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Quinidine Revisited
Felix Yang, MD, Sam Hanon, MD, Patrick Lam, MD, Paul Schweitzer, MD
Beth Israel Medical Center, University Hospital for the Albert Einstein College of Medicine, New York, NY.
ABSTRACT
One of the earliest antiarrhythmic drugs developed, quinidine had a significant role in the treatment of
many arrhythmias. After concerns for increased risk of ventricular arrhythmia and death with quinidine
emerged, the use of quinidine fell dramatically in favor of newer antiarrhythmic medications. However,
recent trials have generated renewed interest in the use of quinidine. In particular, quinidine appears to be
safe and efficacious in combination with verapamil for the treatment of atrial fibrillation. Quinidine has
also been used successfully to treat idiopathic ventricular fibrillation, Brugada syndrome, and Short QT
syndrome. Although it is one of the oldest drugs in our armamentarium, quinidine continues to have a role
in modern cardiology.
© 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 317-321
KEYWORDS: Antiarrhythmic drug therapy; Arrhythmia; Atrial fibrillation; Brugada syndrome; Idiopathic ventricular
fibrillation; Short QT syndrome; Quinidine
First described in 1848 by Van Heymingen and named by
Pasteur in 1853, quinidine has a long history as an antiarrhythmic. An alkaloid that may be derived from the cinchona tree bark and also prepared from quinine, quinidine
prolongs the effective refractory period and reduces automaticity in the heart. It is, therefore, useful in the treatment
of a wide variety of arrhythmias. The therapeutic qualities
of quinidine, a class IA antiarrhythmic, do not come without
hazards, however. The phenomenon termed “quinidine syncope” was first described in the 1950s, and it was later
realized that quinidine could predispose patients to ventricular fibrillation. Subsequently, its use in the treatment of
atrial fibrillation has dramatically decreased. However,
there has been growing evidence to support its use in conditions such as idiopathic ventricular fibrillation, Brugada
syndrome, and short QT syndrome. In addition, there is
renewed interest in the combination of verapamil and quinidine for the treatment of atrial fibrillation.
Funding: None.
Conflict of Interest: None of the authors have any conflicts of interest
associated with the work presented in this manuscript.
Authorship: All authors had access to the data and played a role in
writing this manuscript.
Requests for reprints should be addressed to Felix Yang, MD, Beth
Israel Medical Center Heart Institute, 350 East 17th Street, Baird Hall 5th
Floor, New York, NY 10003.
E-mail address: [email protected]
0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2008.11.019
ATRIAL FIBRILLATION
Quinidine is moderately efficacious in the acute conversion of atrial fibrillation to normal sinus rhythm.1-3 In
addition, it is comparable to disopyramide, flecainide,
propafenone, and sotalol in maintaining sinus rhythm.2 In
comparison with placebo, class IA drugs had a favorable
treatment difference of 21.5% compared with placebo,
class IC drugs had a treatment difference of 33.1%, and
class III drugs had a treatment difference of 17.4%.4
There was no mortality difference found between the
drug classes, although most of the studies in this analysis
had short follow-up periods.
CONCERNS OF QUINIDINE
The most common side effects of quinidine are gastrointestinal. Infrequently, quinidine can cause thrombocytopenia and agranulocytosis. In 1964, Selzer and Wray5
described a phenomenon that they coined “quinidine syncope.” They described patients who syncopized secondary to ventricular arrhythmias. The most characteristic
feature of the attacks of ventricular fibrillation was their
paroxysmal and repetitive nature. These attacks usually
occurred within 1 to 3 hours after the last dose of quinidine and were usually sudden and seldom preceded by a
warning prodrome.
Further concern about the use of quinidine for atrial
fibrillation developed in the early 1990s. Coplen et al6
pooled data from 6 trials between 1970 and 1984 and
318
The American Journal of Medicine, Vol 122, No 4, April 2009
constructed life table estimates of control groups and the
REVIVAL OF QUINIDINE: ATRIAL FIBRILLATION
patients still in sinus rhythm at 3, 6, and 12 months after
Experimental and clinical data suggest that verapamil is
cardioversion for quinidine. The pooled rate difference beable to suppress after-depolarizations produced by antiartween the quinidine and control groups was 23% to 24%
rhythmic drugs of class I and III, which are likely to lead to
(P ⬍ .001 at all 3 time intervals), indicating that quinidine
torsades de pointes.13-16 The addition of verapamil also is
was more effective than no antiardesirable to avoid high ventricular
rhythmic therapy in suppressing
rates during arrhythmia recurrecurrences of atrial fibrillation.
