Atrial Fibrillation
Antiarrhythmic Drug Therapy for Atrial Fibrillation
Peter Zimetbaum, MD
A ntiarrhythmic medications have been available for
nearly 100 years and remain a mainstay in the manage-
ment of atrial fibrillation (AF). Goals of therapy with the use
of these drugs include a reduction in the frequency and
duration of episodes of arrhythmia as well an emerging goal
of reducing mortality and hospitalizations associated with
AF. The use of these drugs has been limited by both
proarrhythmic and noncardiovascular toxicities as well as
often modest antiarrhythmic efficacy. Despite these limita-
tions, antiarrhythmic drugs remain widely prescribed for the
management of symptomatic AF, and a host of new antiar-
rhythmic drugs are in various stages of clinical development.
This review will focus primarily on antiarrhythmic drug use
in patients with AF in the absence of significant structural
heart disease or congestive heart failure.
The Decision to Maintain Sinus Rhythm
A multitude of studies have evaluated the health-related
outcomes associated with a strategy of rate compared with
rhythm control in patients with AF.1–5 These studies, which
included primarily patients aged ⱖ60 years with at least 1
risk factor for stroke, failed to demonstrate a mortality benefit
associated with a rhythm control strategy. This equivalence in
outcome was in part related to toxicities associated with
antiarrhythmic drug therapy as well as excess stroke risk in
patients in whom anticoagulation was discontinued.6 Impor-
tant groups of patients, including younger individuals without
thromboembolic risk factors and the elderly (⬎80 years),
were excluded from these trials, but the results were none-
theless applicable to a large percentage of the AF population.
As a likely consequence of these landmark studies, rates of
AF-associated hospitalization, cardioversion, and antiarrhyth-
mic drug use plateaued or fell in the years after their
publication.7 This trend has been reversed in the latter part of
this decade, with an increase in rhythm control strategies
driven largely by increased rates of AF ablation and an
⬇2%/y increase in antiarrhythmic drug prescriptions.7,8 At
present, practice guidelines recommend antiarrhythmic ther-
apy for patients with significant symptoms despite adequate
rate control.9 This designation of rate control as the primary
strategy for AF will likely be challenged with further ad-
vances in ablative and pharmacological therapies for AF. In
addition to the aforementioned considerations, I also consider
maintenance of sinus rhythm in young patients (⬍60 years)
From Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA.
Correspondence to Peter Zimetbaum, MD, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd,
Boston, MA 02215. E-mail pzimetba@bidmc.harvard.edu
(Circulation. 2012;125:381-389.)
© 2012 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
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381
who have not been adequately represented in the previously
cited studies and for whom the long-term implications of
permanent AF are unknown. Given the recognition that
leaving a patient in permanent AF will likely render future
rhythm control therapies less effective, a strategy of sinus
rhythm maintenance in younger patients is particularly worth-
while if one wishes to remain a candidate for developing
rhythm control strategies.
Currently Available Antiarrhythmic Drugs
Antiarrhythmic drugs do not lend themselves to a neat
classification scheme. Many of these drugs have effects on
multiple ion channels and adrenergic receptors as well as a
myriad of cardiac and noncardiovascular side effects. The
majority of available antiarrhythmic drugs exert predominant
effects on cardiac sodium or potassium currents. The sodium
channel blocking drugs are often called membrane-stabilizing
agents because they decrease the excitability of cardiac
tissue. Quinidine and disopyramide have intermediate sodium
channel blocking activity and exhibit use dependence. This
means that the predominant effect on conduction (sodium
channel blockade) is seen at rapid heart rates. In fact, these
agents largely affect potassium channels (IKr) at normal or
slow heart rates and low concentrations and therefore display
“reverse use dependence” for potassium channel blockade.
Propafenone and flecainide have the slowest dissociation
kinetics of the sodium channel blocking drugs and therefore
have more bound drug and produce a greater degree of
conduction slowing at rapid heart rates (use dependence).
Drugs with significant effects on potassium currents pro-
long the action potential duration and refractory periods.
Sotalol and dofetilide are potassium channel blocking drugs
that display reverse use dependence such that repolarization
is prolonged at slow heart rates. Amiodarone and dronedar-
one affect a broad range of channels including sodium,
calcium, and multiple potassium channels.
