A PROSPECTIVE REGISTRY OF EMPIRIC QUINIDINE
THERAPY FOR ASYMPTOMATIC BRUGADA SYNDROME.
Brugada syndrome is a rare disease first described in 1992. 1 It is a genetic disease
involving mutations in myocardial ion channels that play a major role in myocardial
depolarization and repolarization.2, 3
The majority of genotyped patients have
mutations causing malfunction of the channel responsible for the inward sodium
current.4 However, the disease is genetically heterogeneous and mutations causing
malfunction of other myocardial ion channels have been recently identified. 4-9 The
phenotypic manifestations of the disease include an abnormal electrocardiogram and
a tendency to develop cardiac arrhythmias.1, 10
The abnormal electrocardiogram (ECG) consists of a right bundle branch block pattern
with ST-segment elevation in the right precordial leads (leads V1-V3). Based on the
degree of ST elevation and the morphology of the ST segment, the "Brugada
electrocardiogram" is classified as follows:2 Type 1Brugada pattern is characterized by
a coved ST-segment elevation ≥2 mm (0.2 mV) followed by a negative T wave. Type 2
ST-segment elevation has a saddleback appearance with a high takeoff ST-segment
elevation of ≥2 mm, a trough displaying <1 mm ST elevation, and then either a
positive or biphasic T wave. Type 3 has either a saddleback or coved appearance with
an ST-segment elevation of <1 mm. Type 2 and type 3 ECG are not diagnostic of the
Brugada syndrome. These 3 patterns may be observed spontaneously in serial ECG
tracings from the same patient11 but only type I is considered diagnostic of Brugada
syndrome. Whenever Brugada syndrome is suspected and only type II and type III
electrocardiograms are recorded, the following diagnostic tests may be performed to
unravel a type I electrocardiogram: 1) placing the precordial electrodes (V1- and V2)
at the second or third intercostal space (instead of the standard location at the fourth
intercostal space).13 or 2) performing a drug challenge test (intravenous infusion of a
sodium channel blocker like flecainide or ajmaline).2, 14
The clinical manifestations of the Brugada syndrome are caused by cardiac
arrhythmias. Sinus node dysfunction or atrioventricular conduction block15 may lead to
bradycardia-related symptoms like weakness or syncope and atrial arrhythmias (like
atrial flutter or atrial fibrillation)16, 17 may lead to palpitations. However, the most
common and serious manifestations of Brugada syndrome are syncope or sudden
death to malignant (mainly polymorphic) ventricular arrhythmias. 1, 10
There is general world-wide consensus that patients with symptomatic Brugada
syndrome, including those with malignant syncope (believed to be due to malignant
ventricular arrhythmias) and those resuscitated after cardiac arrest due to ventricular
fibrillation (VF), ought to be treated with an implantable cardioverter defibrillator (ICD). 2
Quinidine has been proposed as an alternative therapy for selected patients with
symptomatic Brugada syndrome.18-20 On the other hand, the best treatment for
patients with asymptomatic Brugada syndrome is still a matter of considerable
debate.21, 22 The standard of care for such patients has involved risk stratification with
electrophysiologic studies (EPS): Patients who have no inducible arrhythmias are
generally left without treatment whereas ICD implantation has been widely
recommended for patients who have inducible VF at EPS. 2 However, this therapeutic
approach to asymptomatic Brugada syndrome is probably causing more harm than
The problems of the present therapeutic approach.
All over the world, patients with asymptomatic Brugada syndrome are undergoing
electrophysiologic studies (EPS);25, 26
depending on the aggressiveness of the EPS
protocol, 20%-80% of such patients will have inducible ventricular fibrillation (VF)23, 25-
and many will undergo implantation of an implantable cardioverter defibrillator
However, the rate of spontaneous VF among patients undergoing
prophylactic ICD implantation for "asymptomatic Brugada syndrome with inducible VF"
appears to be only 1% per year according to a multicenter European study.29
Accordingly, ICD implantation might be unnecessary for the vast majority of patients.
On the other hand, 28%29 - 32%28 of these young individuals develop very serious
complications directly related to ICD implantation. Thus, the wisdom of guiding our
therapeutic approach by the results of EPS is increasingly questioned.22, 24-26
Why is it that the EPS-guided approach is not working?
There is general agreement that the risk for cardiac arrest for patients with negative
EPS is only 1-2%.24 It should be emphasized, however, that these low values relate to
a mean follow-up period of less than 4 years.26 The long-term risk for patients with
asymptomatic Brugada syndrome and negative EPS could conceivably be higher.