rences caused by enhanced atrioCLINICAL SIGNIFICANCE
However, the odds of dying in the
ventricular conduction promoted
quinidine-treated group were 3
by the vagolytic effect of
● In combination with verapamil, quinitimes higher than in the control
quinidine.17,18
dine is a relatively safe and effective
group (odds ratio [OR] ⫽ 2.98,
The Prevention of Atrial Fibrilalternative to sotalol and amiodarone
P ⬍ .05).
lation
after Cardioversion Trial
for the maintenance of sinus rhythm in
Southworth and colleagues’7
(PAFAC)
examined the fixed
patients with atrial fibrillation.
meta-analysis in 1999 reiterated
combination of quinidine and vedoubts about the safety of quini● Quinidine has been shown to prevent
rapamil in comparison with sodine. Sotalol and quinidine were
tachyarrhythmias and may prevent sudtalol and placebo in patients with
comparable in their ability to
persistent atrial fibrillation after
den cardiac death in patients with idiomaintain sinus rhythm at 6 months
DC cardioversion.19 A total of 848
pathic ventricular fibrillation, Brugada
(⬃50%), and both are superior to
patients with persistent atrial fisyndrome, and short QT syndrome.
control (34%). However, there
brillation who were successfully
was a trend for both agents to incardioverted were randomized to
crease mortality with long-term
sotalol, quinidine plus verapamil,
therapy. Mortality estimates were 2.2% for sotalol, 3.0% for
or placebo. After a mean follow-up of 266 days, there was
quinidine, and 1.1% for control.
no statistical difference in the recurrence rate between quinMost recently, the Cochrane Database8 pooled 45 studies
idine plus verapamil (65%) versus sotalol (67%). In addito analyze the outcomes of antiarrhythmics for maintaining
tion, the recurrence rate for persistent atrial fibrillation was
sinus rhythm after cardioversion of atrial fibrillation. At 1
reduced with quinidine plus verapamil versus placebo (38%
year of follow-up, class IA drugs (disopyramide, quinidine)
vs 77%). Adverse events while taking sotalol and quinidine
were associated with increased mortality compared with
plus verapamil were comparable with the exception that all
controls (OR 2.39; 95% confidence interval [CI], 1.03-5.59,
10 torsades de pointes episodes occurred while taking sotalol.
P ⫽ .04) and increased proarrhythmia. Quinidine alone demNotably, 65% of all proarrhythmic and potentially life-threatonstrated a nonsignificant but clear trend to increase morening adverse events occurred during the first 4 days of
tality (OR 2.26; 95% CI, 0.93-5.45, P ⫽ .07). When missing
treatment. This study suggested that the use of quinidine be
patients were counted as deaths, the trend became significant
reconsidered given the promising synergy with verapamil.
(OR 2.29; 95% CI, 1.05-5.01, P ⫽ .04).
In the Suppression of Paroxysmal Atrial TachyarrhythIn addition to the concerns regarding the use of quinidine
mias Trial (SOPAT), a fixed combination of quinidine and
for atrial fibrillation, there was growing evidence of harm
verapamil (480/240 mg/d or 320/160 mg/d) was found to be
with its use in the treatment of ventricular arrhythmias. As
as effective as sotalol (320 mg/d) in reducing the recurrence
the results of the Cardiac Arrhythmia Suppression Trial9 put
rate of symptomatic paroxysmal atrial fibrillation.20 The
an end to the use of class IC agents in patients with vencombination prolonged the time to first recurrence of symptricular arrhythmias post-myocardial infarction, Moosvi et
tomatic paroxysmal atrial fibrillation and reduced the numal10 demonstrated an increase in mortality with quinidine
ber of episodes of symptomatic paroxysmal atrial fibrillawhen used empirically for ventricular arrhythmias in this
tion compared with placebo.21
patient population. Similar concerns were raised in a metaSOPAT did demonstrate a low but definite risk of severe
analysis11 comparing quinidine with flecainide, mexiletine,
side effects. There were more deaths, syncope, and ventrictocainide, and propafenone. The combined risk of dying
ular tachycardia events in the antiarrhythmic groups (placewhile taking quinidine was significantly higher compared
bo ⫽ 2, high-dose quinidine plus verapamil ⫽ 5, low-dose
with the other 4 drugs. Proarrhythmia also was reported in
quinidine plus verapamil ⫽ 4, sotalol ⫽ 7). There were no
20 patients taking quinidine versus 11 patients taking the
cases of torsades de pointes reported throughout the trial.
other 4 drugs (P ⫽ .09). Given the negative climate surSo how does one interpret the data from PAFAC and
rounding class I antiarrhythmics, quinidine use decreased
SOPAT in comparison with the older trials with quinidine?
dramatically. According to data from the National AmbuPrevious experiences with quinidine often involved the use
latory Medical Care Survey, the use of quinidine for mainof digoxin. Four of the 6 trials examined in the metatenance of sinus rhythm decreased from 5.0% in 1991 and
analysis by Coplen et al6 were conducted before a quin12
1992 to 0.0% in 1999 and 2000.