Quinidine derives from the bark of the cinchona plant and
was identified as a potential antiarrhythmic drug a century
ago10 (Tables 1 and 2). It is a vagolytic and ␣ blocking agent
with an intermediate sodium channel blocking effect at rapid
heart rates and higher concentrations and a potassium channel
blocking effect at slower heart rates and normal concentra-
tions. It is rarely used for AF; however, its blocking effect on
Ito has generated interest as a potential therapy for Brugada
DOI: 10.1161/CIRCULATIONAHA.111.019927
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382 Circulation January 17, 2012
Table 1. Effects of Antiarrhythmic Drugs
Antiarrhythmic Drug, Year Channel(s)
of Development/Approval Blocked
Quinidine, 1918 INa, IKr, Ito, IAch, ␣
Disopyramide, 1962 INa, IKr, acetylcholine
Propafenone, 1976 INa, ␤
Flecainide, 1975 INa
Sotalol, 1992, 2000 (AF) IKr, ␤
Dofetilide, 2000 (US only) IKr
Ibutilide (intravenous), 1995 IKr, INa agonist
Amiodarone, 1967 IKr, INa, ICa, ␤, ␣, acetylcholine
Dronedarone, 2009 IKr, INa, ICa, ␤, ␣, acetylcholine
Vernakalant (intravenous), IKur, INa
2010 (Europe only)
AF indicates atrial fibrillation; US, United States.
syndrome and idiopathic ventricular fibrillation.11 Its noncar-
diovascular side effects include diarrhea as well as cincho-
nism (tinnitus and headache) and thrombocytopenia. The
addition of verapamil to suppress quinidine-associated early
afterdepolarizations may reduce the risk of torsades de
pointes (TDP) associated with quinidine use.12 Disopyramide
is distinguished as a sodium channel blocking drug with
potent anticholinergic and negative inotropic effects. The
anticholinergic effects have led to its recommendation for
patients with vagally induced AF despite little supporting
evidence.9 The negative inotropic effects of this drug make it
a viable therapy for patients with AF and hypertrophic
cardiomyopathy.13 It should be avoided in the setting of
narrow-angle glaucoma, prostatic hypertrophy, or myasthenia
gravis. Disopyramide prescriptions represent 1% to 2% of
annual antiarrhythmic drug prescriptions in the United
States.8
Flecainide and propafenone are recommended for the
management of patients with AF without structural heart
disease. They are contraindicated in individuals with prior
myocardial infarction and reduced left ventricular function
because of a risk of ventricular proarrhythmia.14 At present,
they each represent 10% of annual US antiarrhythmic drug
prescriptions.8 Flecainide, in addition to significant sodium
channel blocking activity, has mild IKr blocking effects but is
not generally associated with significant QT prolongation. It
has mild negative inotropic effects and, like propafenone, is
associated with a significant incidence of atrial flutter.15,16
Dizziness and visual disturbance represent the common
noncardiovascular side effects seen in 5% to 10% of patients
taking flecainide.17 Propafenone has ␤ blocking in addition to
sodium channel blocking activity. It also has mild negative
inotropic and chronotropic effects. The major noncardiovas-
cular adverse effects include a metallic taste as well as
dizziness and visual disturbances.
Sotalol is a potassium channel (IKr) blocker and ␤-blocker
with minimal noncardiovascular side effects and a high rate
of utilization (26% of annual prescriptions in the United
States). It is renally cleared and is prescribed twice daily
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Effect on
ECG Manifestations Defibrillation Threshold
May 1 sinus rate; 1 QT (not dose related); 1
1 QRS high dose
May 1 sinus rate; 1 QT (not dose related); 1
1 QRS high dose
May 2 sinus rate, 1 PR, 1 QRS Varies
May 2 sinus rate, 1 PR, 1 QRS 1
2 Sinus rate, may 1 PR, 1 QT (dose related) 2
1 QT (dose related) 2
1 QT (dose related) Not relevant
2 Sinus rate, 1 PR, 1 QRS, 1 QT 1
2 Sinus rate, 1 PR 1
QT prolongation Not relevant
unless the creatinine clearance is between 30 and 60 mL/min,
in which case it should be dosed daily.16 The usual dose range
is 160 to 480 mg/d in divided dosages. It is generally started
at a dose of 80 mg twice daily and uptitrated with attention to
QT prolongation. The potassium channel blocking effect
increases with increasing dosage, and, as a result, the risk of
ventricular proarrhythmia (TDP) increases at a higher dosage.
