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.