Obviously, the negative predictive value of EPS will depend on the aggressiveness of
the EPS protocol used. Unfortunately, using more aggressive EPS protocols to
improve the negative predictive value, particularly if including extrastimulation with
very short coupling intervals, would inevitably reduce the positive predictive value of
the test as well.36
Understanding the significance of a positive EPS in the asymptomatic patient is even
more problematic.24 To begin with, one should realize that it is possible to induce VF
with double or triple ventricular extrastimulation in at least 6% of healthy individuals.24
In fact, the rate of accidental VF induction could be much higher than 6% because (as
explained in detail elsewhere24) 6% to 41% of the healthy individuals participating in
the 5 studies37-41 looking at the specificity of "inducible VF" did not go through the
entire EPS protocol because the study was terminated prematurely to avoid the need
for DC shock when non-sustained polymorphic ventricular tachycardia was induced.
Defining the positive predictive value of EPS in patients with asymptomatic Brugada
syndrome is even more problematic.21, 22 On the one hand, Brugada et al have
presented data showing that 12% of asymptomatic patients with inducible VF will have
cardiac arrest (or spontaneous ventricular arrhythmias triggering ICD therapy) within 3
years of follow-up.23, 27 On the other hand, data from 10 published studies
(summarized by Paul)26 including data for more than 250 patients with inducible VF
suggests that the risk is no more than 4%.24 As explained elsewhere,26 the higher
(12%-risk) figures published by Brugada probably resulted from over-representation of
patients with more severe forms of the disease in their earlier series.
Why are the complication-rates after ICD implantation for Brugada syndrome so
It is not surprising that the complication rate after ICD implantation for Brugada
syndrome (28% in a multicenter European study), is higher than the 12%
complication rate reported in the Antiarrhythmic Versus Implantable Defibrillators
(AVID) trial.42 AVID patients had organic heart disease and, consequently, 16% of
them died within 18 months of ICD implantation.43 The much longer survival of
patients with Brugada syndrome (who are young and free of heart disease) inevitably
places them at increased risk for ICD-related complications in the long term because
the repeated need for ICD replacements significantly increases the risk of device-
related infection.44 Also, the risk for electrode fractures increases over time, especially
in young active males.45 Patients with Brugada syndrome are also at increased risk for
ICD related complications in the short term because they are physically active, tend to
have atrial arrhythmias16, 17, 46 and do not receive beta-blockers. All these factors
significantly increase their risk for inappropriate shocks,28, 29, 45 which seriously impair
quality of life.
Many patients and physicians are finding the above-mentioned morbidity intolerable,
particularly after prophylactic ICD implantation. The search for alternative therapeutic
strategies, like empiric prophylactic therapy with quinidine is therefore justifiable.
The Brugada syndrome has been associated with mutations affecting sodium, calcium
and potassium channels subunits.4-9 Irrespectively of the ion-channel involved, a
prominent ITo (transient outward potassium current) appears to play a predominant
role in arrhythmogenesis.47 Consequently, blocking the ITo channel is a logical
approach and this can be done with quinidine.47 Indeed, the following lines of
evidence support the use of quinidine for the primary prevention of arrhythmic death in
Brugada syndrome: 1) Quinidine prevents phase-II reentry and VF in the wedge-
preparation that mimics Brugada syndrome in vitro.47 2) Quinidine tends to normalize
the electrocardiogram.48 3) Quinidine is extremely effective in preventing the induction
of VF in humans during EPS (76%20-88%18 of patients who have inducible VF at
baseline EPS are rendered non-inducible by quinidine therapy). 4) Quinidine is very
effective for aborting VF-storms.49, 50 5) Non-randomized studies suggest that
quinidine prevents spontaneous arrhythmias in high-risk patients with Brugada
syndrome during long-term follow-up.18, 20 In fact, Belhassen et al have effectively
used quinidine as the sole therapy (without ICD back-up) for patients with symptomatic
Brugada syndrome, including patients who had spontaneous VF before the initiation of
therapy.18 In a recent study, none of the 50 patients with symptomatic or
asymptomatic Brugada syndrome developed symptomatic ventricular arrhythmias
during quinidine therapy.28
Risk vs. benefit considerations of empiric quinidine in Brugada syndrome.
Quinidine often causes side effects (like diarrhea, thrombocytopenia, hepatitis) that
resolve following drug discontinuation. When high doses of quinidine are used,18 one
of 3 patients receiving empiric quinidine have to discontinue the medication because
of drug-intolerance. On the other hand, excellent long-term tolerability has been
reported for patients with Brugada syndrome receiving low doses of quinidine. 51
The main concern relates to the potential proarrhythmic risks of quinidine. A 2%-
8%.risk for torsade de pointes from quinidine has been estimated and this risk
appears to be dose-independent 52 However, these figures mainly reflect the risk for
patients with organic heart disease.52 Also, male gender decreases the risk of drug-
induced torsade de pointes53 and the vast majority of patients with Brugada syndrome
are males. Finally, most cases of quinidine-induced torsade occur soon after the onset
of therapy54 and close monitoring during the first 3 days of therapy should prevent
proarrhythmic complications. Torsade de pointes occurring long after the onset of
therapy is often due to drug interactions or hypokalemia55 and meticulous avoidance
of such risk factors should reduce the risk of torsade de pointes from quinidine in
patients with Brugada syndrome to a minimum.