Dofetilide is also an IKr blocker but without other clinically
significant electrophysiological effects. It is renally cleared
and must be dosed according to creatinine clearance (Tables
1 and 2). It was approved for use in the United States in 2000
with a 3-day mandatory in-hospital loading period and
currently represents ⬇2% of antiarrhythmic drug prescrip-
tions annually.8 Dofetilide is more effective for the mainte-
nance of sinus rhythm than it is for restoring sinus rhythm.18
It has been demonstrated to be reasonably safe in heart failure
and post–myocardial infarction populations.19,20
Amiodarone, although not approved by the Food and Drug
Administration for AF, is the most commonly prescribed
antiarrhythmic drug for AF, representing 45% of annual drug
prescriptions.8 It is a complex iodinated compound that, along
with its active metabolite N-desethylamiodarone, blocks IKr,
INa, IKur, Ito, ICaL, IKAch, and If channels with noncompetitive
antagonism of ␣- and ␤-receptors. It is distinguished by a
half-life of weeks and significant distribution into adipose
tissue. It is the most effective antiarrhythmic drug currently
available but is limited by a myriad of noncardiovascular side
effects21 (Table 1). The major cardiovascular side effect of
amiodarone is sinus bradycardia, with a higher risk of
pacemaker requirement in women.22 QT prolongation is
common but very rarely associated with TDP (⬍0.5%).23 It
should be loaded (600 –1200 mg/d) for a total of 10 g over 10
days to 4 weeks before being reduced to a maintenance dose
of 100 to 200 mg/d. Administration in divided doses and with
food minimizes the gastrointestinal symptoms associated
with its use. Administration with food is also recommended
because it significantly increases the rate and extent of
amiodarone absorption.24 The combination of amiodarone
with the CYP3A4 substrate simvastatin has been associated
 Zimetbaum Antiarrhythmic Drugs for Atrial Fibrillation 383

Table 2. Antiarrhythmic Drug Dosing and Side Effects

Antiarrhythmic
Drug Metabolism/Dose
Quinidine Hepatic CYP3A4 (70%), renal (30%);
dose: sulfate, 600 3 times a day;
gluconate, 324 – 648 every 8 h;
reduced dose for renal failure
Disopyramide Renal/hepatic CYP3A4; dose: 100–400
every 8–12 h; maximum dose, 800
mg/24 h; reduced dose for renal or
hepatic dysfunction
Propafenone Hepatic: 150–300 every 8 h or
sustained release 225–425 twice a day
Flecainide Renal/hepatic CYP2D6; 50–100 mg
twice a day, maximum dose 300–400
mg/d
Sotalol Renal: 80–120 mg twice a day;
maximum dose 240 mg twice a day
Dofetilide, US Renal/hepatic CYP3A4; CrCL ⬎60 (500
only ␮g twice a day), CrCl 40–60 (250 ␮g
twice a day), CrCl 20–39 (125 ␮g
twice a day)
Amiodarone Hepatic; half-life 50 d: oral load 10 g
over 7–10 d, then 400 mg for 3 wk,
then 200 mg/d for atrial fibrillation;
maintenance dose of 400 mg/d for
ventricular tachycardia; dose-reduced
load for bradycardia or QT prolongation;
intravenous: 150–300 mg bolus, then 1
mg/min infusion for 6 h followed by 0.5
mg/min thereafter
Rarely torsades de pointes
Ibutilide Hepatic CYP3A4; 1 mg intravenous over
(intravenous) 10 min; repeat after 10 min if
necessary
Dronedarone Renal, hepatic, gastrointestinal; 400 mg
twice a day
Vernakalant
(intravenous),
Europe only
SIADH indicates syndrome of inappropriate antidiuretic hormone hypersecretion; CrCl, creatinine clearance.
Noncardiovascular Toxicity
Thrombocytopenia, cinchonism, pruritus, rash
Anticholinergic (contraindicated for
narrow-angle glaucoma): dry mouth, urinary
retention, constipation, blurry vision
Metallic taste, dizziness
Dizziness, headache, visual blurring
Bronchospasm
None
Pulmonary (acute hypersensitivity
pneumonitis, chronic interstitial infiltrates);
hepatitis; thyroid (hypothyroidism or
hyperthyroidism); photosensitivity; blue-gray
skin discoloration with chronic high dose;
nausea; ataxia; tremor; alopecia
Nausea
Anorexia; nausea; hepatotoxicity
Dysgeusia; sneezing; paresthesia
Cardiovascular Toxicity
QRS prolongation with toxic doses, torsades
de pointes (not dose related)
Congestive heart failure exacerbation,
torsades de pointes
Atrial flutter with 1:1 conduction; ventricular
tachycardia; may unmask Brugada-type ST
elevation; contraindicated with coronary
disease
Atrial flutter with 1:1 conduction; ventricular
tachycardia; may unmask Brugada-type ST
elevation; contraindicated with coronary
disease
Bradycardia, torsades de pointes
Torsades de pointes
Sinus bradycardia
Torsades de pointes
Bradycardia
Hypotension (contraindicated in presence of
severe aortic stenosis, class 3 or 4
congestive heart failure, or preexisting
hypotension); QT prolongation; increased
risk of ventricular arrhythmias in patients
with congestive heart failure

with an increased risk of myositis25 (Table 3). Conversely,
this risk seems to be smaller when amiodarone is combined
with pravastatin, which does not use the cytochrome P450
system for metabolism. The most important interaction of
amiodarone occurs with the potentiation of the anticoagulant
effect of warfarin through inhibition of CYP2C9. In addition,
amiodarone inhibits P glycoprotein transport and can reduce
digoxin clearance.
