies), syncope, +EPS, and number of patients with ICD. Follow-up ranged from 26 to 40 months.
      Table 3Cumulative analysis of studies in which events were compared in patients with and without ICD
      StudyNo. of patientsFollow-up (mo)ICD implanted/not implantedICD-FVASD (no ICD)
      Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      547Mean 36 ± 31177/37029/17716/370
      Kamakura et al
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      200Mean 48 ± 1570/1303/701/130
      Probst et al
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      967Median 32 (IQR 14–54)379/58822/3797/588
      Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      154Median 40 (IQR 20–67)47/1078/472/107
      Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      308Mean 36 ± 8137/17114/1371/171
      Total2176810/136676/81027/1366
      The study by Eckardt et al
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      was excluded from this analysis because some patients were also included in the multicenter study by Probst et al.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      The study by Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      was also excluded because some patients were also included in the multicenter study by Delise et al.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      *Finally, in the multicenter article published by our group
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      in 2011, 166 cases from Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      had been previously included in the article by Probst et al.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      Those patients from Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      who had taken part in the study by Probst et al
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      were therefore excluded from our original database. Thus, the present analysis included only 154 cases instead of the 320 cases in our original article.
      ICD = implantable cardioverter-defibrillator; ICD-FVA = fast ventricular arrhythmias recorded by implantable cardioverter-defibrillator; IQR = interquartile range; SD (no ICD) = sudden death in patients without implantable cardioverter-defibrillator.
      With regard to outcome, all studies considered total events, calculated as the sum of ICD-FVA and SD occurring in those without an ICD. Total events ranged from 2.6% to 8.2%. SD in all studies ranged from 0% to 1%, with the exception of the study by Brugada et al,
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      which reported a value of 2.9%.
      All 8 selected studies unanimously recognized spontaneous type 1 ECG pattern and syncope as risk factors. The significance of familial SD, however, was controversial. Moreover, the prognostic value of a +EPS proved to be highly controversial. Indeed, Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      and Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      suggested that it had a significant prognostic value while Eckardt et al
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      , Probst et al,
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      and Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      denied that it had any value. Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      suggested a prognostic value only in combination with other risk factors.
      While these conflicting results may be partially explained by nonhomogeneous stimulation protocols, other factors were probably at work. For example, in the PRELUDE study,
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      most events (9 of 14) occurred in patients with –EPS. However, in 182 patients with –EPS, major events occurred in 20% (8 of 39) of the patients with an ICD and only in 0.6% (1 of 143) of those without an ICD (P < .0001). Furthermore, in 126 patients with +EPS, all events occurred in patients with ICD (5 of 98 vs 0 of 28; P = .58).
      Other risk factors recently have been recognized in single studies: QRS fragmentation,
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Morita H.
      • Kusano K.F.
      • Miura D.
      • et al.
      Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome.
      the occurrence/increase of ST-segment elevation after exercise,
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      and the presence of J wave.
      • Takagi M.
      • Aonuma K.
      • Sekiguchi Y.
      • et al.
      The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome.
      However, these risk factors, except QRS fragmentation in the PRELUDE study,
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      were not analyzed in the selected 8 largest studies.
      Finally, both the studies by Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      and by Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      suggested that patients at the highest risk of events were those with spontaneous type 1 ECG pattern and at least 2 adjunctive risk factors (syncope, +EPS, and familial SD). Other studies did not analyze the prognostic significance of multiple risk factors and their combinations.

