The prognosis of asymptomatic subjects remains the most controversial issue in Brugada syndrome (BS). A meta-analysis on the prognostic role of spontaneous type 1 electrocardiographic (ECG) pattern and programmed ventricular stimulation (PVS) in asymptomatic subjects with Brugada electrocardiogram was performed. Current databases were searched until March 2014. Fourteen prospective observational studies were included in the present meta-analysis, accumulating data on 3,536 asymptomatic subjects (2,820 men) with BS phenotype. The mean follow-up period varied from 20 and 77 months. Data regarding 1,398 asymptomatic subjects with spontaneous type 1 ECG pattern of BS were retrieved from 6 studies. During follow-up, arrhythmic events (sustained ventricular tachycardia/fibrillation, appropriate device therapies, or arrhythmic death) occurred in 42 patients (3%). The meta-analysis of these studies demonstrated that asymptomatic subjects with spontaneous type 1 ECG pattern of BS exhibit an increased risk of future arrhythmic events (odds ratio = 3.56, 95% confidence interval 1.70 to 7.47, Z = 3.37, p = 0.0008); 1,104 asymptomatic subjects with BS ECG pattern from 12 studies underwent PVS and were available for analysis. During follow-up, arrhythmic events occurred in 36 subjects (3.3%). Inducible ventricular arrhythmias at PVS were predictive of future arrhythmic events (odds ratio = 3.51, 95% confidence interval 1.60 to 7.67, Z = 3.14, p = 0.002). In conclusion, this meta-analysis showed that asymptomatic subjects with either spontaneous diagnostic ECG pattern or inducible ventricular arrhythmias at PVS are at increased risk.
The Brugada syndrome (BS) is a primary electrical disease characterized by coved-type ST-segment elevation in right precordial leads on surface electrocardiogram, the absence of structural heart disease, and a high risk of ventricular tachycardia/ventricular fibrillation (VT/VF) and sudden cardiac death (SCD). The risk stratification of asymptomatic subjects still remains the most controversial issue in BS. Several clinical, electrocardiographic (ECG), and electrophysiological markers has been proposed for risk stratification of subjects with BS phenotype, but most of them have been tested in already symptomatic cases and have not been tested in a prospective manner in asymptomatic subjects. Although the annual incidence of arrhythmic events in asymptomatic subjects with Brugada ECG pattern is low (∼1%), it cannot be considered as negligible. Furthermore, this event will occur in ∼50% of cases as VT/VF without any warning symptoms. In a recent report, most SCDs occurred in previously asymptomatic subjects. Given that current management of patients with BS is limited to the implantation of a cardioverter defibrillator, which is related to a high rate of complications in young patients, risk stratification of asymptomatic subjects clearly requires improvement. This meta-analysis evaluated current risk stratification tools including the presence of spontaneous diagnostic ECG pattern or inducible ventricular arrhythmias at programmed ventricular stimulation (PVS) as predictors of future arrhythmic events in asymptomatic subjects with BS.
Methods
Meta-analyses of observational studies present particular challenges because of inherent biases and differences in study designs. Consequently, we performed this analysis according to the Strengthening the Reporting of Observational Studies in Epidemiology statement.
We carefully searched MEDLINE (January 1966 to March 2014), EMBASE (January 1980 to March 2014), and the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2014) databases to identify prospective observational studies reporting data regarding the prognostic significance of spontaneous type 1 ECG pattern and PVS in asymptomatic subjects with BS. We used the following keywords: “Brugada syndrome” and “prognosis.” Titles and abstracts of all articles were evaluated and rejected after initial screening according to the following exclusion criteria: (1) no data regarding the asymptomatic subjects with BS, (2) no inclusion of arrhythmic events as an outcome, (3) publication only in the abstract form, and (4) follow-up <12 months. Clinical data and information on length of follow-up and event-rates during follow-up were additional prerequisites. In the case of numerous reports by the same group of authors, only the one with the largest number of patients was considered. Trial eligibility was assessed by 2 investigators (TL and QS). Both reviewers agreed on the inclusion/exclusion status in 90% of the reviewed studies. Disagreements were resolved by discussion or consensus of a third reviewer (KPL).
The quality of each study was evaluated according to the guidelines developed by the US Preventive Task Force and the Evidence-Based Medicine Working Group. The following characteristics were assessed: (1) clear inclusion and exclusion criteria, (2) study sample representative for mentioned population, (3) explanation of sample selection, (4) full specification of clinical and demographic variables, (5) follow-up of at least 1 year, (6) reporting loss of follow-up, (7) clear definition of BS, (8) clear definition of outcomes and outcome assessment, and (9) adjustment of possible confounders in multivariate analysis. Studies were graded as poor quality if they met <5 criteria, fair if they met 5 to 7 criteria, and good if they met ≥8 criteria.