The present study:
A PROSPECTIVE REGISTRY OF EMPIRIC QUINIDINE FOR ASYMPTOMATIC BRUGADA SYNDROME.
This Prospective International Registry will recruit patients with asymptomatic Brugada
syndrome (NIH-Clinical Trial Registry number pending). Brugada syndrome will be
defined according to the Second Consensus Conference 2 and patients will be
considered "asymptomatic" if they do not have a history of cardiac arrest or a history
of syncope with malignant clinical characteristics suggesting arrhythmic origin. In other
words, patients reporting palpitations, atypical chest pain and/or a history of syncope
with clinical characteristics suggestive of benign vasovagal syncope will be counted as
"asymptomatic" and will be accepted to the trial (Figure 1). The Registry encourages
empiric therapy with Hydroquinidine hydrochloride (Serecor, Sanofi-Aventis, France)
600 to 900 mg/day; http://drugs-about.com/drugs/serecor.html). Lower doses of
quinidine have been associated with higher incidence of inducibility of VF during
repeated EPS.51 However, the effects of low-dose quinidine for preventing
spontaneous arrhythmias is less clear and reduced doses are clearly associated with
better long-term tolerability.51 Therefore, patients developing adverse events have the
option of continuing low doses of quinidine (like 300 mg at bed-time). Also, such
patients may then opt to undergo EPS (with subsequent ICD implantation if the EPS is
positive) or may prefer follow-up with no therapy. It is difficult to say at this point which
of all these options will prove to be better in the long-term. Finally, in view of recent
data suggesting that unselected patients with asymptomatic Brugada syndrome are at
low risk for developing spontaneous VF, it is recognized that physicians and patients
may prefer to avoid antiarrhythmic therapy altogether. Such patients are welcomed to
join the Registry (Figure 1).
Aim of the study.
To collect prospective data of patients with asymptomatic Brugada syndrome that will
help define what is the best therapeutic approach for this disease.
Prospective registry. Mode of therapy is not randomized. Instead, the therapeutic
approach (including the option of clinical follow-up with no therapy) is selected by the
physician and primary care physician.
1. Patients with Asymptomatic Brugada syndrome.
"Brugada syndrome" is defined as the presence of a Type-I Brugada
electrocardiogram [coved ST-segment elevation ≥2 mm (0.2 mV) in V1, V2 or
V3] either spontaneously (at rest, in the baseline state or during a febrile
episode) or following a standard drug-challenge test (with flecainide, ajmaline,
procainamide, or pilsicainide) and recorded either with standard electrode
position or with the precordial electrodes placed on the second or third
"Asymptomatic patients" will be defined as patients without a history of cardiac
arrest, a history of "arrhythmic syncope" or a history of "suspected arrhythmic
syncope." Arrhythmic syncope" is a syncope occurring during documented
ventricular tachyarrhythmias. "Suspected arrhythmic syncope" is a syncope
without documented arrhythmias believed to be caused by a tachyarrhythmia
based on clinical judgment. In other words, patients with typical vagal syncope
will be counted as "asymptomatic" and will be accepted to the registry whereas
patients with a clinical history suggesting "syncope other than vagal syncope"
will not be accepted to this Registry.
Genetic confirmation (identification of a disease-causing mutation) will not be
required for establishing the diagnosis of Brugada syndrome but will be
recorded when present.
2. Patients with Questionable Brugada Syndrome who are asymptomatic.
Patients with "Questionable Brugada Syndrome" are defined as patients with
type II or III electrocardiogram who have an inconclusive result during a drug
challenge with a sodium channel blocker. "asymptomatic" is defined as above.
Genetic testing will not be required. However, patients with "Questionable
Brugada" based on electrocardiographic criteria will be defined as "Patients
with Brugada Syndrome" if a disease-causing mutation is identified.
1. A history of cardiac arrest, "arrhythmic syncope" or "suspected arrhythmic
syncope" (as defined above).
2. Evidence of organic heart disease. The evaluation considered mandatory for
excluding heart disease will consist of electrocardiogram, echocardiogram and
exercise stress testing. Additional tests will be performed only if clinically
3. Evidence of non-cardiac disease likely to affect 5-year survival.
1. Patients will receive a complete explanation of the risk and benefits of the
different therapeutic approaches to asymptomatic Brugada syndrome, including
the risk and benefits of a) clinical follow-up with no therapy; b) empiric therapy
with quinidine; c) EPS-based risk stratification and EPS-based therapy with
quinidine or ICD. In view of the conflicting evidence regarding the predictive
value of EPS that emerges from recent trials, performance of EPS studies will
not be recommended.