      Event rates in patients with and without ICD

      We performed a cumulative analysis of 5 of the aforementioned 8 selected largest studies.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      The study by Eckardt et al
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      was excluded from this analysis because part of their population was included in the multicenter study by Probst et al.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      The study by Giustetto et al
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      was also excluded because part of their population was included both in the multicenter study by Probst et al
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      and in that by Delise et al.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      The study of Takagi et al
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      was also excluded because part of their population was included in the multicenter study of Kamakura et al.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      The final analysis included 2176 patients, about one-third of whom had an ICD and two-thirds did not (Table 3).
      Event rates per 1000 patient-years of follow-up were 31.3 (25–39) and 6.5 (4–10) in patients with and without ICD, respectively (P < .001; Figure 1).
      Figure thumbnail gr1
      Figure 1Event rates per 1000 patient-years of follow-up in the cumulative analysis of articles listed in . ICD = implantable cardioverter-defibrillator.

      Prevalence of risk factors in patients with and without ICD implantation in various studies

      The prevalence of risk factors in patients with ICD was not available from the studies by Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      and Probst et al
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      listed in Table 2. These data were available from Kamakura et al,
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      Delise et al,
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      and partially from Priori et al.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      In addition, the studies by Sacher et al
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      and Sarkozy et al,
      • Sarkozy A.
      • Boussy T.
      • Kourgiannides G.
      • et al.
      Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy in Brugada syndrome.
      which analyzed only patients with ICD in detail, were selected (Table 1).
      The prevalence of risk factors in patients without an ICD was not available from all the studies listed in Table 2. No data were available from the study by Probst et al,
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      and only partial data were available from those of Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      and Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      (Table 4).
      Table 4Prevalence of risk factors in patients without previous cardiac arrest who were not candidates for ICD
      StudyNo. of patients
      Patients who did not undergo implantation; the values in parentheses present patients without ICD who underwent EPS.
      Type 1 ECG patternFamilial SDSyncope+EPS/EPS performed
      Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      370 (68)NANANA25/68
      Kamakura et al
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      130 (64)92/1309/13014/13039/64
      Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      210 (139)92/21052/21041/2106/139
      Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      171 (171)NANANA28/171
      Total no. of cases881 (442)184/340 (54%)61/340 (18%)55/340 (16%)98/442 (22%)
      ECG = electrocardiographic; +EPS = positive electrophysiologic study; ICD = implantable cardioverter-defibrillator; SD = sudden death.
      low asterisk Patients who did not undergo implantation; the values in parentheses present patients without ICD who underwent EPS.
      On analyzing the characteristics of patients who had an ICD (Table 1), the prevalence of classical risk factors was 65% for spontaneous type 1 ECG pattern, 39% for familial SD, 45% for syncope, and 80% for +EPS. Overall, the mean number of risk factors per patient was 2.3 (1.5 excluding +EPS).
      By contrast, on analyzing the prevalence of the same risk factors in patients who had not undergone ICD implantation (in studies in which these data were available; Table 4), a spontaneous type 1 ECG pattern was present in 54%, familial SD in 18%, syncope in 16%, and +EPS in 22%. Overall, the mean number of risk factors was 1.1 (0.88 excluding +EPS).
      The prevalence of risk factors was significantly higher in patients with ICD than in those without ICD: spontaneous type 1 ECG pattern, 279 of 429 vs 183 of 340 (P = .002); familial SD, 169 of 429 vs 61 of 340 (P < .001); syncope, 192 of 429 vs 55 of 340 (P < .001); +EPS, 437 of 543 vs 98 of 442 (P < .001) (Figure 2).
      Figure thumbnail gr2
      Figure 2Prevalence of risk factors in patients with and without ICD. Patients with ICD had a mean of 2.3 risk factors while those without an ICD had a mean of 1.1 risk factors. +EPS = positive electrophysiology study; Fam SD = familial sudden death; ICD = implantable cardioverter-defibrillator; type 1 = spontaneous type 1 electrocardiographic pattern.

