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The n e w e ng l a n d j o u r na l of m e dic i n e

clinical therapeutics

Amiodarone for Atrial Fibrillation


Peter Zimetbaum, M.D.

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the author’s clinical recommendations.

A 73-year-old man with stable coronary artery disease, hypertension, and chronic re-
nal insufficiency presents with recurrent atrial fibrillation at 80 to 90 beats per min-
ute. His symptoms include shortness of breath and fatigue. He has had atrial fibrilla-
tion twice in the past year; with each episode, electrical cardioversion resulted in
marked improvement in his symptoms. His echocardiogram shows symmetric left
ventricular hypertrophy with evidence of diastolic dysfunction. His medications in-
clude warfarin and metoprolol (25 mg twice daily). He is referred to a cardiologist,
who recommends rhythm control with oral amiodarone.

The Cl inic a l Probl e m

Atrial fibrillation is the most common cardiac arrhythmia seen in clinical practice. From the Division of Cardiology, Beth Is-
It currently affects more than 2 million Americans, with a projected increase to rael Deaconess Medical Center, Boston.
Address reprint requests to Dr. Zimet-
10 million by the year 2050.1 Atrial fibrillation may occur in a paroxysmal, self-remit- baum at Beth Israel Deaconess Medical
ting pattern or may persist unless cardioversion is performed. It is rarely, if ever, a Center, 185 Pilgrim Rd., Boston, MA 02215,
one-time event but can be expected to recur unpredictably. Symptoms, including or at pzimetba@bidmc.harvard.edu.

palpitations, dyspnea, fatigue, and chest pain, are present in 85% of patients at the N Engl J Med 2007;356:935-41.
onset of the arrhythmia but often dissipate with rate- or rhythm-control therapy.2 Copyright © 2007 Massachusetts Medical Society.
The morbidity and mortality associated with this disorder relate to these symptoms
as well as to hemodynamic and thromboembolic complications. Strategies to main-
tain sinus rhythm have not been shown to reduce total mortality or the risk of stroke
but have been shown to improve functional capacity and quality of life.3-5 The fail-
ure to reduce the mortality associated with rhythm-control strategies is in part due
to the toxicity of the therapies used to maintain sinus rhythm.6

Pathoph ysiol o gy a nd Effec t of Ther a py

The actual mechanism of atrial fibrillation is probably a focal source of automatic


firing, a series of small reentrant circuits, or a combination of the two.7 Atrial fibrilla-
tion is triggered by atrial premature depolarizations, which frequently arise from
muscular tissue in the pulmonary veins or other structures in the left or, less com-
monly, right atrium.8 Clinical factors such as hypertension, aging, and congestive
heart failure, as well as recurrent atrial fibrillation itself, result in structural changes
in the atria, including dilatation and fibrosis.9 This type of mechanical remodeling
promotes the development and perpetuation of atrial fibrillation. Continued rapid
electrical firing in the atria also results in loss of the normal adaptive shortening of
atrial and pulmonary-vein myocyte refractory periods in response to the rapid heart
rate, a process called electrical remodeling.10

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The n e w e ng l a n d j o u r na l of m e dic i n e

