Download Print - Circulation

Arrhythmia/Electrophysiology
Outcome After Implantation of a Cardioverter-Defibrillator
in Patients With Brugada Syndrome
A Multicenter Study
Frédéric Sacher, MD; Vincent Probst, MD, PhD; Yoshito Iesaka, MD; Peggy Jacon, MD;
Julien Laborderie, MD; Frédérique Mizon-Gérard, MD; Philippe Mabo, MD; Sylvain Reuter, MD;
Dominique Lamaison, MD; Yoshihide Takahashi, MD; Mark D. O’Neill, MB, BCh, DPhil;
Stéphane Garrigue, MD, PhD; Bertrand Pierre, MD; Pierre Jaïs, MD; Jean-Luc Pasquié, MD, PhD;
Mélèze Hocini, MD; Michèle Salvador-Mazenq, MD; Akihiko Nogami, MD; Alain Amiel, MD;
Pascal Defaye, MD; Pierre Bordachar, MD; Serge Boveda, MD; Philippe Maury, MD;
Didier Klug, MD, PhD; Dominique Babuty, MD, PhD; Michel Haïssaguerre, MD;
Jacques Mansourati, MD; Jacques Clémenty, MD; Hervé Le Marec, MD, PhD
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Background—Brugada syndrome is an arrhythmogenic disease characterized by an increased risk of sudden cardiac death
(SCD) by ventricular fibrillation. At present, an implantable cardioverter-defibrillator (ICD) is the recommended
therapy in high-risk patients. This multicenter study reports the outcome of a large series of patients implanted with an
ICD for Brugada syndrome.
Methods and Results—All patients (n⫽220, 46⫾12 years, 183 male) with a type 1 Brugada ECG pattern implanted with
an ICD in 14 centers between 1993 and 2005 were investigated. ICD indication was based on resuscitated SCD (18
patients, 8%), syncope (88 patients, 40%), or positive electrophysiological study in asymptomatic patients (99 patients,
45%). The remaining 15 patients received an ICD because of a family history of SCD or nonsustained ventricular
arrhythmia. During a mean follow-up of 38⫾27 months, no patient died and 18 patients (8%) had appropriate device
therapy (10⫾15 shocks/patient, 26⫾33 months after implantation). The complication rate was 28%, including
inappropriate shocks, which occurred in 45 patients (20%, 4⫾3 shocks/patient, 21⫾20 months after implantation). The
reasons for inappropriate therapy were lead failure (19 patients), T-wave oversensing (10 patients), sinus tachycardia (10
patients), and supraventricular tachycardia (9 patients). Among implantation parameters, high defibrillation threshold,
high pacing threshold, and low R-wave amplitude occurred, respectively, in 12%, 27%, and 15% of cases.
Conclusion—In this large Brugada syndrome population, a low incidence of arrhythmic events was found, with an
annual event rate of 2.6% during a follow-up of ⬎3 years, in addition to a significant risk of device-related
complications (8.9%/year). Inappropriate shocks were 2.5 times more frequent than appropriate ones. (Circulation.
2006;114:2317-2324.)
Key Words: death, sudden 䡲 defibrillation 䡲 genetics 䡲 ion channels 䡲 tachyarrhythmias 䡲 Brugada syndrome
䡲 implantable cardioverter-defibrillator
B
rugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of right bundle-branch block,
ST-segment elevation in the right precordial leads and an
increased risk of sudden cardiac death (SCD) as a result of
polymorphic ventricular tachyarrhythmias or ventricular
fibrillation.1
Clinical Perspective p 2324
To date, several studies have demonstrated the vast superiority of implantable cardioverter-defibrillator (ICD) implantation over antiarrhythmic medication in the prevention of
SCD among this population.2– 4 However, the risks and
Received March 22, 2006; revision received September 26, 2006; accepted September 29, 2006
From the Université Bordeaux II, Hôpital Cardiologique du Haut-Lévêque, Bordeaux-Pessac, France (F.S., M.D.O., P. Jais, M. Hocini, P.B., M.
Haïssaguerre, J.C.); Institut du thorax, CHU de Nantes, France (V.P., H.L.M.); Tsuchiura Kyodo Hospital, Japan (Y.I., Y.T.); CHU de Grenoble, France
(P. Jacon, P.D.); CHU de Poitiers, France (J.L., A.A.); CHU de Lille, France (F.M.-G., D.K.); CHU de Rennes, France (P. Mabo); Hopital Saint André,
Bordeaux, France (S.R.); CHU de Clermont-Ferrand, France (D.L.); Clinique Saint Augustin, Bordeaux, France (S.G.); CHU de Tours, France (B.P.,
D.B.); CHU de Montpellier, France (J.-L.P.); CHU de Toulouse, France (M.S.-M., P. Maury); Yokohama Rosai Hospital, Japan (A.N.); Clinique Pasteur,
Toulouse, France (S.B.); and CHU de Brest, France (J.M.).
