Excellent Long-Term Reproducibility of the
Electrophysiologic Efficacy of Quinidine
in Patients with Idiopathic Ventricular Fibrillation
and Brugada Syndrome
BERNARD BELHASSEN, M.D., AHARON GLICK, M.D., and SAMI VISKIN, M.D.
From the Department of Cardiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel, and Sackler School of
Medicine, Tel-Aviv University, Tel-Aviv, Israel
Background: Quinidine is very effective in preventing the reinduction of sustained ventricular fibrillation (VF) during electrophysiologic study (EPS) in patients with idiopathic VF and Brugada syndrome.
However, there are no data on the long-term reproducibility of this EP efficacy.
Methods and Results: Nine patients (seven males and two females, aged 21–72 years), who suffered
from aborted cardiac arrest (n = 8) or recurrent syncope (n = 1) due to Brugada syndrome (n = 5) or
idiopathic VF (n = 4), comprised the study. All patients had inducible sustained VF at baseline that was
prevented by quinidine therapy and underwent another EPS on medication after 1.7–23.6 (9.8 ± 6.8) years
(>5 years in eight patients). Two patients underwent two late EPS on quinidine. The goal of repeat EPS on
quinidine was to ensure persistent long-term drug efficacy (n = 6) or to elucidate the reason of syncopal
episodes during therapy (n = 3). The EPS protocol significantly evolved over the years as it became
more aggressive (more pacing sites and/or more ventricular extrastimuli). All nine patients tolerated the
medication well and had no recurrent documented arrhythmic events during long-term follow-up (mean
15 ± 7 years). No sustained ventricular tachyarrhythmias could be induced in any patient during repeat
late EPS. In six patients, a more aggressive stimulation protocol could be tested at repeat EPS.
Conclusion: The long-term reproducibility of the EP efficacy of quinidine in patients with idiopathic
VF and Brugada syndrome is excellent. EP-guided quinidine therapy represents a valuable long-term
alternative to ICD therapy in these patients. (PACE 2009; 32:294–301)
quinidine, electrophysiologic study, programmed ventricular stimulation, idiopathic ventricular
fibrillation, Brugada syndrome
Introduction
Implantation of an automatic cardioverterdefibrillator (ICD) is recommended by most cardiac electrophysiologists worldwide in patients
with ventricular fibrillation (VF) occurring in patients without organic heart disease (idiopathic
VF) and those affected with the Brugada syndrome.1,2 Antiarrhythmic therapy with quinidine
is frequently used as an adjuvant to control recurrent ventricular arrhythmias in implanted patients.3,4 The policy at our institution during the
last three decades concerning these patients has
been different and based on our published experience5–7 showing: (1) the great efficacy of quinidine
in preventing reinduction of sustained ventricular
tachyarrhythmias during electrophysiology study
(EPS), and (2) the excellent long-term clinical out-
No disclosure.
Address for reprints: Bernard Belhassen, M.D., Department
of Cardiology, Tel-Aviv Sourasky Medical Center, Weizman
Street 6, Tel-Aviv 64239, Israel. Fax: +00-972-3-697-4418;
e-mail: bblhass@tasmc.health.gov.il
Received April 28, 2008; revised August 4, 2008; accepted
September 18, 2008.
come of the patients treated with the drug. Thus,
we usually have left the patient the choice between implantable cardioverter-defibrillator (ICD)
therapy and EP-guided chronic quinidine therapy.8 However, there is only scarce information
available about the long-term EP efficacy of quinidine. In this study, we review our experience on
the long-term EP efficacy of quinidine in a group
of patients who underwent EP-guided quinidine
therapy for idiopathic malignant ventricular tachyarrhythmias.
Methods
Patient Selection
Records of all patients with inducible sustained VF during EPS were reviewed. Criteria for
inclusion in the study included all the following: (1) no recognizable heart disease based on
normal findings during noninvasive (echocardiogram, exercise test, Thallium test) and/or invasive
(right and left ventriculography and coronary angiography) evaluation, (2) normal baseline QT interval on repeated electrocardiograms (ECGs), (3)
EP testing with quinidine showing no inducible
sustained ventricular arrhythmias, (4) long-term
treatment with quinidine following the initial
C 2009 Wiley Periodicals, Inc.