      Prognostic value of classical risk factors in studies evaluating patients with ICD in detail

      Five studies were selected
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      ; these are listed in Table 1. Two of the 5 specifically addressed the outcome of patients with Brugada syndrome who had ICD.
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      All 4 studies addressed the prognostic value of classical risk factors. From these studies, a total population of 566 patients with ICD was recruited. During follow-up, 51 (9%) patients had ICD-FVA. Table 5 shows true-positive, false-positive, true-negative, and false-negative results for each risk factor.
      Table 5Sensitivity, specificity, PPV, and NPV of the various risk factors according to the data from the 5 studies listed in Table 3 (Sacher et al
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      , Sarkozy et al
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      , Kamakura,
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      Delise et al,
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      and Priori et al
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      )
      ParameterSpontaneous type 1 ECG patternFamilial SDSyncope+EPS
      Sensitivity86%39%61%79%
      Specificity36%61%52%21%
      PPV15%11%14%9%
      NPV95%89%91%90%
      ECG = electrocardiographic; +EPS = positive electrophysiology study; PPV = positive predictive value; NPV = negative predictive value; SD = sudden death.
      Best sensitivity was obtained by spontaneous type 1 ECG pattern and +EPS (86% and 79%, respectively), although their specificity was extremely low. All risk factors showed a low PPV (ranging from 9% to 15%). All risk factors showed a high NPV (ranging from 89% to 95%), the highest NPV being observed for a spontaneous type 1 ECG pattern.

      Prognostic value of classical risk factors in studies evaluating patients without ICD in detail

      Six of the 8 largest studies listed in Table 1 prospectively reported cases of SD
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      and 1 of resuscitated cardiac arrest.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      However, only in 3 studies
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      could the prevalence of risk factors be established in patients with these events. These studies recruited 5 cases of SD in 491 (1%) patients. A spontaneous type 1 ECG pattern was present in 5 of 5, familial SD in 1 of 5, and syncope in 0 of 5. EPS was unavailable in 4 and negative in 1.
      From these data, we can deduce a sensitivity of 100% for spontaneous type 1 ECG pattern, 20% for familial SD, and 0% for syncope. Furthermore, we can deduce a PPV of 0% for syncope and of 0%–2% for familial SD.
      A cumulative analysis including specificity and NPV was not possible, as no study (except ours
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      ) reported the characteristics of patients without ICD separately. All these data, however, should be considered with caution owing to the small number of patients.