Correspondence to Dr Frédéric Sacher, Hôpital Cardiologique du Haut-Lévêque, 33604 Bordeaux-Pessac, France. E-mail
[email protected]
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.628537
2317
2318
Circulation
November 28, 2006
benefits of ICD implantation in a large multicenter series of
patients with Brugada syndrome have not been evaluated.
The main objective of the present study was to assess both the
clinical benefit and the complication rate at implantation and
during follow-up in a group of Brugada syndrome patients
implanted with an ICD for primary and secondary prevention
of SCD.
Methods
Study Population
All patients diagnosed with Brugada syndrome and implanted with
an ICD in 14 centers between 1993 and 2005 were included. The
diagnosis was made after an episode of aborted cardiac arrest, during
evaluation of syncope, in asymptomatic patients during routine
examination with characteristic electrocardiographic patterns, or as a
consequence of family screening after the diagnosis of Brugada
syndrome in a family member.
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Diagnosis, Clinical Data, and
Electrophysiological Testing
Patients were included in this study only if they had a type 1 ECG at
baseline on at least one occasion or after provocation with a class I
antiarrhythmic drug. A type 1 ECG was defined as a prominent
coved ST-segment elevation displaying J-wave amplitude or STsegment elevation ⱖ2 mm or 0.2 mV at its peak followed by a
negative T wave.5 The choice of class I drug was determined by its
availability in the participating hospitals. Intravenous ajmaline (1
mg/kg body weight at a rate of 10 mg/min), flecainide (2 mg/kg body
weight over 10 minutes with a maximum of 150 mg), or procainamide (10 mg/kg at a rate of 100 mg/min) was used. In addition,
treadmill exercise testing and biochemical analysis excluded acute
ischemia and metabolic or electrolyte disturbances.
The following clinical data were collected in all 14 participating
centers: circumstances of diagnosis, indication for ICD implantation,
age at diagnosis, gender, family history of SCD (⬍45 years of age),
results of pharmacological testing for unmasking the characteristic
coved-type ECG pattern, and invasive electrophysiological testing
(EPS). Patients with a previous history of syncope, documented
sustained ventricular arrhythmia, or resuscitated SCD were considered symptomatic.
Baseline EPS was recommended in all patients and was performed
in 198 patients (90%). A maximum of 3 ventricular extrastimuli were
delivered from 2 ventricular sites unless ventricular fibrillation or
sustained ventricular tachyarrhythmia (lasting ⬎30 seconds, causing
syncope, or requiring intervention for termination) was elicited at a
previous step. Premature beats were started in late diastole, and
coupling intervals were then reduced in 10-ms or 20-ms decrements
to 200 ms or until refractoriness was reached. Inducible ventricular
arrhythmia was defined as any ventricular arrhythmia lasting ⬎30
seconds, causing syncope/circulatory collapse, or requiring intervention to be terminated. Therefore, patients with inducible, asymptomatic, nonsustained ventricular arrhythmia that terminated spontaneously before syncope were classified as noninducible. The decision
of single- versus dual-chamber ICD implantation and device manufacturer was at the discretion of the participating center.
ICD Implantation and Follow-Up
High defibrillation threshold (DFT) was defined as requiring a shock
energy ⬎21 joules to terminate ventricular fibrillation (VF). High
pacing threshold was defined as requiring a device output ⬎2 V at
0.4-ms pulse width for right ventricular capture. Low R-wave
amplitude was defined as ⬍5 mV. In the absence of symptoms or
device therapy, patients were seen routinely every 3 to 6 months for
clinical review and device interrogation, according to local practice.
In the event of a shock, patients were seen at the ICD clinic within
24 hours and the device interrogated. Appropriate shocks were
defined as shocks delivered for ventricular tachycardia (VT) or VF,
and inappropriate shocks were defined as those delivered in the
absence of ventricular arrhythmia. Device effectiveness was assessed
by the number of patients who had an appropriate defibrillation after
ICD implantation. Only the first appropriate shock was considered
for analysis.
Statistical Analysis
Data were analyzed with the SPSS software package for paired and
unpaired data and for survival curves. The event-rate curve was
generated according to the Kaplan-Meier method. The time to
occurrence of clinical events (appropriate shock, inappropriate
shock, and complications) was analyzed with Cox proportionalhazards model with adjustment for age and indication for ICD when
indicated. Fisher exact or ␹2 tests (for ethnicity, family history of
SCD, history of supraventricular tachycardia, inducibility at EPS,
SCN5a mutation, and ICD implantation data) were used to compare
TABLE 1. Initial Characteristics of the 220 Patients With Brugada Syndrome According to
ICD Indication
Resuscitated
SCD (n⫽18)
Syncope
(n⫽88)
Asymptomatic
(n⫽114)
P Between
3 Groups
Total
(n⫽220)
Sex, male
15 (83)
72 (82)
96 (84)
0.64
183 (83)
Age, y
43⫾13
46⫾12
46⫾12
0.57
46⫾12
White
15 (83)
81 (92)
109 (96)
205 (93)
Asian
2 (11)
7 (8)
3 (3)
12 (6)
African
1 (6)
0
2 (1)
3 (1)
Family history of SCD
6 (33)
23 (26)
62 (54)
0.001
History of supraventricular tachycardia
0 (0)
13 (15)
19 (17)
0.21
32 (15)
Spontaneous type 1 ECG
13 (72)
63 (71)
61 (54)
0.037
137 (62)
No. of patients with EPS
11 (61)
77 (88)
110 (96)
0.01
198 (90)
Ethnicity
Inducible at EPS
Single-chamber ICD
Patients with genetic test
SCN5a mutation
Values are n (%) or mean⫾SD.