C 2009, The Authors. Journal compilation 294
March 2009
PACE, Vol. 32
PACE, Vol. 32
M 28
M 52
F 24
M 27
M 40
M 21
M 43
F 51
M 72
1
2
3
4
5
6
7
8
9
Abbreviations: A = age; BL = blood level (mg/L); BS = Brugada syndrome; F = female; IVF = idiopathic ventricular fibrillation; NI = noninducible; M = male; NA = nonavailable;
NSVT = nonsustained ventricular tachycardia; Pt = patient; S = sex; * = quinidine hydrochloride.
NSVT(24)
NSVT(7)
2.5
3.2
1,500
1,500
13/6/02
16/2/06
NSVT(7)
NI
NSVT(60)
NI
NSVT(34)
NSVT(15)
NSVT(14)
NI
NI
2.57
NA
NA
3.8
1.5
NA
2.9
1.2
NA
1,500
1,500
1,500
1,500
1,500
1,500
1,500
600*
750
7/11/02
14/7/92
3/9/02
11/7/95
13/2/99
13/7/99
23/11/99
23/10/07
24/5/05
NI
NI
NSVT(7)
NI
NI
NSVT(9)
NI
NI
NSVT(17)
2.0
5.2
2.3
3.8
2.6
3.9
4.5
6.2
1.29
1,500
1,500
1,500
1,500
1,500
1,500
1,500
1,500
750
5/4/79
22/11/81
27/2/85
16/11/87
4/2/92
31/7/94
22/11/94
2/12/97
23/9/03
Results
BL
Dose
Date
Diagnosis
IVF
VF + BS
VF + BS
IVF
IVF
VF + BS
VF + BS
IVF
Syncope + BS
Results
BL
Dose
Date
BL
Dose
Quinidine Bisulphate
Quinidine Bisulphate
Date
EPS No. 2
Results
March 2009
S/A
The study group comprised nine patients,
seven males and two females, ranging in age from
21 to 72 (40 ± 16.5) years (Table 1). Five patients
Pt
Results
Study Patients (Table I)
EPS No. 1
Definitions
Sustained VF was a ventricular tachyarrhythmia manifesting a continuously varying morphology with a mean cycle length <200 ms that required cardioversion for termination or resulted
in clinical cardiac arrest before spontaneous termination. Nonsustained ventricular tachycardia
(NSVT) was a tachycardia of ≥6 complexes that
was shorter than 30 seconds in duration and was
not associated with loss of consciousness. Arrhythmias were “noninducible” when <6 repetitive ventricular complexes were induced.
Results of Electrophysiological Drug Testing in Nine Patients
Table I.
EPS Protocol
EPSs were performed using a protocol of
programmed ventricular stimulation (PVS) that
evolved over the years. From 1979 to 1982, PVS
was performed only from the right ventricular
apex, using three basic cycle lengths (600, 500,
and 400 ms) and a maximum of two extrastimuli.
In 1983, pacing from the right ventricular outflow
tract (RVOT) was added and the number of basic cycle lengths was decreased to two (usually
600 and 400 ms). The use of triple extrastimulation in our laboratory was introduced in 1988.
In addition, our protocol has included repetition
(10 times) of double extrastimulation (since 1979)
and repetition (five times) of triple extrastimulation (since 1988) both at the shortest coupling intervals. This was done at each pacing site and for
each of the cycle lengths tested. We previously
found that repetition of extrastimulation increases
the sensitivity of PVS protocols.11 The stimulus
current intensity was set at five times the diastolic
threshold (but never >3 mA).
EPS No. 3
drug testing, and (5) repeat EP testing on quinidine ≥1 year following the first drug study.
From February 1979 to December 2007, 76
patients (87% males, 38% with spontaneous VF)
with inducible VF and no obvious heart disease
underwent repeat EP testing with quinidine in our
laboratory. In 71 (93.4%) of these patients, quinidine bisulphate (750–2,000 mg/day) effectively
prevented the reinduction of sustained ventricular arrhythmias. Nine (12.6%) of the 71 patients
underwent repeat EPS on quinidine >1 year after
the initial drug testing and comprised the study
group. The case report of one of the patients has
been reported elsewhere.9,10 All the study patients
were included in our previous publications.5–7
Quinidine Bisulphate
QUINIDINE FOR IDIOPATHIC VF AND BRUGADA SYNDROME
295
BELHASSEN, ET AL.
Figure 1. ECG tracings obtained at hospital admission (November 24, 1997) of a 57-year-old woman with a history
of multiple syncopes (no. 10) during the few weeks prior to admission. Ventricular extrasystoles of variable coupling
interval (some of them very short coupled) are seen in panel A. Panel B shows an episode of rapid nonsustained
polymorphic ventricular tachycardia, triggered by a very short coupled ventricular extrasystole. In panel C, a similar
long-lasting episode resulting in syncope is shown.