      Discussion

      Patients with type 1 Brugada ECG pattern may suffer SD. Correct risk stratification in these patients is therefore important both to prevent SD and to avoid unnecessary ICD implantation. Indeed, patients with ICD may suffer from several complications (infections, catheter damage, and inappropriate discharge) that are deleterious, especially in young patients.
      All studies that have addressed the issue of risk stratification in patients with type 1 Brugada ECG pattern
      • Brugada P.
      • Brugada J.
      Right bundle branch block, persistent ST-segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome.
      • Wilde A.A.
      • Antzelevitch C.
      • Borggrefe M.
      • et al.
      Proposed diagnostic criteria for the Brugada syndrome: Consensus report.
      • Priori S.G.
      • Napolitano C.
      • Gasparini M.
      • et al.
      Natural history of Brugada syndrome: insights for risk stratification and management.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Brugada P.
      • Brugada R.
      • Mont L.
      • Rivero M.
      • Geelen P.
      • Brugada J.
      Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      • Morita H.
      • Kusano K.F.
      • Miura D.
      • et al.
      Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome.
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      are registry-based population studies. There have been no randomized studies allocating patients with risk factors to ICD or no-ICD groups. Furthermore, all prospective studies that have tried to stratify risk in patients with type 1 Brugada ECG pattern have evaluated a combined end point constituted by FVA-ICD and SD in patients without ICD. ICD-FVA are only a surrogate of SD, as nonlethal arrhythmias may be counted. Therefore, the real incidence of SD in patients with type 1 Brugada ECG pattern is uncertain. Moreover, the prognostic value of single risk factors with regard to ICD-FVA and SD in patients without ICD is also uncertain. Finally, as ICD-FVA and SD have a low incidence, most studies have recruited a relatively small number of cases.
      In the present study, we analyzed the largest available studies that have tried to stratify risk in patients with type 1 Brugada ECG pattern. A preliminary analysis of the 8 largest studies
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Eckardt L.
      • Probst V.
      • Smits J.P.P.
      • Bahr E.S.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment elevation Brugada syndrome.
      • Takagi M.
      • Yokoyama Y.
      • Aonuma K.
      • Aihara N.
      • Hiraoka M.
      Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      shows that most events occur in patients with ICD while SD in patients without ICD is rare over a follow-up ranging from 20 to 40 months. An exception is constituted by the study by Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      (2.9% SD rate), which probably recruited patients at the highest risk.
      Our cumulative analysis of 2176 patients revealed that the incidence of events (ICD-FVA) in patients with an ICD proved to be over 5 times higher than that of SD or aborted SD in patients without an ICD (Table 2 and Figure 1). This conclusion emerges from 5 studies
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      that were homogeneous in terms of the prevalence of classical risk factors, including +EPS, and the proportion of patients in whom ICD were implanted (about one-third; Table 2).
      We also made a cumulative analysis of studies that evaluated the prognostic value of risk factors separately in patients with and without ICD. With regard to patients with an ICD, 5 studies were selected
      • Kamakura S.
      • Ohe T.
      • Nakazawa K.
      • et al.
      Long-term prognosis of probands with Brugada-pattern ST elevation in leads V1-V3.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Sarkozy A.
      • Sorgente A.
      • Boussy T.
      • et al.
      The value of a family history of sudden death in patients with diagnostic type 1 Brugada ECG pattern.
      • Sacher F.
      • Probst V.
      • Iesaka Y.
      • Jacon P.
      • et al.
      Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study.
      that recruited a population of 566 patients. An analysis of these patients revealed the limited clinical value of any single risk factor in predicting ICD-FVA. Indeed, no classic risk factor proved to be a prognostic gold standard. Sensitivity ranged from 39% (familial SD) to 86% (spontaneous type 1 pattern). Specificity was extremely low, ranging from 21% to 61%. In addition, all risk factors displayed a low PPV, ranging from 9% (+EPS) to 15% (spontaneous type 1 ECG pattern). By contrast, their NPV was high (89%–95%), with type 1 spontaneous ECG pattern displaying the highest value.
      For patients without an ICD, only in 3 studies
      • Giustetto C.
      • Drago S.
      • Demarchi P.G.
      • et al.
      Risk stratification of patients with Brugada type electrocardiogram: a community-based prospective study.
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      could the prevalence of risk factors be established in patients with these events. These studies recorded 5 cases of SD in 491 patients. A spontaneous type 1 ECG pattern was present in 5 of 5, familial SD in 1 of 5, syncope in 0 of 5, and EPS was unavailable in 4 and negative in 1. Thus, few data on the prediction of SD are available and, paradoxically, with the exception of spontaneous type 1 ECG pattern, the risk factors considered seem to be of little use.
      Other new risk factors have recently been proposed—QRS fragmentation,
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      • Morita H.
      • Kusano K.F.
      • Miura D.
      • et al.
      Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome.
      the occurrence/increase of ST-segment elevation after effort,
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      and the presence of J wave
      • Takagi M.
      • Aonuma K.
      • Sekiguchi Y.
      • et al.
      The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome.
      —which should have interesting clinical application. However, most of these studies
      • Morita H.
      • Kusano K.F.
      • Miura D.
      • et al.
      Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome.
      • Makimoto H.
      • Nakagawa E.
      • Takaki H.
      • et al.
      Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome.
      • Takagi M.
      • Aonuma K.
      • Sekiguchi Y.
      • et al.
      The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome.
      in which these risk factors have been investigated were not part of our cumulative analysis, as they did not satisfy our inclusion criteria.
      The main finding to emerge from our study is that in patients with type 1 Brugada ECG pattern without previous cardiac arrest, most events occur in patients with ICD while SD is rare in those without ICD. This raises the question “Why?” Two hypotheses can be advanced:
      1. The first hypothesis is that, in clinical practice, candidates for ICD implantation are well stratified. This hypothesis is supported by the modality of selection adopted by all authors. Indeed, our cumulative analysis of available studies showed that patients who had undergone ICD implantation had a mean of more than 2 risk factors, the most common being +EPS (80%), followed by spontaneous type 1 ECG pattern (65%), syncope (45%), and familial SD (39%). By contrast, patients who had not undergone implantation had a mean of 1.1 risk factor; specifically, only 22% had +EPS, 54% type 1 ECG pattern, 16% syncope, and 18% familial SD. These data demonstrate that, in clinical practice, when the decision to implant an ICD was made, a polyparametric approach was adopted.
      2. The second hypothesis is that the number of events recorded by ICD overestimates the risk of SD because potentially self-terminating and nonlethal arrhythmias may be counted.
      • Ellenbogen K.A.
      • Levine J.H.
      • Berger R.D.
      • et al.
      Are implantable cardioverter defibrillator shocks a surrogate for sudden death in patients with non-ischemic cardiomyopathy?.
      There is no proof of this assumption; indeed, in patients without an ICD, we have no data on the incidence of self-terminating arrhythmias, regardless of whether asymptomatic or causing presyncope or syncope but not SD. Nevertheless, this hypothesis is intriguing and could explain why in the PRELUDE study,
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE Registry.
      in 126 patients with +EPS all events occurred in patients with ICD (5 of 98 vs 0 of 28; P = .58) while in 182 patients with –EPS major events occurred in 20% (8 of 39) of the patients with ICD and only in 0.6% (1 of 143) of those without an ICD (P < .0001). Moreover, if this hypothesis is true, the high prevalence of events and of +EPS in patients with ICD could mean that EPS predicts ICD-FVA that may not necessarily be lethal.