0.11
91 (41)
4 (36)
58 (75)
95 (86)
⬍0.001
157 (79)
15 (83)
78 (88)
103 (90)
0.55
196 (89)
9 (50)
38 (43)
50 (44)
0.65
97 (44)
5 (56)
6 (16)
18 (36)
0.11
29 (30)
Sacher et al
TABLE 2.
Brugada Syndrome and ICD
2319
Outcome of the 220 Patients With Brugada Syndrome According to ICD Indication
Asymptomatic vs
Syncope
Median follow-up,* mo
Patients with appropriate shocks
Resuscitated SCD
(n⫽18)
Syncope
(n⫽88)
Asymptomatic
(n⫽114)
P Between
Groups
25.5 (10.5-49.5)
39.5 (19.5-59)
31 (17-54.5)
0.33
4 (22)
Median delay to first shock, mo
2.5 (2-7.5)
Median shock
5.5 (1-10.75)
9 (10)
5 (4)
24 (6.5-48)
16 (1.5-43)
6 (2-17)
4 (2.5-11.5)
Asymptomatic vs
Resuscitated SCD
HR (95% CI)
P
HR (95% CI)
P
0.43 (0.24-0.74)
0.002
0.44 (0.22-0.88)
0.02
0.27
0.33
Patients with complications
5 (28)
22 (25)
35 (31)
0.74 (0.41-1.34)
0.32
0.57 (0.28-1.14)
0.11
Patients with inappropriate shocks
3 (17)
19 (22)
23 (20)
0.80 (0.47-1.37)
0.42
1.03 (0.56-1.88)
0.94
17 (94)
78 (88)
101 (89)
0.95
High DFT
2 (12)
12 (15)
10 (10)
0.91
High pacing threshold
5 (29)
19 (24)
29 (29)
0.82
Low R-wave amplitude
1 (6)
9 (12)
19 (19)
0.11
ICD implantation data available
Data are mean⫾SD, n (%), or median (25th–75th quintiles) when indicated. HR indicates hazard ratio; CI, confidence interval.
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
categorical variables. One-way ANOVA was performed to compare
continuous variables when data were normally distributed, whereas
we used the Kruskal-Wallis test to compare follow-up between
groups and the number of shocks. A probability value ⬍0.05 was
considered statistically significant. When applicable, data are expressed as mean⫾SD or median (25th quintile, 75th quintile).
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Clinical Characteristics and Indication for
ICD Implantation
The study population characteristics are summarized in Table
1 (220 patients; 83% male; mean age 46⫾12 years at
diagnosis; median age 46 years; range 7 to 75 years). The vast
majority of patients were white (93%), with Asian and
African ethnicity accounting for 6% and 1% of patients,
respectively. In 137 individuals (62%), a spontaneous covedtype ECG (type 1 ECG) was found at baseline. In the
remaining individuals, class I antiarrhythmic drug administration unmasked the diagnostic type 1 ECG. A spontaneous
type 1 ECG was more frequently seen in symptomatic (71%)
TABLE 3.
than in asymptomatic patients (54%; P⫽0.02). The SCN5A
mutation was found in 29 of 97 patients in whom the results
of genetic testing were available.
At diagnosis, 114 patients (52%) were asymptomatic, 88
patients (40%) had previously had at least 1 episode of
syncope with no clear extracardiac cause, and 18 patients
(8%) had been resuscitated from VF. Among the 114 asymptomatic patients, indications included: (1) a type 1 Brugada
ECG pattern and inducible ventricular arrhythmias (n⫽99);
(2) a type 1 Brugada ECG pattern without inducible arrhythmias but with a family history of Brugada syndrome and SCD
(n⫽11); and (3) a type 1 Brugada ECG pattern and spontaneous nonsustained ventricular arrhythmia (n⫽4). A family
history of SCD was found in 91 patients (41%). Supraventricular arrhythmias were described in 32 (15%) patients
(atrial fibrillation, n⫽23; atrial flutter, n⫽3; junctional
tachycardia, n⫽4; and atrial tachycardia, n⫽2).
A single-chamber ICD was implanted in 196 patients,
whereas 24 patients received a dual-chamber device. Implantation data (DFT, pacing threshold, and R-wave amplitude)
were available in 196 patients.