Two blinded reviewers (TL and QS) independently performed data extraction using a standard data extraction form to determine eligibility for inclusion and extract data. The extracted data elements of this review included: (1) publication details: first author’s last name and publication year of the studied population; (2) study design; (3) characteristics of the studied population: sample size, age, gender, number of subjects with spontaneous BS ECG pattern, number of subjects with family history of SCD, detailed information regarding PVS, number of subjects with implantable cardioverter defibrillator (ICD), duration of follow-up, number of withdrawals, and dropouts; and (4) outcome assessment: the primary outcome was the occurrence of sustained VT/VF or appropriate device therapies or arrhythmic death determined by individual study methods.
Results of the arrhythmic outcome are expressed as relative ratio with 95% confidence interval (CI) for each study. Heterogeneity was first examined using the standard chi-square test of heterogeneity. Because this test has poor power in the situation of few studies, we considered the presence of significant heterogeneity at the 10% level of significance and values of I 2 exceeding 56% as an indicator of significant heterogeneity. If the chi-square test for heterogeneity was significant, a pooled effect was calculated with a random-effects model that was used to take into account within-study and between-study variance, otherwise, with a fixed-effects model. Statistical significance for treatment effect was defined at p values <0.05. Publication bias was evaluated using the funnel plot. All analyses were performed using Review Manager, version 5.0.12 (Revman; The Cochrane Collaboration, Oxford, United Kingdom).
Results
Three hundred nine records were identified by the primary literature search. After screening the titles and abstracts, 283 studies were excluded because they were laboratory studies, review articles, or irrelevant to the present study. We, therefore, retrieved 26 potentially relevant reports for detailed review. Twelve of them were further excluded because of incomplete data on asymptomatic subjects (n = 6), insufficient outcome data in asymptomatic subjects with PVS and type 1 BS ECG phenotype (n = 3), and duplicate reports (n = 3) ( Figure 1 ). A total of 3,536 asymptomatic subjects (2,820 men) with BS from 14 studies were finally included in our meta-analysis. The mean age of the study patients ranged from 34 to 61 years. The mean follow-up period varied from 20 to 77 months. There were 8 single-center and 7 multicenter studies ( Table 1 ).
| Brugada | Gasparini | Morita | Mok | Ajiro | Brugada | Furushima | Ohkubo | |
|---|---|---|---|---|---|---|---|---|
| Type of study | MC | SC | SC | MC | SC | SC | SC | SC |
| Year of publication | 2002 | 2002 | 2003 | 2004 | 2005 | 2005 | 2005 | 2007 |
| Total patients | 334 | 21 | 41 | 50 | 46 | 547 | 24 | 34 |
| Male | 255 (76%) | 18(86%) | 41 (100%) | 47 (94%) | 44 (96%) | 408 (75%) | 23 (96%) | 33 (97%) |
| Age (years) | 42±16 | 34±15 | 45±10 | 53±15 | 46±14 | 41±15 | 61±16 | 52±13 |
| Family history of SCD | 180 (54%) | 8 (38%) | 2 (5%) | 7 (14%) | 15 (33%) | 253 (46%) | 0 (0%) | 3(9%) |
| Spontaneous type 1 Brugada ECG | 234 (70%) | 19 (90%) | 41 (100%) | 28 (56%) | 43 (94%) | 391 (71%) | 8 (33%) | NA |
| Drug-induced Brugada ECG | 100 (30%) | 2 (10%) | 0 (0%) | 22 (44%) | 3 (6%) | 156 (29%) | 16 (67%) | 22 (65%) |
| PVS | ||||||||
| Stimulation sites | RVA | RVA+RVOT | RVA+RVOT+LV | RVA+RVOT | RVA+RVOT | RVA | RVA+RVOT | RVA+RVOT |