idine– digoxin interaction was reported in 1978.22 It is now
Yang et al
Table 1
Quinidine Revisited
Quinidine: Drug Information
Absorption
Peak plasma concentration
Half-life
Protein binding
Metabolism
Excretion
Plasma levels for
antiarrhythmic effects
Notable drug interactions
70% from Gut
1-3 h
6-8 h (increased in liver or renal
disease); longer with slowrelease preparation
80%-90%
Mainly by liver via hydroxylation
Urine (15%-25% as unchanged
drug)
2-5 ␮g/mL (3-5.5 ␮mol/L)
Amiodarone, verapamil, and
diltiazem might increase
quinidine levels.
Digoxin, metoprolol,
propranolol, mexiletine, and
nifedipine levels might be
increased by quinidine.
Warfarin effects might be
increased by quinidine.
recommended that digoxin dosage be reduced by 50% because quinidine significantly reduces the renal tubular secretion of digoxin (Table 1). Some of the arrhythmia-related
deaths may have been due to digoxin toxicity.
Southworth and colleagues7 demonstrated a nonsignificant trend for mortality with long-term treatment. Of the 7
studies examined for quinidine, 4 were the same studies
examined by Coplen and colleagues,6 which predated
knowledge of the quinidine– digoxin interaction. The majority of deaths (9/15 patients) in the quinidine pool occurred in these older studies. Finally, the Cochrane database
examined 7 studies pertaining to quinidine. Three studies
were pre-1978, 2 studies were conducted in the 1980s with
higher dose quinidine, and 2 studies were the PAFAC and
SOPAT. Although one cannot deny that multiple studies
have reported a trend for worse outcomes with quinidine,
one should recognize that the absolute numbers are small, a
number of studies acted as a common denominator in the
meta-analyses, and improved knowledge of the drug– drug
interactions of quinidine would likely have resulted in improved morbidity and mortality.
Because verapamil may prevent torsades de pointes induced by quinidine, the combination of quinidine with verapamil in PAFAC and SOPAT may account for the improved outcomes in these 2 studies.23 PAFAC and SOPAT
also used lower doses of quinidine (320-480 mg/d vs 8001800 mg/d) than in older studies. In a systematic review by
Lafuente-Lafuente et al,24 a nonsignificant trend to increased mortality was seen with quinidine (OR ⫽ 2.26; 95%
CI, 0.93-5.45; P ⫽ .07). However, when selectively pooling
trials with adequate allocation concealment or those including more than 250 patients, there were only 2 trials that met
criteria: PAFAC and SOPAT. Combined data from these 2
319
trials demonstrated no effect on mortality. Quinidine may
therefore have a role as a drug in combination with verapamil in the maintenance of atrial fibrillation.
IDIOPATHIC VENTRICULAR FIBRILLATION
Quinidine may have a role in patients with idiopathic ventricular fibrillation with a normal resting electrocardiogram
(ECG). Although the natural history of this patient population is not well defined, some studies suggest a high risk of
recurrent major arrhythmic events.25,26 Among 34 patients
with idiopathic ventricular fibrillation (5 of whom had classic ECG criteria for Brugada syndrome), sustained polymorphic ventricular tachycardia or ventricular fibrillation
was induced in 27 patients (79%) at the baseline electrophysiologic study.27 Class IA drugs, primarily quinidine (in
25/27 inducible patients; dosed 1000 to 2000 mg/d), effectively prevented reinduction of polymorphic ventricular
tachycardia or ventricular fibrillation in 26 of 27 patients.
During a mean follow-up of 9.1 ⫾ 5.6 years, none of the
patients experienced a sustained symptomatic ventricular
arrhythmia or sudden death. The mechanism by which quinidine suppresses ventricular tachycardia or ventricular fibrillation in patients with idiopathic ventricular fibrillation
with a normal ECG is unknown. However, the fact that
ventricular tachycardia and ventricular fibrillation can be
induced reproducibly with programmed electrical stimulation in a substantial percentage of patients suggests a reentrant or triggered mechanism.