Predictive Factors of Appropriate Shocks
Appropriate Shock,
n (%) (n⫽18)
Sex, male
Family history of SCD
History of supraventricular tachycardia
Unadjusted HR
(95% CI)
P
Adjusted HR*
(95% CI)
P
16 (89)
0.58 (0.13-2.53)
0.47
0.47 (0.10-2.22)
0.34
5 (28)
0.31 (0.10-0.96)
0.04
0.33 (0.10-1.07)
0.07
2 (11)
1.03 (0.23-4.61)
0.97
1.52 (0.32-7.26)
0.60
Spontaneous type 1 ECG
15 (83)
1.40 (0.45-4.32)
0.56
0.95 (0.29-3.09)
0.93
No. of patients with EPS
15 (83)
1.30 (0.63-2.60)
0.50
0.86 (0.40-1.86)
0.70
0.73 (0.34-1.60)
0.44
0.63 (0.27-1.45)
0.27
Inducible at EPS
Patients with genetic test
SCN5A mutation
ICD implantation data available
13 (87)
8 (44)
2 (25)
16 (89)
High DFT
2 (13)
0.45 (0.09-2.20)
0.32
0.38 (0.06-2.33)
0.30
High pacing threshold
6 (38)
1.69 (0.61-4.69)
0.31
2.00 (0.72-5.56)
0.19
Low R-wave amplitude
2 (13)
0.76 (0.17-3.45)
0.72
1.46 (0.30-7.19)
0.65
*Adjusted for age and indication of ICD.
2320
Circulation
November 28, 2006
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Figure 1. Kaplan-Meier curve of effectiveness of ICD in Brugada syndrome
depending on its indication.
When analyzed according to the indication for ICD implantation (resuscitated SCD, a history of syncope, or asymptomatic), a significant difference between the groups was
found with regard to family history of SCD, spontaneous type
1 ECG pattern, and inducibility during EPS (Table 1).
Outcome
During a mean follow-up of 38⫾27 months (median 31
months; range 1 to 150 months) after ICD implantation, no
death occurred (Table 2). Eight percent of this population
experienced appropriate shocks. Between the 3 groups defined according to ICD indication, only the rate of appropriate
shocks received was statistically different (SCD 22%, syncope 10%, asymptomatic 4%; P⫽0.025) during follow-up. A
total of 289 ICDs have been implanted in the 220 Brugada
patients studied (1.3⫾0.5 devices/patient; 1 device in 157
patients, 2 in 57 patients, and 3 in 6 patients). Complications
occurred in 28% of the patients, including inappropriate
shocks in 20% of the cases.
Effectiveness of ICD
The effectiveness of ICD therapy, defined as the percentage
of patients with at least 1 appropriate shock, is 8% in this
large series of high-risk patients. The average annual rate of
appropriate shocks is 2.6% (1.5% in asymptomatic patients).
Kaplan-Meier analysis demonstrated differences in the time
to the first appropriate shocks depending on symptoms
(Figure 1). Two patients had shocks for monomorphic VT
(cycle length 350 and 280 ms), and 16 patients had shocks for
polymorphic VT or VF (mean cycle length 199⫾37 ms
[range 160 to 260 ms]). Patients with appropriate therapy had
10⫾15 shocks (median 4, range 1 to 65 shocks) occurring
26⫾33 months (median 16, range 1 to 140 months) after ICD
implantation.
Seven patients presented with an arrhythmic storm (ⱖ3
episodes within 24 hours) and were treated as previously
described6,7 with quinidine or ablation (4 patients) in the
event of quinidine failure. They had frequent ventricular
ectopies similar to the initiating one during this period of
time. In 2 patients, ventricular arrhythmia storms occurred in
TABLE 4.
Sacher et al
Brugada Syndrome and ICD
Unadjusted HR
(95% CI)
P
2321
Predictive Factors of Inappropriate Shock
Inappropriate Shock,
n (%) (n⫽45)
Adjusted HR*
(95% CI)
P
Sex, male
38 (84)
0.96 (0.43-2.15)
0.92
1.01 (0.45-2.29)
0.98
History of supraventricular tachycardia
14 (31)
2.55 (1.26-5.17)
0.009
2.45 (1.18-5.06)
0.02
Spontaneous type 1 ECG
25 (56)
0.69 (0.39-1.08)
0.09
0.54 (0.29-1.02)
0.06
Single-chamber ICD
42 (93)
0.55 (0.17-1.78)
0.32
0.60 (0.18-1.96)
0.39
T-wave oversensing
10 (22)
10.83 (4.81-24.41)
⬍0.001
14.18 (5.94-33.82)
⬍0.001
ICD implantation data available
38 (84)
High DFT
3 (8)
0.25 (0.06-1.09)
0.06
0.26 (0.06-1.15)
0.08
High pacing threshold
14 (37)
1.70 (0.86-3.38)
0.13
1.63 (0.81-3.27)
0.17
Low R-wave amplitude
14 (37)
3.01 (1.47-6.16)
0.003
2.83 (1.34-6.00)
0.007
*Adjusted for age and indication of ICD.
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
the context of infection with shocks occurring both night and
day. In the 11 remaining patients with isolated shocks, 4
patients had shocks at night (midnight to 6 AM), 6 patients
had shocks during the day (6 AM to midnight), and 1 patient
had shocks during both periods.