| Extra stimuli | Up to 3 | Up to 3 | Up to 3 | Up to 3 | Up to 3 | Up to 3 | Up to 3 | Up to 2 |
| Basic cycle lengths (ms) | 600/500/430 | 600/500/400 | 600/400 | NA | 600/400 | NA | 600/400 | 600/400 |
| Patients with PVS | 252 (75%) | 21 (100%) | 41 (100%) | 30 (60%) | 36 (78%) | 408 (75%) | 22 (92%) | 34 (100%) |
| Inducible sVT | 130 (52%) | 18 (86%) | 13 (32%) | 19 (63%) | 24 (67%) | 163 (40%) | 20 (91%) | 28 (82%) |
| Patients with ICD | 146 (44%) | 17 (81%) | NA | 10 (20%) | 32 (70%) | NA | 21 (88%) | 18 (53%) |
| Follow-up (Months) | 33±39 | 20±12 | 28±24 | 26±10 | 44±36 | 28±42 | 33±16 | 47±34 |
| Asymptomatic patients | 190 (57%) | 12 (57%) | 41 (100%) | 30 (60%) | 18 (39%) | 167 (31%) | 9 (38%) | 23 (68%) |
| Male | 135 (40%) | 11(52%) | 41 (100%) | 27 (54%) | 16 (34%) | 137 (25%) | 8 (33%) | 22 (65%) |
| Age (years) | 40±16 | 34±14 | 45±10 | 55±16 | 46±12 | 44±12 | 34±14 | 56±11 |
| Family history of SCD | 131 (39%) | 5 (24%) | 2 (5%) | 5 (10%) | 6 (13%) | 0 (0%) | 0 (0%) | 2 (6%) |
| Spontaneous type1 Brugada ECG | 111 (33%) | NA | 41 (100%) | NA | NA | 154 (28%) | NA | NA |
| Drug-induced Brugada ECG | 79 (24%) | NA | 0 (0%) | NA | NA | 13 (2%) | NA | 14 (41%) |
| Patients with PVS | 136 (41%) | 12 (57%) | 41 (100%) | 11 (22%) | 11 (24%) | 125 (23%) | 8 (33%) | 23 (68%) |
| Inducible sVT, n (%) | 45 (18) | 9(43) | 13 (32) | 3 (10) | 6 (17) | 36(9) | 8(36) | 17(50) |
| Quality Score | 9 | 8 | 8 | 8 | 8 | 7 | 8 | 7 |
| Giustetto | Kamakura | Probst | Delise | Sacher | Yoshioka | |
|---|---|---|---|---|---|---|
| Type of study | SC | MC | MC | MC | MC | SC |
| Year of publication | 2009 | 2009 | 2010 | 2011 | 2013 | 2013 |
| Total patients | 166 | 330 | 1029 | 320 | 378 | 127 |
| Male | 138 (83%) | 315 (95%) | 745 (72%) | 258 (81%) | 310 (82%) | 117 (92%) |
| Age (years) | 45±14 | 51±15 | 45(35-55) | 43(33-54) | 46±13 | 47±15 |
| Family history of SCD | 39 (23%) | 45 (14%) | 264 (26%) | 94 (29%) | 135 (36%) | 20 (16%) |
| Spontaneous type 1 Brugada ECG | 72 (43%) | 173 (52%) | 468 (45%) | 174 (54%) | 226 (60%) | 28 (22%) |
| Drug-induced Brugada ECG | 94 (57%) | 72 (22%) | 561 (55%) | 146 (46%) | 152 (40%) | 99 (78%) |
| PVS | ||||||
| Stimulation sites | RVA+RVOT | RVA+RVOT | NA | RVA+RVOT | Two ventricular sites | NA |
| Extra stimuli | Up to 2 | Up to 3 | Up to 3 | Up to 3 | Up to 3 | NA |
| Basic cycle lengths (ms) | 600/400 | NA | NA | 600/400 | NA | NA |
| Patients with PVS | 135 (81%) | 232 (70%) | 638 (62%) | 245 (77%) | 311 (82%) | 0 (0%) |
| Inducible sVT | 46 (34%) | 138 (59%) | 262 (41%) | 96 (39%) | 228 (73%) | NA |
| Patients with ICD | 56 (34%) | 125(38%) | 433(42%) | 110(34%) | 378 (100%) | NA |
| Follow-up (Months) | 30±21 | 49±15 | 32(14-54) | 40(20-67) | 77±42 | 52±18 |
| Asymptomatic patients | 103 (62%) | 207 (63%) | 654 (64%) | 215 (67%) | 166 (44%) | 78 (61%) |
| Male | NA | 220 (95%) | 452 (44%) | NA | 140 (37%) | 70 (90%) |
| Age (years) | NA | 52±14 | 45(35-55) | NA | 47±12 | 45±5 |
| Family history of SCD | 9 (5%) | 22 (7%) | 195 (19%) | 46 (14%) | 86 (23%) | 15 (19%) |
| Spontaneous type1 Brugada ECG | 69 (42%) | 108 (33%) | 268 (26%) | NA | 92 (24%) | 16 (20%) |
| Drug-induced Brugada ECG | 34 (20%) | 46 (14%) | 386 (38%) | NA | 74 (20%) | 62 (80%) |
| Patients with PVS | 81(49%) | 123(37%) | 369(36%) | 154(48%) | 150(40%) | 0(0%) |
| Inducible sVT | 17 (13%) | 61 (26%) | 137 (21%) | 50 (20%) | 130 (42%) | NA |
| Quality Score | 7 | 8 | 8 | 7 | 8 | 7 |
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