BRUGADA SYNDROME
Brugada syndrome was first described in 1992 and is characterized by a typical electrogram pattern (right bundle
branch block and persistent ST-segment elevation in the
right precordial leads) with the susceptibility for ventricular
fibrillation and sudden cardiac death.28 It is a primary electrical disorder and may be responsible for up to 12% of all
sudden deaths.29
Quinidine is a useful agent in the treatment of Brugada
syndrome. The use of quinidine in Brugada syndrome is
justified in its action on the potassium currents, including
Ito.30 Antzelevitch31 showed that the Ito current in the right
ventricular epicardium plays a pivotal role in the pathogenesis of Brugada syndrome. The basis of the phase 2 reentry
(trigger of the episodes of ventricular fibrillation) in Brugada syndrome is considered to be the loss of the action
potential dome in the right ventricular epicardium, where
Ito is more prominent. This is caused by an outward shift in
the balance of currents, principally Ito and ICa, at the end of
phase 1 of the action potential. The loss of this action
potential plateau results in marked abbreviation of epicardial action potentials, transmural dispersion of repolarization, and susceptibility to phase 2 reentry.32 In animal models, agents that inhibit Ito exert an antiarrhythmic effect by
restoring the action potential dome in the epicardium.33,34
Agents such as 4-aminopyridine, quinidine, and disopyramide inhibit Ito and therefore prevent ventricular tachycar-
320
dia/ventricular fibrillation by restoring the action potential
dome and homogenizing repolarization. As molecular genetic observations have demonstrated mutations in the cardiac sodium channel SCN5A in families with Brugada syndrome, a reduction or loss of sodium channel activity may
contribute to the ECG phenotype and susceptibility to ventricular tachycardia/ventricular fibrillation in patients with
Brugada syndrome by leaving Ito unopposed, leading to
loss of the epicardial action potential dome. Quinidine is the
only agent available that has significant Ito-blocking
properties.
The literature is increasing on the successful prevention
and treatment of ventricular tachycardia/ventricular fibrillation in patients with Brugada syndrome using quinidine.
Although quinidine only attenuated the Brugada ECG pattern in 3 of 25 high-risk patients examined by Belhassen et
al,35 quinidine prevented ventricular fibrillation induction at
electrophysiologic study in 22 of 25 patients (88%). In
addition, no symptomatic ventricular arrhythmias were documented in 19 patients receiving quinidine therapy after a
mean follow-up of 56 months. Case reports also have documented successful treatment of ventricular tachycardia/
ventricular fibrillation with quinidine in patients with Brugada syndrome.36-39 Last, low doses (300-600 mg/d) of
quinidine also might be a useful adjunct for patients with
Brugada syndrome with frequent implantable cardioverter
defibrillator discharges.40
SHORT QT SYNDROME
The short QT syndrome was initially described in 1999 and
is an inheritable primary electrical disease of the heart.
Characterized by a QT less than 300 ms, patients with the
short QT syndrome have increased risk of developing atrial
fibrillation and sudden cardiac death. Reentry and lifethreatening tachyarrhythmias associated with the syndrome
are due to the shortening of the effective refractory period in
combination with an increased dispersion of repolarization.
Mutations in the human ether-a-go-go gene have been
described where IKr is dramatically increased, leading to
heterogenous abbreviation of the action potential duration
and refractoriness and rendering the channel relatively unresponsive to IKr blockers, such as sotalol and ibutilide.41
The increase of IKr results in a shortened QT/QTc, and thus
an increase in the risk for sudden cardiac death. Kangaroos,
who are known to have short QT intervals, are known for
their high incidence of sudden cardiac death.42
Although cardioverter defibrillator implantation is the
therapy of choice for patients with short QT syndrome,
medical therapy is useful and revolves around normalizing
the QT interval. In a study examining class IA, IC, and III
antiarrhythmic drugs, only hydroxyquinidine produced a
significant QT prolongation.41 Hydroxyquinidine produced
a QT prolongation from 263 ⫾ 12 ms to 362 ⫾ 25 ms (calculated QT from 290 ⫾ 13 ms to 405 ⫾ 26 ms). Administration of hydroxyquinidine resulted in noninducibility of
ventricular fibrillation on programmed ventricular stimula-
The American Journal of Medicine, Vol 122, No 4, April 2009
tion. In short QT syndrome, quinidine may produce a reequilibration of ionic currents, particularly via its ability to
block the slow component of the delayed rectifier current
IKs. Quinidine therefore suppresses the hyperfunctioning
IKr responsible for some cases of short QT syndrome with
a mutation in the human ether-a-go-go gene. The normal
rate dependence of the QT interval is restored by quinidine
and ventricular tachycardia, and ventricular fibrillation is
rendered noninducible.43
CONCLUSIONS
Although the use of quinidine has declined substantially
over the last 2 decades, there is cause for renewed interest
in its use. In patients with structurally normal hearts and
highly symptomatic atrial fibrillation, maintenance of sinus
rhythm with quinidine in combination with verapamil is a
viable option. Quinidine also has a role in the prevention of
tachyarrhythmias and sudden cardiac death in patients with
idiopathic ventricular fibrillation, Brugada syndrome, and
short QT syndrome. One of the earliest antiarrhythmic
drugs, quinidine still has a role in tachyarrhythmias. Used
carefully in the appropriate patient populations, quinidine is
a reasonably safe and effective antiarrhythmic drug.
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