Amiodarone requires surveillance for liver, lung, and
thyroid toxicity.21 Hepatic toxicity is manifest as low-level
transaminase elevation, which, if not detected and managed
with discontinuation of amiodarone, can result in cirrhosis.
Pulmonary toxicity can manifest as an acute hypersensitivity
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type of reaction with patchy infiltrates after weeks of therapy
or as a more chronic process with interstitial fibrosis. Adult
respiratory distress syndrome and solitary pulmonary nodules
have also been described as manifestations of amiodarone
therapy.26 The recognition of pulmonary toxicity requires a
high index of suspicion with attentiveness to complaints of
cough and dyspnea. The diagnosis remains one of exclusion,
but high-resolution computed tomographic scan or histo-
pathological demonstration of intra-alveolar foamy macro-
phages with cytoplasmic lamellar inclusions in bronchial
washings can be helpful.27 Amiodarone inhibits the conver-
sion of T4 to T3, and an elevated thyrotropin is expected in
the initial months of therapy. Hypothyroidism should not be
384 Circulation January 17, 2012
Table 3. Selected Drug Interactions
Selected Drug Interactions
Quinidine 1 Digoxin and amiodarone concentrations; quinidine
inhibits CYP2D6 and may increase drugs metabolized by
this enzyme (eg, 1 effect of tricyclic antidepressants,
haloperidol, some ␤-blockers, fluoxetine, narcotics);
quinidine metabolism is inhibited by cimetidine; quinidine
metabolism is increased by phenobarbital, phenytoin,
and rifampicin
Disopyramide None
Propafenone May decrease the metabolism of warfarin; increased
digoxin levels
Flecainide May increase digoxin levels; flecainide levels are
increased by amiodarone, haloperidol, quinidine,
cimetidine, and fluoxetine
Sotalol No significant interactions
Dofetilide Contraindicated with verapamil, ketoconazole, cimetidine,
megestrol, prochlorperazine, and trimethoprim;
hydrochlorothiazide increases dofetilide levels; must
discontinue amiodarone at least 3 mo before dofetilide
initiation
Ibutilide None
Amiodarone Inhibits CYP450 enzymes; increases concentrations of
warfarin, digoxin, cyclosporine, alprazolam,
carbamazepine, statins (simvastatin), phenytoin, and
quinidine; increases the effect of dabigatran but does not
appear to be clinically relevant
Dronedarone Inhibits CYP3A4; will increase levels of alprazolam,
carbamazepine, dihydropyridine, cyclosporine, statins,
digoxin; verapamil (but not diltiazem) increases
dronedarone levels; contraindicated in the presence of
strong CYP3A4 inhibitors such as ketoconazole,
itraconazole, cyclosporine, clarithromycin, and ritonavir;
increases effects of dabigatran
diagnosed unless the free T4 is depressed. Hyperthyroidism
most often presents in the months to first few years after
initiation of therapy. Recurrent AF may be a sign when other
typical manifestations of hyperthyroidism are often absent.
Type 1 amiodarone-related hyperthyroidism frequently oc-
curs in the setting of a preexisting nodule or Grave’s disease.
Type 2 is a destructive thyroiditis that ultimately results in
hypothyroidism.28 The adverse effects of amiodarone can
present or persist after discontinuation of therapy because of
its long half-life.
Dronedarone is the first of a group of drugs that have been
designed to resemble amiodarone with fewer noncardiovas-
cular side effects. It is similar in structure to amiodarone with
the addition of a methylsufonamide group and absence of
iodine moieties. An initial study designed to assess the effect
of dronedarone on mortality in patients with advanced con-
gestive heart failure demonstrated an increased mortality in
the dronedarone-treated group.29 It is therefore contraindi-
cated in patients with decompensated congestive heart failure.