In the syncope group (n⫽88), 9 patients (10%) experienced
appropriate shock(s) during a median follow-up of 39.5
months. During that time, 6 patients (7%) had syncope
recurrence without any arrhythmia recorded on the ICD data
log (5 cases were due to neurocardiogenic syncope and 1 to
a confirmed epileptic seizure).
With regard to the 5 asymptomatic patients who experienced appropriate therapies, 4 patients had a spontaneous
type 1 Brugada ECG pattern at baseline, whereas 1 patient did
not. All had sustained inducible ventricular arrhythmia at
EPS.
Of note, the 11 asymptomatic patients with no inducible
ventricular arrhythmia at pre-implantation EPS and a history
of SCD in a brother or father did not experience appropriate
shocks after a mean follow-up of 56⫾31 months, although 3
patients had inappropriate device therapies.
In this population, a Cox proportional hazards model failed
to find any factor predictive of appropriate device discharge
(Table 3) except for the presence of symptoms (resuscitated
SCD) before implantation (Table 2).
Complications of ICD
Complications occurred in 62 patients (28%). Early complications, which occurred during the first months, included
pneumothorax (3 patients), pericardial effusion (2 patients),
reintervention for lead displacement (5 patients), vein thrombosis (with pulmonary embolism in 1) (2 patients),2 and
hematoma (2 patients). Late complications during follow-up
(from 1 month after implantation) were lead failure requiring
extraction and reimplantation (19 patients), pocket and/or
lead infection that required both lead and generator replacement (3 patients), pericardial effusion (1 patient), pocket
revision for deeper implantation of a superficial lead (2
patients), device failure (1 patient), and severe psychological
difficulties (2 asymptomatic patients). Complications also
included inappropriate shocks (Table 4), which occurred in
45 patients (20%; 4⫾3 shocks/patient) 21⫾20 months after
ICD implantation. Reasons for inappropriate shocks were
lead dysfunction (19 patients) (Figure 2), T-wave oversensing
(10 patients), sinus tachycardia (10 patients), and supraventricular arrhythmias (9 patients). One patient suffered an
inappropriate shock that induced VF that could not be
terminated by the device because of lead failure. External
defibrillation was successful.
High DFT was documented in 24 (12%) of 196 patients
and high pacing threshold in 53 (27%) of 196 patients at
implantation or during follow-up. Mean R-wave amplitude
was 10⫾4 mV, and 29 (15%) of 196 patients had low R-wave
amplitude. Patients with shocks due to T-wave oversensing
were more likely to have low R-wave amplitude (70% versus
24%, P⫽0.02) at implantation.
Factors predictive of inappropriate shocks were a history of
supraventricular tachycardia (P⫽0.02), T-wave oversensing
(P⬍0.001), and a low R-wave amplitude (P⫽0.007) (Table
4). Patients with inappropriate shocks tended to be younger
(age 43⫾13 years versus 47⫾12 years, P⫽0.07).
Discussion
The aim of this study was to evaluate long-term outcome in
a large series of patients implanted with an ICD for a
diagnosis of Brugada syndrome. The major finding of this
study is that during a follow-up period of ⬎3 years after
implantation, there is a 2.5-fold greater frequency of inappropriate (20%) than appropriate shocks (8%), with an overall
complication rate of 28%. No arrhythmic death occurred at
implantation or during follow-up in this young, otherwise
healthy population.
Patient Selection for Device Implantation
Appropriate shocks were more frequent in symptomatic than
in asymptomatic patients (12% versus 4%; P⫽0.05). These
data are relevant to and in agreement with other reports on
SCD risk stratification.8 –10 Although there is a consensus to
implant ICDs in symptomatic patients, the choice of appropriate treatment for asymptomatic patients is fraught with
difficulty, principally because of a limited ability to identify
those individuals at high risk for SCD. Identification of late
potentials has been proposed,11 and, although EPS is the only
tool used to stratify risk of SCD in asymptomatic patients in
the Second Consensus Conference,12 the role of EPS remains
controversial.13 In the 18 patients implanted with ICDs after
2322
Circulation
November 28, 2006
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Figure 2. A, Stored electrogram of inappropriate shock related to lead failure. B, Stored electrogram of an appropriate shock in the
same patient 3 months after device and lead replacement.
a resuscitated SCD, 11 patients had EPS, and only 4 of these
patients had an inducible ventricular arrhythmia (Table 1). It
is difficult to reconcile the prediction of ventricular arrhythmia by EPS in asymptomatic patients with a negative study in
patients with resuscitated SCD. This is in agreement with
Kanda et al,14 who reported that EPS is unable to predict
arrhythmic events in symptomatic patients.