In all nine patients who had inducible sustained VF at baseline, no sustained ventricular
tachyarrhythmias could be induced during treatment with quinidine bisulfate (Quiniduran,* Teva
Laboratories, Tivka, Israel) at doses ranging from
750 mg (one patient) to 1,500 mg (eight patients)
(Figs. 2 and 3). The effective quinidine serum
blood levels ranged from 1.3 to 6.2 mg/L (mean
3.5 ± 1.6 mg/L). In six of these nine patients,
no significant arrhythmias were induced while
asymptomatic NSVT including 7–17 beats was induced in the remaining three patients.
ride quinidine (Serecor,* Sanofi-Aventis Laboratories, Paris, France) due to discontinuation of the
production of quinidine bisulphate.12 In seven of
the eight patients who underwent initial and repeat EPS on the same quinidine salt, an identical
drug dosage of 1,500 mg/day was tested. In five
patients, the serum quinidine levels obtained at
the initial and repeat EPS were 3.82 ± 1.65 and
2.39 ± 1.05 mg/L, respectively (P = 0.14 using
paired Wilcoxon signed-ranks test).
No sustained ventricular tachyarrhythmias
could be induced in any of the nine patients during repeat EP testing on quinidine (Figs. 4 and 5).
This was observed despite the fact that in four
of the nine patients, the PVS protocol was more
aggressive at repeat study (triple extrastimulation
could be tested at repeat EPS while only double extrastimulation was applied at the initial
EPS).
Repeat EPS on Quinidine (Table I)
Repeat EP study was performed in all nine patients after 1.7–23.6 (9.8 ± 6.8) years of quinidine
therapy (≥5 years in eight of nine patients). The
goal of the repeat EPS on quinidine was to ensure
persistent long-term drug efficacy (n = 7 patients)
or to elucidate the reason of syncopal episodes
during therapy (n = 2; patients 5 and 9). In all
patients but one, the repeat drug study was performed on the same quinidine salt (bisulphate). In
one patient the EPS was performed on hydrochlo-
Third EPS on Quinidine (Table I)
In two of the nine patients (patients 6 and 7),
a third EPS was performed during quinidine therapy 3 years and 6 years, respectively, after the second drug study. In patient 7 it was performed to
reassess drug efficacy while in patient 6 it was
justified by the occurrence of a syncopal episode
during quinidine therapy. In both patients, only
NSVT could be induced.
(one female) had Brugada syndrome and four patients had idiopathic VF. Eight patients had cardiac arrest with documented VF (Fig. 1) and one
patient with the Brugada syndrome had recurrent
syncope of unknown cause.
Initial EPS on Quinidine (Table I)
296
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QUINIDINE FOR IDIOPATHIC VF AND BRUGADA SYNDROME
Figure 2. Baseline electrophysiologic study (November 25, 1997). Induction of sustained rapid polymorphic ventricular tachycardia with triple extrastimulation from the right ventricular apex. The tachycardia was terminated with
DC shock.
Clinical Course
All nine patients tolerated the medication
well during long term and had no recurrent
documented arrhythmic events during follow-up
ranging from 4.5 to 29 (mean 15 ± 7) years. However, an ICD was implanted in two patients (patients 3 and 6). Patient 3 was 24 years old at the
time of initial cardiac arrest. After 17 uneventful
years of quinidine therapy, she opted for the ICD
option (of note, this patient had two uneventful
pregnancies and normal childbirth during quinidine therapy). Patient 6 initially presented with a
history of recurrent syncope and had documented
VF at the emergency room. He remained asymptomatic for 8 years on 1,500-mg quinidine (which
was found effective at two EP studies performed
5 years apart) but later had unexplained syncope
that prompted a third EP study on quinidine. Although this study only showed the induction of a
4-second episode of NSVT, it could not be ruled
out that that the syncopal episode was due to
a spontaneous longer episode of NSVT. Therefore, an ICD was implanted without discontinuing
PACE, Vol. 32
quinidine therapy. Three months and 1 year later,
the patient had recurrent syncope but ICD interrogation failed to reveal any arrhythmia in both
instances.
One patient (no. 2) who had normal coronary
angiography in 1981 at the time of his cardiac arrest underwent coronary artery bypass grafting for
multivessel disease with preserved left ventricular function 18 years later. All remaining eight patients had no change in their cardiac status during
follow-up.