      Study limitations

      This study is not a multicenter prospective study, but a retrospective cumulative analysis of the largest published studies.
      The data obtained from our analysis were checked by the respective authors who provided some data that were unavailable in their original articles. However, we did not obtain all original data. Consequently, we were unable to make further analyses that would have been interesting.

      Conclusions

      The available data show that in patients with type 1 Brugada ECG pattern and without previous cardiac arrest, we currently have an acceptable ability to predict ICD-FVA but have insufficient data to predict SD. In any case, all these data suggest that SD is rare in Brugada syndrome, particularly in patients without ICD, who account for two-thirds of the total population.
      In addition, ICD-FVA are rare in patients without spontaneous type 1 ECG (ie, with only drug-induced type 1) pattern, such as in those who are asymptomatic, those without familial SD, and those with –EPS, thanks to the extremely high NPV of all these factors.
      Consequently, an extensive indication for ICD implantation should be avoided in patients without risk factors or with only single risk factors (including +EPS). By contrast, ICD implantation should be proposed in the presence of multiple risk factors (syncope, familial SD, and +EPS), particularly in patients with spontaneous type 1 ECG pattern, as suggested by Brugada et al
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      in 2003, by Antzelevitch et al
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      in 2005, and by Delise et al
      • Delise P.
      • Allocca G.
      • Marras E.
      • et al.
      Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach.
      in 2011.

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      Linked Article

      • Erratum
        Heart RhythmVol. 11Issue 4
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          In the article titled “Event rates and risk factors in patients with Brugada syndrome and no prior cardiac arrest: A cumulative analysis of the largest available studies distinguishing ICD-recorded fast ventricular arrhythmias and sudden death” by Pietro Delise,MD, Giuseppe Allocca,MD, Nadir Sitta, MD, Paola DiStefano, MS that was published in the February issue of HeartRhythm journal (2014; 11: 252-258), there were errors in the text citations of tables and references. The corrections are underlined.
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