The hemodynamic consequences of atrial fi- Cl inic a l Use


brillation result primarily from the loss of atrio-
ventricular synchrony but also from the rapid rate Amiodarone is approved by the Food and Drug
and irregularity of the ventricular response.9 Pa- Administration for the treatment of lethal ven-
tients with clinical syndromes that impair dia- tricular arrhythmias but not for the management
stolic compliance (e.g., left ventricular hypertro- of atrial fibrillation. Nonetheless, it is widely pre-
phy) are most likely to have functional deterioration scribed for this indication.17,18
and symptoms, with loss of the atrial contribution The safe and effective use of amiodarone re-
to ventricular filling; such patients are also there- quires a firm understanding of its unusual phar-
fore most likely to benefit from restoration of si- macokinetics as well as the potential for drug
nus rhythm. interactions and adverse events. Amiodarone is a
The precise mechanism through which anti- highly lipophilic compound with a large volume
arrhythmic drugs such as amiodarone suppress of distribution (66 liters per kilogram of body
atrial fibrillation remains unknown.11 Amioda- weight). This property results in a delayed onset
rone (with its active metabolite, desethylamio- of action (an interval of 2 to 3 days) and a long
darone) blocks sodium, potassium, and calcium elimination half-life (up to 6 months).19 As a result,
channels. It is also a relatively potent noncom- there is a substantial lag between the initiation,
petitive alpha-blocker and beta-blocker but has no modification, or discontinuation of treatment
clinically significant negative inotropic effect.9,11 with amiodarone and a change in drug activity.
At rapid heart rates, sodium channel blockade is Amiodarone is metabolized to desethylamioda-
increased.12 rone in the liver, and its use should be avoided
The consequences of these channel-blocking in patients with advanced hepatic disease. There
effects can be demonstrated electrophysiologi- is no clinically significant renal metabolism of
cally. Most important, potassium-channel block- amiodarone, and the dose is not affected by re-
ade slows repolarization, causing an increase in nal dysfunction or dialysis. Amiodarone crosses
the duration of the action potential and in the re- the placenta in pregnant women and is excreted
fractoriness of cardiac tissue; this has the effect in varying amounts in breast milk.20 Its use should
of prolonging the QT interval (Fig. 1). Amiodarone therefore be avoided in women who are pregnant
is also uniquely effective in preventing experimen- or breast-feeding.
tally induced atrial electrical remodeling.13 Amiodarone is an excellent choice for use in
patients with structural heart disease or conges-
Cl inic a l E v idence tive heart failure.9,21 It is generally reserved as an
alternative to other agents for patients without
Amiodarone has consistently been demonstrated underlying heart disease, given its multitude of
to be superior to other antiarrhythmic medica- side effects.9 Many physicians hesitate to use amio-
tions for the maintenance of sinus rhythm.14-16 darone in young patients because of the concern
The Canadian Trial of Atrial Fibrillation random- about side effects related to long-term use.
ly assigned 403 patients with paroxysmal or per- Contraindications to the use of amiodarone
sistent atrial fibrillation to treatment with amio- include severe sinus-node dysfunction and ad-
darone or with propafenone or sotalol.14 During vanced conduction disease (except in patients with
a mean follow-up period of 468±150 days, recur- a functioning artificial pacemaker). The drug
rence of atrial fibrillation was documented in 63% should also be used cautiously in patients with
of patients taking propafenone or sotalol, as com- severe lung disease (which may interfere with the
pared with 35% of those taking amiodarone. The detection of adverse effects).
Sotalol Amiodarone Atrial Fibrillation Efficacy Before choosing amiodarone for the treatment
Trial compared the efficacy of sotalol, amioda- of atrial fibrillation, clinicians should consider
rone, and placebo in 665 patients with persistent other options. Rate control alone (i.e., the use of
atrial fibrillation.15 Recurrence of atrial fibrilla- agents to maintain a slow ventricular response
tion after 1 year was documented in 35% of pa- rate in atrial fibrillation) is often as effective as
tients taking amiodarone, 60% of those taking rhythm control in managing the symptoms of
sotalol, and 82% of those taking placebo. this arrhythmia, and it has been shown to be at

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clinical ther apeutics

A Normal B Atrial fibrillation C Amiodarone treatment

Sinus
node

Left
atrium

Normal QT interval Prolonged QT interval

Normal duration Normal duration Prolonged duration


of action potential of action potential of action potential

Figure 1. Electrophysiological Action of Amiodarone.


COLOR FIGURE
During normal sinus rhythm (Panel A), myocardial activation is initiated in the sinus node, with a resulting coordinated wavefront of de-
polarization that spreads across both atria (arrows) to the atrioventricular node and specialized conductionRev5 01/25/07
system (green). Atrial fibril-
lation (Panel B) is triggered by atrial premature depolarizations arising in the region of the pulmonary Author
veins (red asterisk) and propa-
Dr. Zimetbaum
gates in an irregular and unsynchronized pattern (arrows). The resulting pattern of ventricular activation
Fig is
# irregular
1 (as shown on the
electrocardiographic recording). Amiodarone (Panel C) has several electrophysiological effects. Chief among
Title these in the control of atri-
al fibrillation is the effect on the potassium channel blockade, which slows repolarization, thus prolonging the action potential and the
ME
refractoriness of the myocardium. Waves of depolarization are more likely to encounter areas of myocardium that are unresponsive;
thus, propagation is prevented. Although the prolongation of the action potential is most apparent onDE
Dr. Jarcho
the electrocardiogram as an ef-
fect on the ventricular myocardium (prolonged QT interval), a similar effect occurs in the atria. Artist Daniel Muller
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully

least as effective as rhythm control with respect depends on the clinical setting.9 Finally,
Issue date inva-
03/01/2007
to the long-term outcome.3 Therefore, a trial of sive procedures, such as pulmonary-vein isolation,
rate control should always be considered. Other have an increasing role in the management of this
antiarrhythmic drugs, such as sotalol and propafe- disorder,22 although in most cases, these approach-
none, should also be considered, with the rec- es have been used only after the failure of other
ognition that the balance of risks and benefits therapies.
for these agents as compared with amiodarone Before initiating treatment with amiodarone,

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The n e w e ng l a n d j o u r na l of m e dic i n e

it is critical to establish therapeutic anticoagula- dose at least reduced by 50%. The INR must be
tion, because the potential exists for conversion monitored closely during amiodarone loading and
to sinus rhythm (with a consequent risk of throm- maintenance therapy. It is usually necessary to
boembolism) at any point during the drug-load- reduce the warfarin dose by 25 to 50% when the
ing phase. The recommended criterion for anti- drug is coadministered with amiodarone.
coagulation is an international normalized ratio The cost of amiodarone is typically about $1.25
(INR) of 2.0 to 3.0 for 3 consecutive weeks or a per tablet in the United States. In addition, the
transesophageal echocardiogram demonstrat- initial screening tests performed before treatment
ing the absence of left atrial thrombus. begins (chest radiography and tests of pulmonary,
Amiodarone therapy is initiated with a load- thyroid, and liver function) cost approximately
ing dose of approximately 10 g in the first 1 to $250, with a similar expense annually to screen
2 weeks. This loading dose can be given in divided for adverse effects.
doses — for example, 400 mg given orally twice
a day for 2 weeks followed by 400 mg given orally A dv er se Effec t s
each day for the next 2 weeks. Reducing the in-
dividual dose and administering it three times Amiodarone is associated with both cardiovas-
daily may reduce the gastrointestinal intolerance cular and noncardiovascular adverse events (Ta-
sometimes associated with amiodarone loading. ble 1). Side effects resulting in discontinuation
A more protracted loading period with a lower of therapy occur in 13 to 18% of patients after
daily dose may be used when sinus- or atrioven- 1 year.12,15 The most frequent cardiovascular side
tricular-node dysfunction is a concern. effect is bradycardia, which is often dose-related,
It is relatively safe to initiate treatment with occurs more frequently in elderly patients than in
amiodarone in the ambulatory setting.23 Electro- younger patients, and can often be mitigated by
cardiographic monitoring (with 12-lead electro- dose reduction.24,25 Prolongation of the QT inter-
cardiography or an event recorder) should be per- val is seen in most patients but is associated with
formed at least once during the loading period to a very low incidence of torsades de pointes (<0.5%)
evaluate the patient for excessive prolongation of as compared with other drugs that prolong the
the QT interval (>550 msec) or bradycardia. Pro- QT interval (e.g., sotalol and dofetilide).17
longation of the QT interval is common and gen- Clinical evidence of hypothyroidism occurs in
erally responds to dose reduction.15 up to 20% of patients taking amiodarone. It devel-
Given the delay in the onset of antiarrhythmic ops most often in patients with preexisting auto-
action with amiodarone, it is common for atrial immune thyroid disease and those living in areas
fibrillation to persist or recur during the loading replete with iodine (that is, they are not iodine-
phase of drug administration; however, this does deficient).26 Hypothyroidism is easily managed
not predict rates of sinus rhythm at 1 month.24 with levothyroxine and generally is not cause for
Approximately 30% of patients have a reversion discontinuing amiodarone.12,26 Hyperthyroidism
to sinus rhythm during this loading phase, and occurs in 3% of patients in areas where dietary
the remainder can undergo electrical cardiover- iodine is sufficient but in 20% of patients in
sion, which has a high rate of success.15,23 iodine-deficient areas. It can be difficult to rec-
Once the loading phase is completed, the main- ognize clinically because many of the typical ad-
tenance dose of amiodarone for atrial fibrillation renergically mediated signs are blocked by amio-
is 200 mg a day. Monitoring of levels of amioda- darone. The recurrence of atrial fibrillation during
rone or desethylamiodarone is not recommended, maintenance amiodarone therapy should prompt
given the lack of correlation between drug levels an evaluation for amiodarone-induced hyperthy-
and efficacy or adverse events.12 However, moni- roidism. Management requires the assistance of an
toring with the use of various laboratory tests experienced endocrinologist and may require dis-
for evidence of adverse effects is recommended. continuation of amiodarone therapy. Thyrotropin
Amiodarone interferes with the hepatic me- levels should be checked in all patients before
tabolism of many medications, the most common amiodarone therapy is initiated and at least every
of which are digoxin and warfarin. Generally, di- 6 months thereafter.12
goxin should be discontinued if possible, or the Pulmonary toxicity is one of the most serious