Subsequent efficacy studies and a major safety study in
healthier patients with AF and without decompensated heart
failure have shown no significant extracardiovascular toxic-
ities and a reduction in hospitalizations and cardiovascular
mortality associated with this drug.30,31 In addition, a sub-
study of A Placebo-Controlled, Double-Blind, Parallel-Arm
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Trial to Assess the Efficacy of Dronedarone 400 mg BID for
the Prevention of Cardiovascular Hospitalization or Death
From Any Cause in Patients With Atrial Fibrillation/Atrial
Flutter (ATHENA) demonstrated a reduction in stroke asso-
ciated with dronedarone use.32 Dronedarone has been the only
antiarrhythmic drug that has demonstrated a reduction in
stroke risk in patients with AF.33 It is unclear whether this
stroke reduction was due to the maintenance of sinus rhythm
or some other factor. In the Permanent Atrial Fibrillation
Outcome Study Using Dronedarone on Top of Standard
Therapy (PALLAS) dronedarone use in patients with perma-
nent atrial fibrillation was associated with an excess risk of
stroke, cardiovascular death and hospitalizations.33a There
was an increase in the serum digoxin concentration in the
dronedarone treated patients which was unlikely to be solely
responsible for the adverse outcomes. Dronedarone does not
increase the international normalized ratio in association with
warfarin use. It raises the serum creatinine level through
impaired tubular secretion without an effect on renal function.
Dronedarone, like amiodarone, interacts with the P glycopro-
tein transporting system, and digoxin should be dose reduced
or discontinued. Dronedarone, like amiodarone, interacts with
CYP3A4 and in combination with simvastatin may increase
the risk of myositis. Dronedarone is generally well tolerated
other than a 10% incidence of gastrointestinal side effects.34
The absorption and gastrointestinal tolerance are improved if
administered with meals. Grapefruit significantly increases
the levels of dronedarone and should be avoided. Recently,
the Food and Drug Administration released a warning for
dronedarone based on 2 reported cases of severe hepatotox-
icity occurring within 6 months of treatment initiation.35 The
Food and Drug Administration has recommended that signs
and symptoms of liver disease be monitored; however, no
mandate for routine liver function test evaluation has been
issued. The European Medicines Agency has recommended
routine liver function test monitoring for the first 6 months of
therapy (http://www.ema.europa.eu/ema/). At present drone-
darone should be avoided in patients with permanent atrial
fibrillation and it is recommended that the rhythm be assessed
at least every three months.
Selected Antiarrhythmic Therapies
in Development
Most new antiarrhythmic medications are formulated with the
intent of reducing proarrhythmic toxicity. Vernakalant is one
such new multichannel blocking antiarrhythmic drug. It acts
predominantly on the atrial potassium currents (Ito, IAch, IKur)
with a use- or rate-dependent effect on cardiac sodium
channels, including the late sodium current INaL. It appears to
be far more effective for the conversion of AF than atrial
flutter, particularly if administered within 7 days of arrhyth-
mia onset. Multiple studies to date have demonstrated no
significant proarrhythmia.36 –38 The intravenous formulation
is under investigation in the United States but has been
approved in Europe. The oral formulation is in clinical
development. The major side effects of vernakalant include
cough, sneezing, and dysgeusia.38
Budiodarone is another structural analogue of amiodarone
with similar multichannel blocking properties. It is an iodin-
 Zimetbaum
Figure. Left panel demonstrates atrial flutter with QRS prolongation in a patient taking flecainide. Direct current cardioversion was per-
formed emergently because of hemodynamic collapse with resolution of sinus rhythm and a narrow QRS complex (right).
ated compound but is metabolized by plasma and tissue
esterases rather than the CYP3A4 system. This difference
allows more rapid metabolism and a lower likelihood of side
effects. This agent has been evaluated in a study of patients
with paroxysmal atrial fibrillation and pacemakers.38a The
continuous monitoring afforded by pacemakers allows a true
determination of recurrence not fully reflected in most anti-
arrhythmic drug studies. In this study, the duration and
frequency of recurrent AF episodes were diminished.
Ranolazine is a new drug approved for the management
of chronic angina. It blocks a number of currents including
peak and late INa, I CaL, and IKr. Preliminary clinical data
with the use of ranolazine as an anti-ischemic drug have
demonstrated a reduction in supraventricular arrhythmias
including AF.39 Experimental data have demonstrated the
synergistic potential for the combination of ranolazine
with amiodarone or dronedarone to reduce the develop-
ment of and facilitate the termination of AF.40,41 In
addition, it is postulated that the late sodium current
contributes to the prolongation of the action potential
duration associated with reduced IKr at slow heart rates.