In this series of patients, the annual rate of appropriate
shocks is 1.5% among patients who are asymptomatic. The
number of patients needed to treat (NNT) to save 1 life
would then be 23 patients. Had we strictly adhered to the
Second Consensus criteria for device implantation in
Brugada syndrome,12 the 16 asymptomatic patients who
did not have a spontaneous type 1 ECG pattern nor a
family history of SCD would not have undergone EPS and
should not have received an ICD. Another 15 patients (11
patients with a family history of SCD but no inducible
ventricular arrhythmia at EPS and 4 patients with spontaneous nonsustained ventricular arrhythmia) also would not
have been implanted with ICDs. Therefore, if patients had
been treated according to the Second Consensus criteria,
the mean annual appropriate shock rate in our study would
have been 1.9% in asymptomatic patients (NNT⫽17),
which is lower than the mean annual event rate of trials
dealing with primary prevention of SCD in structural heart
disease (5.1% for patients recruited in the Sudden Cardiac
Death in Heart Failure Trial [SCD-HeFT]).15 However, in
our young population, if we assume 35 additional years of
life and a mean annual event rate of 1.9%, 66.5% of the
patients would experience appropriate device therapy.
Furthermore, although there is a consensus to implant
symptomatic patients with ICDs, it is difficult to be certain of
the true cause of syncope in all cases of Brugada syndrome.
In the present study, a clear history of syncope in the context
of a manifest or drug-revealed type I ECG led to the diagnosis
of Brugada syndrome and device implantation in 88 patients.
After a median follow-up of 39.5 months, 17% of this group
had a recurrence of syncope. Intriguingly, device interrogation revealed no arrhythmia in 7% and ventricular arrhythmia
in 10%. The development of an objective tool to better
stratify the risk of arrhythmic events would contribute greatly
to the management of patients with a diagnosis of Brugada
syndrome.
Timing of Appropriate Device Discharge
Among the 18 patients with appropriate shock, 7 patients
experienced arrhythmic storms with multiple shocks delivered during both the day and night. The 11 other patients had
isolated ventricular arrhythmias, which were nocturnal
(n⫽4), diurnal (n⫽6), or both (n⫽1). These results are not in
accordance with the study by Matsuo et al,16 who found that
two thirds of arrhythmic events occurred between midnight
and 6 AM in 6 patients. Although some of the events may have
happened during periods of relative vagal predominance,
ventricular arrhythmias may also occur without vagal stimulation in Brugada patients.
Sacher et al
Complications
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Complications of ICD implantation occurred in 62 patients
(28%). The first concern is that the population with ICDs is
young and active, with a long life expectancy leading to
multiple device replacements. One of the major problems in
this population is lead dysfunction; not only did this result in
inappropriate shocks, but it also increased the frequency of
lead extraction and replacement (9%). Strict adherence to a
cephalic approach could be a way to minimize the risk, but
there are no objective data to support this hypothesis. Most of
the inappropriate shocks for sinus tachycardia or supraventricular tachycardia occurred before 2004. More recently, we
programmed only 1 VF zone above 210 to 220 bpm to avoid
inappropriate shocks in these young active patients who may
also have supraventricular tachycardias.17 Particular attention
should be paid to R- and T-wave amplitudes during implantation. In our study, patients with shocks related to T-wave
oversensing more often had low R-wave amplitude at implantation (70% versus 24%; P⫽0.02). When available, T-wave
oversensing algorithms should be used. Daily transtelephonic
home monitoring may also be helpful, as was the case in 2
patients where T-wave oversensing and myopotentials were
interpreted as VF, leading to the devices charging but
aborting therapy on redetection of sinus rhythm before
defibrillation. Remote interrogation facilitated an expedited
clinic visit and device reprogramming, thereby preventing the
inevitable delivery of an inappropriate therapy.
An important concern is the deleterious psychological
impact of ICD implantation on young asymptomatic patients.
Anxiety and psychological distress are more frequent in
young patients with an ICD,18 especially if the diagnosis was
made during a fortuitous ECG. In our series, 2 asymptomatic
patients developed severe psychological difficulties leading
to the loss of employment.
ICD Implantation Parameters
With regard to implantation data, it has been suggested that
Brugada patients have high DFTs19 and high pacing thresholds. We found that 12% of the patients had a DFT ⬎21
joules, whereas 4.6%20 to 6.2% of patients with structural
heart disease21 are reported to have a high DFT. A previous
study by Watanabe et al19 found 18% of 22 Brugada patients
with a DFT ⬎25 joules versus 0% in the group implanted
with ICDs for structural heart disease. Two hypotheses have
been proposed to explain these findings. First, the right
ventricular outflow tract seems to be a critical area in Brugada
patients,22 and the energy required to achieve an adequate
current density to prolong refractoriness in the majority of the
myocardium and especially in the epicardium of the right
ventricular outflow tract may be more important. Secondly,
the refractoriness of the myocardium induced by the defibrillation shock may fail to prevent VF reinitiation because of a
short VF cycle length and short ventricular refractory period19
in this population.
A high pacing threshold at implantation or during
follow-up is seen in up to 27% of Brugada patients. This
surprising observation may be explained by 3 phenomena: (1)
pacing is rarely necessary in Brugada patients, and the
implanting physician focuses more attention on obtaining a
Brugada Syndrome and ICD
2323
low DFT than a low pacing threshold; (2) although only 5
patients needed reintervention for lead displacement in this
population, a higher rate of microdisplacement may account
for the increased pacing threshold observed; and (3) the
myocardium of Brugada patients may require a higher energy
to be depolarized.