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clinical ther apeutics

Table 1. Adverse Effects of Oral Amiodarone.

Adverse Effect Incidence Recommended Monitoring Special Considerations


Cardiac Baseline electrocardiogram at least Consider reduction of loading dose in
Bradycardia 5% once during loading period, es- elderly patients and those with un-
Prolonged QT interval In most pecially if conduction disease is derlying sinoatrial or atrioventricu-
patients present; yearly thereafter lar conduction disease; reduce
Torsades de pointes <1% dose or discontinue if QT interval
exceeds 550 msec
Hepatic 15% Aspartate and alanine aminotrans- Avoid in patients with severe liver
ferase measurements at base- disease
line and every 6 months there-
after
Thyroid Thyroid-function tests at baseline Avoid in presence of preexisting, non-
Hyperthyroidism 3% and two or three times a year functioning thyroid nodule; higher
Hypothyroidism 20% thereafter incidence of thyroid effects in pa-
tients with autoimmune thyroid
disease
Pulmonary <3% Pulmonary-function tests at base- Discontinue amiodarone immediately
line and if symptoms develop; if pulmonary effects suspected
chest radiograph at baseline
and yearly thereafter
Dermatologic 25–75% Routine Recommend use of sunscreen with a
high sun protection factor
Neurologic 3–30% Routine Consider dose reduction
Ophthalmologic Examination at baseline if there is Avoid in presence of preexisting optic
Corneal deposits 100% underlying abnormality; exami- neuritis
Optic neuritis <1% nations as needed thereafter

complications of amiodarone use. It occurs in less discontinuing the drug but can result in cirrhosis if
than 3% of patients and is thought to be related unheeded. Liver-function tests should be measured
to the total cumulative dosage.12 In the Atrial Fi- at baseline and every 6 months thereafter.9,12,28
brillation Follow-up Investigation of Rhythm Man- Corneal microdeposits are seen in virtually all
agement study, there was a slightly increased inci- patients receiving long-term amiodarone thera-
dence of pulmonary toxicity in patients with py and are rarely of clinical significance.12 Optic
preexisting pulmonary disease, but mortality from neuropathy has been reported in less than 1% of
pulmonary causes and overall mortality were not patients, but it may be a result of associated medi-
higher among these patients than among those cal conditions rather than an effect of amioda-
without preexisting pulmonary disease.27 The man- rone. Nonetheless, the potential severity of optic
agement of acute pulmonary toxicity involves dis- neuropathy warrants discontinuation of amioda-
continuation of therapy, supportive management, rone therapy if the condition is suspected. Oph-
and, in extreme cases, corticosteroid administra- thalmologic examinations are recommended at
tion.12 Screening pulmonary-function tests and baseline only for patients with preexisting ab-
chest radiography should be performed at base- normalities.
line, and chest radiography should be performed Dermatologic side effects of amiodarone use
yearly thereafter.9,12 Pulmonary-function tests include photosensitivity, with susceptibility to sun-
should be repeated if symptoms develop. burn, particularly in patients with a fair complex-
Hepatic toxicity is a rare complication of amio- ion. Avoidance of direct exposure to the sun and
darone therapy when the drug is used in low doses. use of sunscreen can diminish this reaction.
Amiodarone can cause nonalcoholic steatohepa- A gray-bluish skin discoloration may be seen in
titis, which is manifested as an asymptomatic in- patients who take large doses of amiodarone for
crease in hepatic aminotransferase levels (more long periods.29 Alopecia is also an infrequent side
than two times the upper limit of the normal effect of amiodarone.
range). This condition can generally be reversed by Neurologic side effects, which occur in up to