Discussion
Efficacy of Quinidine
In contrast to the present general skepticism
of the cardiologic community toward the use of
class 1 antiarrhythmic drugs and especially quinidine in patients with ventricular arrhythmias, the
literature has shown the extraordinary efficacy of
this drug in the treatment of malignant arrhythmias occurring in patients with no demonstrable heart disease. The first patients with idiopathic VF reported, back in 1929 and 1949, were
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BELHASSEN, ET AL.
Figure 3. Repeat electrophysiologic study after 1 week of treatment with quinidine bisulfate (1,500 mg/day). No
ventricular arrhythmias could be induced with up to five extrastimuli delivered from both the right ventricular apex
and the right ventricular outflow tract.
treated with quinidine after multiple episodes of
spontaneous polymorphic VT and VF were clearly
documented.13,14 Both patients had an excellent
response to the medication. Interestingly, a second
publication reporting the long-term follow-up of
the patient initially reported in 1949 established
that this patient eventually died of cancer at old
age, without ever experiencing a recurrence of
his arrhythmia while on quinidine therapy for
40 years.15 In addition, quinidine is being successfully used as a first-line therapy for abolishing arrhythmic storms in patients with Brugada
syndrome.3,4
Our group reported the first largest series of
patients with idiopathic VF or Brugada syndrome
in whom quinidine was found to be very effective (96%) in preventing VF reinducibility during
EPS.6 Similar results were found by others.16–21 In
this study, we report the first series of nine pa-
298
tients with inducible VF in whom the repeat EP
efficacy of quinidine was confirmed late (>5 years
in eight patients) following the initial drug
testing.
In patients with Brugada syndrome, the efficacy of quinidine has been attributed to various mechanisms: (1) strong inhibition of Ito
current that restores electrical homogeneity and
abolishes phase 2 reentry,2 and (2) anticholinergic effects. In patients with idiopathic VF, the
mechanism of the efficacy of quinidine is much
obscure.6
Effect of Stimulation Protocol
Our study has spread over three decades,
and major changes in the stimulation protocol occurred during this period. Therefore, one
could wonder whether the use of more aggressive PVS protocols at repeat drug study would
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QUINIDINE FOR IDIOPATHIC VF AND BRUGADA SYNDROME
Figure 4. Repeat electrophysiologic study performed approximately 10 years later during treatment with quinidine hydrochloride (600 mg/day). Only single repetitive ventricular complexes
are induced with triple extrastimulation from the right ventricular apex.
have revealed drug failure among some patients
studied earlier with less aggressive protocols. The
results of our study showed that this was not
the case. All four patients in whom drug efficacy
was first tested with double extrastimulation and
who were subsequently tested with more aggressive PVS protocols showed a similar efficacy of
quinidine.
Figure 5. Same findings as in Figure 4 during programmed ventricular stimulation from the right
ventricular outflow tact.
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BELHASSEN, ET AL.
Study Limitations
Following the first drug study, eight of our
nine patients did not develop any change in their
cardiac condition during follow-up as expected
from the fact they had no obvious heart disease
at study inclusion. However, one patient subsequently developed significant coronary artery disease with preserved left ventricular function. Had
this patient suffered an acute myocardial infarction during quinidine therapy it might have altered the later EP results. Therefore, close patient
follow-up is necessary in order to detect any
change in cardiac status or other abnormalities
(such as electrolyte disturbances) that may affect
the safety of long-term quinidine therapy.
Clinical Implications
The results of our study suggest that EPguided therapy with quinidine is a very reasonable
long-term therapeutic alternative to ICD therapy
for patients with idiopathic VF or Brugada syndrome provided several conditions are fulfilled:
(1) the patients have inducible VF at baseline EPS,
(2) quinidine prevents the reinduction of VF, (3)
the patients exhibit a good tolerance to the medication, (4) repeated assertion of drug compliance
during follow-up is obtained, (5) the patients are
committed to a life-long drug therapy, and (6) no
significant change in cardiac status occurs during follow-up. Such a therapeutic option can be
safely recommended to patients who refuse the
implantation of an ICD or to patients for whom
cost constraints resulting from implantation and
replacements of ICD over the years will make impossible the ICD option. Other potential candidates are young patients in whom multiple ICD replacements are expected during long term as well
as patients in whom ICD needs to be explanted due
to complications. Finally, our results suggest that
patients with Brugada syndrome and inducible
VF, but no previous cardiac arrest, and in whom
controversial results presently exist concerning
the predictive value of EPS,22,23 may benefit from
the quinidine option rather than ICD therapy, taking in account the high incidence of complications observed with ICD, some of them potentially
lethal.24
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