Finally, according to these findings, only single-chamber
ICDs should be implanted in these patients, and dual-chamber
ICDs should be reserved for patients with an indication for
atrial or ventricular pacing. Moreover, to avoid complications, particular attention to lead placement is required, and 1
single VF zone ⬎210 bpm should be programmed. A monitoring zone ⬎180 bpm could be used.
Study Limitations
This is a retrospective study, and the population included was
identified across 14 different centers. Although every effort
was made to collect the data in a uniform and thorough
manner, some measurement bias may have occurred. Furthermore, device programming was not uniform in all centers. In
patients with a mean age of 46⫾12 years, a follow-up of 3
years is relatively short to comment on their true long-term
outcome.
Because of the low number of events during follow-up,
statistical analysis of survival times may suffer from low
power. Conclusions on predictors of appropriate shocks
cannot be drawn from the present data, but the observed
differences indicate important trends that are of clinical
relevance.
Conclusion
This study reports data in a large cohort of patients implanted
with an ICD for Brugada syndrome. A low incidence of
arrhythmic events (ie, an annual appropriate shock rate of
2.6%) was found after the ECG abnormality was diagnosed
and/or the first clinical event. The complication rate was 28%
during a follow-up of 3 years. Inappropriate shocks were
found to be 2.5 times more frequent (20%) than appropriate
shocks (8%) during this period. Therefore, particular attention to ICD implantation technique and subsequent device
programming is required to minimize the occurrence of
inappropriate shocks.
Appendix
No. of Patients Included at Each Center
Centre hospitalier universitaire (CHU) de Bordeaux, 49;
CHU de Nantes, 44; CHU de Tours, 25; CHU de Lille, 21;
CHU de Toulouse, 19; CHU de Rennes, 12; CHU de Brest,
11; Tsuchiura Kyodo Hospital, 10; CHU de Grenoble, 8;
CHU de Clermont-Ferrand, 6; CHU de Montpellier, 5; CHU
de Poitiers, 5; Clinique Pasteur, 3; and Yokohama Rosai
Hospital, 2.
Acknowledgments
We thank Christine Poulain, Maider Bessouet, and Christine Fruchet
(RN) for their contribution to data entry. We acknowledge the
contribution of Sylvie Maurice-Tison, MD, PhD (ISPED, Université
Bordeaux 2, France) for statistical analysis.
2324
Circulation
November 28, 2006
Disclosures
None.
12.
References
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
1. Brugada P, Brugada J. Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J Am Coll Cardiol. 1992;20:
1391–1396.
2. Brugada J, Brugada R, Brugada P. Right bundle-branch block and
ST-segment elevation in leads V1 through V3: a marker for sudden death
in patients without demonstrable structural heart disease. Circulation.
1998;1097:457– 460.
3. Brugada J, Brugada R, Brugada P. Pharmacological and device approach
to therapy of inherited cardiac diseases associated with cardiac arrhythmias and sudden death. J Electrocardiol. 2000;33[Suppl]:41– 47.
4. Nademanee K, Veerakul G, Mower M, Likittanasombat K, Krittayapong
R, Bhuripanyo K, Sitthisook S, Chaothawee L, Lai MY, Azen SP.
Defibrillator Versus beta-Blockers for Unexplained Death in Thailand
(DEBUT): a randomized clinical trial. Circulation. 2003;107:2221–2226.
5. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada
P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA.
Study Group on the Molecular Basis of Arrhythmias of the European
Society of Cardiology. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002;106:2514 –2519.
6. Mok NS, Chan NY, Chiu AC. Successful use of quinidine in treatment of
electrical storm in Brugada syndrome. Pacing Clin Electrophysiol. 2004;
27:821– 823.
7. Haissaguerre M, Extramiana F, Hocini M, Cauchemez B, Jais P, Cabrera
JA, Farre J, Leenhardt A, Sanders P, Scavee C, Hsu LF, Weerasooriya R,
Shah DC, Frank R, Maury P, Delay M, Garrigue S, Clementy J. Mapping
and ablation of ventricular fibrillation associated with long-QT and
Brugada syndromes. Circulation. 2003;108:925–928.
8. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada
P. Long-term follow-up of individuals with the electrocardiographic
pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. 2002;105:73–78.
9. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P,
Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E,
Faggiano G, Nastoli J. Natural history of Brugada syndrome: insights for
risk stratification and management. Circulation. 2002;105:1342–1347.
10. Eckardt L, Probst V, Smits JP, Bahr ES, Wolpert C, Schimpf R, Wichter
T, Boisseau P, Heinecke A, Breithardt G, Borggrefe M, LeMarec H,
Bocker D, Wilde AA. Long-term prognosis of individuals with right
precordial ST-segment-elevation Brugada syndrome. Circulation. 2005;
111:257–263.
11. Ikeda T, Sakurada H, Sakabe K, Sakata T, Takami M, Tezuka N, Nakae
T, Noro M, Enjoji Y, Tejima T, Sugi K, Yamaguchi T. Assessment of
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
noninvasive markers in identifying patients at risk in the Brugada syndrome: insight into risk stratification. J Am Coll Cardiol. 2001;37:
1628 –1634.
