4. Discussion
A main finding from this meta-analysis is that the pooled annual incidences of MAE in subjects with spontaneous Type-1 Brugada pattern was 4-fold higher than the pooled annual incidences of MAE in those with drug challenge induced Type-1 Brugada pattern. Another important finding was that the annual incidences of MAE in drug challenge induced Type-1 Brugada pattern in asymptomatic patients was as low as 2.1 per 1000 person-years. However, drug challenge induced Type-1 Brugada pattern in symptomatic patients has similar incidence of MAE when compared to spontaneous Type-1 Brugada pattern (IRR=1.0). The utilization of drug challenge induced Type-1 Brugada pattern for diagnosing Brugada syndrome in asymptomatic patient is limited. However, the presence of ventricular tachyarrhythmia during drug challenge testing was an independent predictor of MAE in Brugada syndrome patients.
Brugada syndrome has been approximated to be the cause in 4% of all SCD and 20% of SCD in patients with structurally normal hearts (2). Implantable cardioverter defibrillator (ICD) implantation is a class I recommendation in BrS patients with a documented history of MAE (31). However, a majority of newly diagnosed BrS patients, especially those with a drug challenge induced Type-1 Brugada pattern, have no previous history of MAE (32). It thus remains a challenge to identify asymptomatic patients who are at risk for MAE and therefore might benefit from an ICD (31).
Disopyramide and procainamide were the first two SCB reported to transiently slow down conduction and repolarization in BrS(33). Ajmaline (1 mg/kg), procainamide (10 mg/kg), and flecainide (2 mg/kg) were later tested as provocative drugs in BrS evaluation. Their sensitivity for unmasking Type-1 Brugada pattern was found to be at 100% and positive results were 100% in a small study (n=34). Drug challenged test provoked Type-1 Brugada pattern in all patients (n=11) who had sodium channel mutation without baseline ST elevation ECG (34). Positive drug challenge testing is widely used and considered in current guidelines as diagnostic of BrS regardless of symptoms (6). However, drug challenge testing may over-diagnose BrS. Most BrS patients (approximately 70%) in Europe were diagnosed with asymptomatic Brugada syndrome but positive ajmaline test (3). Ajmaline was more likely to provoke Type-1 Brugada pattern than procainamide but the false-positive results of Ajmaline was undetermined (35). A BrS syndrome diagnosis criteria “Shanghai Score System” was proposed in the recent J-Wave Syndrome Expert Consensus Conference Report to assign fewer points to drug challenge induced Type-1 Brugada pattern than spontaneous Type-1 Brugada pattern (2.0 VS 3.5 points respectively) (1).
Our study results are in line with the recent J-Wave Syndrome Expert Consensus Conference in that SCB drug challenge testing may over-diagnose BrS. The pooled annual incidences of MAE in drug challenge induced Type-1 Brugada pattern subjects is only 6.1 per 1000 person-years and only 2.1 per 1000 person-years in asymptomatic patients who had drug challenge induced Type-1 pattern, compared to 23.5 per 1000 person-years in spontaneous Type-1 Brugada pattern. The utilization of drug challenge induced Type-1 Brugada pattern for diagnosing Brugada syndrome in asymptomatic patients is therefore limited. However, drug challenge induced Type-1 Brugada pattern in symptomatic patients has a similar incidence of MAE when compared to asymptomatic spontaneous Type-1 Brugada pattern in our pooled analysis (IRR=1.0). In the FINGER registry, the incidence of MAE in asymptomatic BrS patients was very low at 5 per 1000 person-years as well (3). In 10 years of follow-up in the BrS ICD registry, the incidence of appropriate shock was 48 per 1000 person-years in patients with aborted sudden cardiac arrest, 19 per 1000 person-years for BrS patients with syncope, and only 12 per 1000 person-years for those who were asymptomatic at implantation (36). Recent meta-analysis of clinical outcomes after ICD implantation in BrS showed high incidence of ICD-related complications, including inappropriate shocks 33 per 1000 person-years, lead malfunction 16 per 1000 person-years, lead dislocation, 6 per 1000 person-years lead dislocation 4 per 1000 person-years (37). The lower annual incidence of MAE in drug challenge induced Type-1 Brugada pattern versus the lower incidence of ICD related complications should be taken into account when considering ICD implantation in patients.
The presence of ventricular tachyarrhythmia during drug challenge testing was an independent predictor of MAE in BrS patients. There has been disagreement between studies regarding the association between ventricular tachyarrhythmia during drug challenge testing and risk of MAE in BrS patients. However, our pooled OR from 4 studies suggested that ventricular tachyarrhythmia during drug challenge testing could be a useful marker of increased risk of MAE in patients with BrS, especially in asymptomatic patients. We also demonstrated that spontaneous Type-1 Brugada pattern was associated with a higher risk of MAE than drug challenge induced Type-1 Brugada pattern, similar to previous studies.