Inhibition of INa with ranolazine or vernakalant may
reduce the risk of TDP associated with IKr inhibition. It
remains to be determined whether combination therapy
with ranolazine or vernakalant and IKr blockers such as
sotalol, quinidine, or dofetilide will reduce the risk of
TDP.42– 44
Proarrhythmic Toxicity of
Antiarrhythmic Drugs
Sodium channel blocking drugs slow conduction and, in
susceptible patients with preexisting scar or ischemia, can
promote the development of reentry and ventricular
tachyarrhythmias.14 As noted, atrial flutter is a common
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Antiarrhythmic Drugs for Atrial Fibrillation 385
arrhythmia in patients treated with sodium channel blocking
drugs for AF. Typically, the atrial rate is much slower than
300 bpm and can result in 1:1 atrioventricular conduction
with a wide QRS morphology due to slowed conduction
(Figure). This accelerated ventricular rate accompanied by
prolonged conduction can result in hemodynamic collapse.45
For this reason, many clinicians choose to use atrioventricular
nodal blocking drugs with flecainide and propafenone. We
routinely evaluate QRS duration after initiation of sodium
channel blocking drugs with exercise to test the use-
dependent properties of this drug. It is our practice (without
supporting data) to reduce the dose or discontinue the therapy
if the QRS duration exceeds 125% of the baseline value.
Sodium channel blocking drugs can also present a risk of
proarrhythmia in patients with loss-of-function sodium chan-
nel mutations such as some patients with Brugada syndrome.
These abnormalities in sodium channel function may influ-
ence the degree of conduction slowing or transmural voltage
gradient (ST elevation in the right precordial leads), which
may predispose to ventricular proarrhythmia.46,47 Quinidine,
because of its effects on Ito, does not exacerbate the ST
elevation that may be seen with other sodium channel
blocking drugs. It is our practice to discontinue sodium
channel blocking drugs in patients who develop precordial ST
elevation.
Drugs with potassium channel blocking activity carry a
risk of TDP. In most instances, this occurs through reduction
in the potassium current IKr. This complication is most
commonly seen at slow heart rates, particularly after a pause
with conversion of AF to sinus rhythm.48 Hypokalemia,
hypomagnesemia, female gender, baseline prolonged QT
interval, or congenital long-QT syndrome and concomitant
use of other QT-prolonging therapies are all risk factors for
TDP. The risk of QT prolongation and TDP is dose related
386 Circulation January 17, 2012

Table 4. Recommendations for Antiarrhythmic Drug Use Table 5. Selected Studies of Comparative Efficacy of
Antiarrhythmic Drugs
Severe
Ventricular Percentage
Coronary Hypertrophy No. of Patients, of Patients
No Structural Artery Heart (Hypertrophic Average Without
Heart Disease Disease Failure Cardiomyopathy) Duration of Documented
First line Study Follow-Up Drugs AF Recurrence
51
Flecainide Sotalol Amiodarone Amiodarone CTAF 403, 16 mo Amiodarone 65
Propafenone Amiodarone Dofetilide Sotalol 37
Dronedarone Dronedarone Propafenone 37
52
Sotalol Dofetilide SAFE-T 665, 33 mo Amiodarone 65
Second line Sotalol 25
Amiodarone Disopyramide Placebo 10
Dofetilide PAFAC53 848, 9 mo Sotalol 33
Avoid Avoid Avoid Quinidine plus 35
flecainide, flecainide, flecainide, verapamil
propafenone propafenone, propafenone Placebo 17
dronedarone DIONYSOS 34
504, 7 mo Amiodarone 58
Dronedarone 36
with sotalol and dofetilide but not with quinidine or disopyr- AF indicates atrial fibrillation; CTAF, Canadian Trial of Atrial Fibrillation;
amide. QT prolongation is an expected finding with amiod- SAFE-T, Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; PAFAC, Prevention
of Atrial Fibrillation After Cardioversion; and DIONYSOS, Efficacy and Safety of
arone but is very rarely associated with proarrhythmia.
Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in
Ventricular hypertrophy may predispose to the development Patients With Atrial Fibrillation.
of afterdepolarizations and thus may represent a substrate
more prone to TDP in the presence of QT-prolonging ⬎65% (Table 5).33,34,51,52 In general, the rate of maintaining
medications (potassium channel blocking drugs).49 sinus rhythm is closer to 30% to 50% at 1 year for the other
tested antiarrhythmic drugs.51–53 Dofetilide has also been
Drug Selection and Comparative Efficacy of associated with an ⬇50% rate of maintaining sinus rhythm at
Drugs for Maintaining Sinus Rhythm 1 year, with the greatest success in those patients who can
The clinical use of these drugs for AF is guided first by the tolerate the maximum dosage.18
risk of toxicity and then by efficacy (Table 4). Recently Dronedarone has been compared with amiodarone in a
published guidelines for drug selection in patients with AF short-duration study of comparative efficacy and safety.34 In
from both the American College of Cardiology Foundation/ this study, the absence of chemical cardioversion and recur-
American Heart Association/Heart Rhythm Society and Eu- rence of AF after cardioversion occurred more often with
ropean Society of Cardiology agree on the use of flecainide, dronedarone than amiodarone (64% versus 42%). Two larger
propafenone, sotalol, dronedarone, or amiodarone in patients studies comparing dronedarone with placebo over a longer
without significant underlying heart disease (ie, heart failure, duration of follow-up (12 months) documented efficacy rates
coronary artery disease, or severe left ventricular hypertro- of ⬇35% for maintenance of sinus rhythm.30 A mixed
phy).9,50 The European guidelines suggest that disopyramide treatment comparative analysis of the available antiarrhyth-
be considered for patients with a vagal trigger associated with mic drugs used in randomized controlled trials found amiod-
AF, whereas quinidine, procainamide, and disopyramide are arone to be associated with the greatest rates and dronedarone
completely omitted from the US guidelines. Dofetilide is not with the lowest rates of sinus rhythm.33 Dronedarone was the
approved for use in Europe but is indicated in all clinical best tolerated of the antiarrhythmic drugs, with the lowest
categories in the US guidelines. Both guidelines agree on the rates of severe adverse events and a significant reduction in
use of sotalol, amiodarone, and dronedarone for patients with the risk of stroke.33,34
coronary artery disease and amiodarone for patients with It is our practice to use propafenone, flecainide, sotalol,
symptomatic congestive heart failure. Patients with left ven- and dronedarone as first-line therapies in patients without
tricular hypertrophy have the same drug choices as those structural heart disease (Table 4). Dofetilide and amiodarone
without structural heart disease; however, severe left ventric- are second choices because of the in-hospital loading require-
ular hypertrophy is considered a risk for toxicity with most ment of the former and the risk of noncardiovascular toxici-
potassium and sodium channel blocking drugs. The European ties with the latter. We occasionally choose amiodarone as a
Society of Cardiology guidelines suggest dronedarone or first-line therapy in elderly patients without structural heart
amiodarone for severe left ventricular hypertrophy, whereas disease for whom long-duration therapy and therefore side
the US guidelines suggest only amiodarone. effects are unlikely. We choose sotalol or dronedarone as
Amiodarone has been directly compared with dronedarone, first-line therapy for patients with coronary artery disease and
sotalol, and propafenone and found to be substantially more relatively preserved left ventricular function. If coronary
effective, with a 1-year rate of maintaining sinus rhythm of artery disease is associated with left ventricular dysfunction,
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 Zimetbaum
we choose dofetilide or amiodarone. Patients with AF and
congestive heart failure are treated with dofetilide or amiod-
arone. In our practice, we also consider disopyramide as an
option in women with preserved ventricular function and in
patients with hypertrophic cardiomyopathy, particularly if
they already have a pacemaker or implantable cardioverter-
defibrillator.13 Our goal with the use of any antiarrhythmic
drug is a reduction in the frequency of symptomatic AF.
Occasional recurrences of AF on an antiarrhythmic drug are
expected and do not necessarily constitute a reason to
discontinue therapy if the frequency and symptoms associ-
ated with AF have been reduced significantly.
Drugs for Cardioversion of AF
Chemical cardioversion can be accomplished with intrave-
nous or oral antiarrhythmic drugs. In general, the conversion
success of antiarrhythmic drug therapy is significantly higher
for acute (⬍7 days) compared with longer-duration AF.