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado
D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W,
Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the
second consensus conference: endorsed by the Heart Rhythm Society and
the European Heart Rhythm Association Circulation. 2005;111:
659 – 670; erratum in Circulation 2005;112:e74.
Controversies in cardiovascular medicine. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation. 2005;112:279 –292.
Kanda M, Shimizu W, Matsuo K, Nagaya N, Taguchi A, Suyama K,
Kurita T, Aihara N, Kamakura S. Electrophysiologic characteristics and
implications of induced ventricular fibrillation in symptomatic patients
with Brugada syndrome. J Am Coll Cardiol. 2002;39:1799 –1805.
Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R,
Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, ClappChanning N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip
JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–237.
Matsuo K, Kurita T, Inagaki M, Kakishita M, Aihara N, Shimizu W,
Taguchi A, Suyama K, Kamakura S, Shimomura K. The circadian pattern
of the development of ventricular fibrillation in patients with Brugada
syndrome. Eur Heart J. 1999;20:465– 470.
Bordachar P, Reuter S, Garrigue S, Cai X, Hocini M, Jais P, Haissaguerre
M, Clementy J. Incidence, clinical implications and prognosis of atrial
arrhythmias in Brugada syndrome. Eur Heart J. 2004;25:879 – 884.
Sears SF Jr, Conti JB. Quality of life and psychological functioning of icd
patients. Heart. 2002;87:488 – 493.
Watanabe H, Chinushi M, Sugiura H, Washizuka T, Komura S, Hosaka
Y, Furushima H, Watanabe H, Hayashi J, Aizawa Y. Unsuccessful
internal defibrillation in Brugada syndrome: focus on refractoriness and
ventricular fibrillation cycle length. J Cardiovasc Electrophysiol. 2005;
16:262–266.
Epstein AE, Ellenbogen KA, Kirk KA, Kay GN, Dailey SM, Plumb
VJ. Clinical characteristics and outcome of patients with high defibrillation thresholds: a multicenter study. Circulation. 1992;86:1206 –1216.
Russo AM, Sauer W, Gerstenfeld EP, Hsia HH, Lin D, Cooper JM,
Dixit S, Verdino RJ, Nayak HM, Callans DJ, Patel V, Marchlinski FE.
Defibrillation threshold testing: is it really necessary at the time of
implantable cardioverter-defibrillator insertion? Heart Rhythm. 2005;
2:456 – 461.
Morita H, Fukushima-Kusano K, Nagase S, Takenaka-Morita S, Nishii N,
Kakishita M, Nakamura K, Emori T, Matsubara H, Ohe T. Site-specific
arrhythmogenesis in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2003;14:373–379.
CLINICAL PERSPECTIVE
With increasing awareness of Brugada syndrome among both physicians and cardiologists, the incidence of this cardiac
channelopathy is continuing to grow. The present therapeutic approach is either follow-up with no treatment or
implantation of an implantable cardioverter-defibrillator (ICD). Although there is a consensus to implant symptomatic
patients with ICDs, the choice of appropriate treatment for asymptomatic patients is fraught with difficulty, principally
because of a limited ability to identify those individuals at high risk of sudden cardiac death. As a consequence of improved
recognition of this condition and advances in ICD technology, implantation rates among the young are increasing.
Although the successful prevention of sudden cardiac death by device implantation is often paramount in the cardiologist’s
mind, our study shows that the decision to offer ICDs to these patients is not straightforward—patient selection, device
implantation, and programming must be meticulous to minimize the morbidity burden associated with both the diagnosis
and its treatment. With a mean follow-up of 38⫾27 months, 8% of patients had an appropriate shock, and 28% had
complications, with 20% having inappropriate shock. In the group given ICDs because of syncope, 10% had an appropriate
shock and 7% had a recurrence of syncope without any arrhythmic event. An objective tool to better stratify the risk of
arrhythmic events in Brugada syndrome is eagerly awaited.
Downloaded from http://circ.ahajournals.org/ by guest on June 11, 2017
Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada
Syndrome. A Multicenter Study
Frédéric Sacher, Vincent Probst, Yoshito Iesaka, Peggy Jacon, Julien Laborderie, Frédérique
Mizon-Gérard, Philippe Mabo, Sylvain Reuter, Dominique Lamaison, Yoshihide Takahashi,
Mark D. O'Neill, Stéphane Garrigue, Bertrand Pierre, Pierre Jaïs, Jean-Luc Pasquié, Mélèze
Hocini, Michèle Salvador-Mazenq, Akihiko Nogami, Alain Amiel, Pascal Defaye, Pierre
Bordachar, Serge Boveda, Philippe Maury, Didier Klug, Dominique Babuty, Michel
Haïssaguerre, Jacques Mansourati, Jacques Clémenty and Hervé Le Marec
Circulation. published online November 20, 2006;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2006 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2006/11/20/CIRCULATIONAHA.106.628537.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/