2. Patients agreeing to participate in this Registry will be entered into the Registry
data base. "Agreeing to participate" means signing the informed consent form.
The informed consent form will specifically emphasize that – at the present time
– the optimal therapeutic approach for asymptomatic Brugada syndrome is
unknown. The informed consent form will emphasize the risk and benefits of
each potential therapy (including observation with no therapy, quinidine therapy
and ICD implantation). The informed consent form will also specifically mention
that the patient and his/her physician agree to provide sufficient contact
information to allow for adequate collection of follow-up data for a minimum of 5
years of follow-up. The contact information will include the patient's full name
and contact information as well as those of the primary care physician and an
immediate relative that could be contacted by the Registry if contact with the
patient is lost.
3. Patients entering the Registry will authorize their physician to enter clinical data
and scanned electrocardiograms to the Registry data-base. The Registry
principal investigators will review this information. The Registry principal
investigators may decide that the patient does not qualify for the Registry
according to the inclusion/exclusion criteria and will define the patient as "Not
Registered." Alternatively, based on the clinical and electrocardiographic data
the principal investigators will define the patient as "Registered" and will classify
the patient into one of the following categories:
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Based on the clinical history the patient will be classified as "totally
asymptomatic" or as "patient with syncope believed to be of vagal etiology"
(patients with syncope believed to be of arrhythmic origin are excluded).
The electrocardiogram will be classified as: a) Type-I Brugada at baseline ECG;
b) Type-I electrocardiogram recorded only during a febrile episode; c) Type-I
electrocardiogram recorded only with the electrodes positioned at a high
intercostal space; d) Type I electrocardiogram recorded only during a challenge
test with sodium channel blocker; e) Questionable Brugada (when Type I
electrocardiogram is not recorded and the drug-challenge with sodium channel
blocker is inconclusive.
4. Patients accepted to the Registry will be encouraged to start empiric quinidine
therapy with hydroquinidine hydrochloride (Serecor, Sanofi-Aventis, France)
900 mg/day or with equivalent doses of quinidine. However, patients preferring
to avoid antiarrhythmic therapy will also be welcomed to join the Registry as
long as informed consent is provided as above.
5. For patients opting to start quinidine therapy, hospitalization to provide
electrocardiographic monitoring for 48 - 72 hours during the onset of quinidine
therapy will be encouraged for males and mandatory for females. There is no
clear-cut definition of "excessive QT prolongation" during quinidine therapy and
the degree of QT prolongation that accurately distinguishes "therapeutic" from
"proarrhythmic" effects of quinidine have not been defined. Therefore, the
decision to discontinue quinidine because of "excessive QT prolongation" will
be the responsibility of the primary attending physician. However, the principal
investigators of the Registry will provide expert opinion in this regard.
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6. Patients on quinidine therapy will be requested to perform blood tests (including
a complete blood count, liver function tests, kidney function tests and sodium
and potassium serum levels) within one week after initiation of therapy, one
month after the initiation of therapy and twice a year thereafter.
7. Patients with dose-dependent adverse events from quinidine (like diarrhea) will
be encouraged to reduce the dosage and continue therapy with the maximally
tolerated dosage. Patients who cannot tolerate more than 300 mg serecor daily
will be encouraged to take the medication at bedtime.
8. Patients with dose-independent adverse events from quinidine (like
thrombocytopenia) will discontinue the medication and will select one of the
following therapeutic approaches: a) clinical follow-up with no therapy or b)
EPS-guided risk stratification and therapy with ICD if inducible. The selection of
therapy will be the responsibility of the patient and his primary physician but the
Registry will encourage clinical observation with no therapy at this point,
especially for patients who do not have a Type-I electrocardiogram at rest.
9. All patients and their immediate family members will be encouraged to undergo
training in basic cardiopulmonary resuscitation (CPR) techniques and will be
advices about the availability of External Automatic Defibrillators (EAD) for
home use. Patients will also be advised of the availability of Implantable Holter
and home-monitoring devices that could potentially detect asymptomatic
arrhythmias during long-term follow-up.
10. All patients will be informed of the possibility that some medications may be
proarrhythmic and dangerous for patients with Brugada syndrome. The use of
these medications will be strongly discouraged: class 1C antiarrhythmic drugs
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(like propafenone and flecainide); beta-blockers, calcium-channel blockers and
11. The Registry will provide no funding for medications, hospitalizations, EAD or
12. The Registry will collect follow-up information twice yearly from each patient,
his/her physician and (if needed) from the patient's immediate relative if
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