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30% of patients, include ataxia, tremor, peripheral recommend reserving amiodarone as an alterna-
polyneuropathy, insomnia, and impaired memo- tive agent for most patients with atrial fibrilla-
ry. These effects are often dose-related and occur tion, the exceptions being those who have clini-
more often in elderly patients than in younger pa- cal heart failure or hypertension with substantial
tients. left ventricular hypertrophy.9 For patients at very
high risk for recurrence of atrial fibrillation (e.g.,
A r e a s of Uncer ta in t y those with severe mitral regurgitation), amioda-
rone may be the best choice of a first-line agent,
The side effects of low-dose amiodarone therapy given the low likelihood that treatment with oth-
(200 mg daily) in patients taking the drug for er antiarrhythmic agents will be successful.
more than 5 years — the duration of clinical stud-
ies that have been conducted — are unknown. R ec om mendat ions
Some patients, particularly those who are elderly
and those with relatively little body fat, can be For the patient described in the vignette, it is rea-
treated with a very low dose (100 mg per day). sonable to attempt to maintain sinus rhythm be-
There are no available data from clinical trials cause of the presence of symptoms in spite of a
that support this reduced-dose strategy, but it is well-controlled ventricular response. His symp-
common practice. toms are probably due to diastolic dysfunction.
Amiodarone is frequently used for the pre- The presence of coronary artery disease limits
vention and treatment of atrial fibrillation as- the choice of antiarrhythmic drug to amiodarone,
sociated with cardiac surgery, including the maze sotalol, and dofetilide. The patient’s renal insuf-
procedure for cure of atrial fibrillation.9 Atrial ficiency makes sotalol and dofetilide unattractive
fibrillation associated with cardiac surgery oc- options. The preferred agent to maintain sinus
curs most frequently in the first few days after rhythm in this patient is therefore amiodarone.
surgery but can also occur weeks after surgery. Baseline screening studies should include tests
For patients undergoing cardiac surgery, amio- of liver, thyroid, and pulmonary function as well
darone is given at a dose of 600 mg a day for 1 to as chest radiography. The warfarin dose should
2 weeks before surgery and is continued for 4 to be decreased by at least 25% when the loading
6 weeks after surgery. Although this approach is dose of amiodarone is administered. It is reason-
supported by data from clinical trials, beta-block- able to initiate amiodarone therapy in the outpa-
ers have also been reported to reduce rates of tient setting. A slightly reduced loading dose (e.g.,
postoperative atrial fibrillation,30 and none of the 600 mg per day in one dose or divided doses for
major studies of amiodarone compared it with 3 to 4 weeks) is reasonable, given that the patient’s
the use of a beta-blocker alone. baseline heart rate is already well controlled on
The use of amiodarone in combination with a low dose of a beta-blocker (which may suggest
other antiarrhythmic drugs has not been thor- underlying atrioventricular-node conduction dis-
oughly studied. One intriguing combination is ease). The patient should undergo electrocardi-
that of angiotensin-receptor blockers with amio- ography weekly or should be discharged with a
darone. Emerging data suggest that the combi- loop recorder to monitor heart rhythm, heart rate,
nation of these two agents is more effective than and duration of the QT interval. If conversion has
either is alone.31 not occurred by the end of the loading period,
electrical cardioversion should be performed, fol-
Guidel ine s lowed by a reduction in the dose of amiodarone
to 200 mg daily. The warfarin dose may need to
Recently published guidelines of the American be increased as the amiodarone dose is reduced.
Heart Association, the American College of Car- No potential conflict of interest relevant to this article was
reported.
diology, and the European Society of Cardiology

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clinical ther apeutics

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n engl j med 356;9  www.nejm.org  march 1, 2007 941


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