Ibutilide is an intravenous IKr blocker that also enhances the
late inward sodium current.54 Ibutilide is ⬇50% effective at
restoring sinus rhythm. It is slightly more effective for atrial
flutter than for AF.54 Patients must be monitored closely for
QT prolongation and TDP for at least 2 hours after infusion.54
Amiodarone can also be used as an intravenous converting
agent; however, it is weakly effective for this purpose.38,55 In
the absence of conversion, intravenous amiodarone provides
rate-controlling effects. Oral amiodarone can be used to
convert AF to sinus rhythm. This agent can be loaded over the
course of 3 to 4 weeks with a rate of conversion of ⬇27%.52
Flecainide and propafenone are available as intravenous
agents in Europe but not in the United States. High-dose oral
flecainide (200 –300 mg) or propafenone (450 – 600 mg) has
been used as a “pill in the pocket” approach in patients
presenting within an average of 30 minutes of arrhythmia
onset. The overall rate of conversion in this study was
⬎85%.56 This should be restricted to patients without struc-
tural heart disease and should be first tested as a safe strategy
in a monitored setting.
Vernakalant has been evaluated in a series of clinical trials
for the conversion of AF.36,37 A recent study compared
vernakalant with intravenous amiodarone and demonstrated a
50% rate of conversion of AF at 90 minutes with vernakalant
compared with a 5% conversion rate with amiodarone.38
Outpatient Initiation of Antiarrhythmic Drugs
Some controversy exists regarding the safety of the outpatient
initiation of antiarrhythmic drugs. This caution primarily
relates to concerns for QT prolongation and TDP, particularly
at the time of conversion from AF to sinus rhythm.48 As
noted, dofetilide is the primary drug for which inpatient
initiation is mandated. Sotalol is also approved for AF with a
recommendation for inpatient initiation. The Sotalol Amiod-
arone Atrial Fibrillation Efficacy Trial (SAFE-T) initiated
either sotalol or amiodarone in the outpatient setting during
AF without adverse effect and with an equivalent rate of
restoring sinus rhythm. It is our practice to load all antiar-
rhythmic drugs other than dofetilide in the outpatient setting.
We initiate these therapies once sinus rhythm has been
established and monitor for proarrhythmia with scheduled
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Antiarrhythmic Drugs for Atrial Fibrillation 387
daily transmissions as well as additional symptomatic trans-
missions using an event recorder for 10 days.57,58 We rou-
tinely load amiodarone during AF for up to a month before
electric cardioversion.
Upstream Therapies
The concept of preventing the development of atrial electric
and mechanical remodeling and thereby reducing the likeli-
hood of AF is referred to as “upstream” therapy. Potential
agents in this category include blockers of the renin-angio-
tensin axis, aldosterone inhibitors, polyunsaturated fatty ac-
ids, and statins.59 The angiotensin-converting enzyme inhib-
itors and angiotensin receptor blockers have been studied for
the primary and secondary prevention of AF. There are
reasonable data to support the use of angiotensin receptor
blockers for the reduction of new-onset AF in patients with
hypertension but without significant structural heart dis-
ease.60 – 62 Conversely, the benefit of these therapies in pa-
tients with congestive heart failure or multiple cardiovascular
risk factors has been less robust.60 Similarly, the benefit of
angiotensin-converting enzyme inhibitors or angiotensin re-
ceptor blockers for the secondary prevention of AF has not
been demonstrated.59,60 At present, there are no conclusive
data to support the use of aldosterone inhibitors or polyun-
saturated fatty acids for the primary or secondary prevention
of AF.59 Studies of statins for the primary or secondary
prevention of AF have been conflicting and do not support
specific antiarrhythmic recommendations.59,63 It is likely that
agents in this category of upstream therapy will be most
effective when administered before the development of sig-
nificant atrial fibrosis.
Antiarrhythmic drugs continue to play an important role in
the management of AF. A thorough understanding of the
patient groups most appropriate for individual therapies is
critical for the safe and effective use of these drugs. Newer
approaches to antiarrhythmic drug therapy include the pre-
vention or reversal of atrial remodeling as well as the
development of conventional ion channel blocking drugs with
less potential for proarrhythmia. The ultimate goal of these
therapies is also likely to evolve beyond the conventional
metric of time to first AF recurrence. Newer end points
including AF burden, stroke risk, hospitalization, mortality,
cost, and quality of life will all likely play important roles in
the development of new therapies.
Disclosures
None.
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KEY WORDS: antiarrhythmic agents 䡲 antiarrhythmic drugs 䡲
atrial fibrillation 䡲 atrial fibrillation arrhythmia 䡲 atrial flutter
 Antiarrhythmic Drug Therapy for Atrial Fibrillation
Peter Zimetbaum

Circulation. 2012;125:381-389
doi: 10.1161/CIRCULATIONAHA.111.019927
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