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clinical therapeutics
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.
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
Sinus
node
Left
atrium
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,
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
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
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
References
1. Miyasaka Y, Barnes M, Gersh B, et al. tions for future prevalence. Circulation Cohen DJ, Zimetbaum P. Influence of age,
Secular trends in incidence of atrial fibril- 2006;114:119-25. [Erratum, Circulation sex, and atrial fibrillation recurrence on
lation in Olmsted County, Minnesota, 1980 2006;114:e498.] quality of life outcomes in a population of
to 2000, and implications on the projec- 2. Reynolds MR, Lavelle T, Essebag V, patients with new-onset atrial fibrillation:
the Fibrillation Registry Assessing Costs, from mechanisms to clinical practice. 22. Wazni OM, Marrouche NF, Martin
Therapies, Adverse events and Lifestyle Heart 2000;84:339-46. DO, et al. Radiofrequency ablation versus
(FRACTAL) study. Am Heart J 2006;152: 12. Goldschlager N, Epstein AE, Nacca- antiarrhythmic drugs as first-line treat-
1097-103. relli G, Olshansky B, Singh B. Practical ment of symptomatic atrial fibrillation:
3. Wyse DG, Waldo AL, DiMarco JP, et guidelines for clinicians who treat patients a randomized trial. JAMA 2005;293:2634-
al. A comparison of rate control and rhythm with amiodarone. Arch Intern Med 2000; 40.
control in patients with atrial fibrillation. 160:1741-8. 23. Kochiadakis GE, Igoumenidis NE, So-
N Engl J Med 2002;347:1825-33. 13. Shinagawa K, Shiroshita-Takeshita A, lomou MC, Kaleboubas MD, Chlouverakis
4. Van Gelder IC, Hagens VE, Bosker HA, Schram G, Nattel S. Effects of antiarrhyth- GI, Vardas PE. Efficacy of amiodarone for
et al. A comparison of rate control and mic drugs on fibrillation in the remodeled the termination of persistent atrial fibril-
rhythm control in patients with recurrent atrium: insights into the mechanism of lation. Am J Cardiol 1999;83:58-61.
persistent atrial fibrillation. N Engl J Med the superior efficacy of amiodarone. Circu- 24. Hauser TH, Pinto DS, Josephson ME,
2002;347:1834-40. lation 2003;107:1440-6. Zimetbaum P. Early recurrence of arrhyth-
5. Chung MK, Shemanski L, Sherman 14. Roy D, Talajic M, Dorian P, et al. Ami- mia in patients taking amiodarone or class
DG, et al. Functional status in rate- versus odarone to prevent recurrence of atrial 1C agents for treatment of atrial fibrilla-
rhythm-control strategies for atrial fi- fibrillation. N Engl J Med 2000;342:913- tion or atrial flutter. Am J Cardiol 2004;
brillation: results of the Atrial Fibrilla- 20. 93:1173-6.
tion Follow-up Investigation of Rhythm 15. Singh BN, Singh SN, Reda DJ, et al. 25. Idem. Safety and feasibility of a clini-
Management (AFFIRM) Functional Sta- Amiodarone versus sotalol for atrial fi- cal pathway for the outpatient initiation
tus Substudy. J Am Coll Cardiol 2005;46: brillation. N Engl J Med 2005;352:1861- of antiarrhythmic medications in patients
1891-9. 72. with atrial fibrillation or atrial flutter.
6. Steinberg JS, Sadaniantz A, Kron J, et 16. AFFIRM First Antiarrhythmic Drug Am J Cardiol 2003;91:1437-41.
al. Analysis of cause-specific mortality in Substudy Investigators. Maintenance of 26. Pearce EN, Farwell AP, Braverman LE.
the Atrial Fibrillation Follow-up Investi- sinus rhythm in patients with atrial fibril- Thyroiditis. N Engl J Med 2003;348:2646-
gation of Rhythm Management (AFFIRM) lation: an AFFIRM substudy of the first 55. [Erratum, N Engl J Med 2003;349:
study. Circulation 2004;109:1973-80. antiarrhythmic drug. J Am Coll Cardiol 620.]
7. Allessie M, Ausma J, Schotten U. Elec- 2003;42:20-9. 27. Olshansky B, Sami M, Rubin A, et al.
trical, contractile and structural remodel- 17. Kaufman ES, Zimmerman PA, Wang T, Use of amiodarone for atrial fibrillation
ing during atrial fibrillation. Cardiovasc et al. Risk of proarrhythmic events in the in patients with preexisting pulmonary
Res 2002;54:230-46. Atrial Fibrillation Follow-up Investigation disease in the AFFIRM study. Am J Car-
8. Haissaguerre M, Jais P, Shah DC, et al. of Rhythm Management (AFFIRM) study: diol 2005;95:404-5.
Spontaneous initiation of atrial fibrillation a multivariate analysis. J Am Coll Cardiol 28. Sanyal AJ, American Gastroentero-
by ectopic beats originating in pulmonary 2004;44:1276-82. logical Association. AGA technical review
veins. N Engl J Med 1998;339:659-66. 18. Zimetbaum P, Ho KK, Olshansky B, et on nonalcoholic fatty liver disease. Gas-
9. Fuster V, Ryden LE, Cannom DS, et al. al. Variation in the utilization of antiar- troenterology 2002;123:1705-25.
ACC/AHA/ESC 2006 Guidelines for the rhythmic drugs in patients with new-onset 29. Ahmad S. Amiodarone and reversible
Management of Patients with Atrial Fibril- atrial fibrillation. Am J Cardiol 2003;91:81- alopecia. Arch Intern Med 1995;155:1106.
lation: a report of the American College of 3. 30. Mitchell LB, Exner DV, Wyse DG, et al.
Cardiology/American Heart Association 19. Mitchell LB, Wyse DG, Gillis AM, Duff Prophylactic Oral Amiodarone for the Pre-
Task Force on Practice Guidelines and the HJ. Electropharmacology of amiodarone vention of Arrhythmias that Begin Early
European Society of Cardiology Commit- therapy initiation: time courses of onset After Revascularization, Valve Replace-
tee for Practice Guidelines (Writing Com- of electrophysiologic and antiarrhythmic ment, or Repair: PAPABEAR: a random-
mittee to Revise the 2001 Guidelines for effects. Circulation 1989;80:34-42. ized controlled trial. JAMA 2005;294:3093-
the Management of Patients with Atrial 20. Ito S. Drug therapy for breast-feeding 100.
Fibrillation): developed in collaboration women. N Engl J Med 2000;343:118-26. 31. Madrid AH, Bueno MG, Rebollo JM, et
with the European Heart Rhythm Associ- 21. Singh SN, Fletcher RD, Fisher SG, et al. Use of irbesartan to maintain sinus
ation and the Heart Rhythm Society. Circu- al. Amiodarone in patients with conges- rhythm in patients with long-lasting atri-
lation 2006;114:e257-e354. tive heart failure and asymptomatic ven- al fibrillation: a prospective and random-
10. Nattel S. New ideas about atrial fibril- tricular arrhythmia: Survival Trial of An- ized study. Circulation 2002;106:331-6.
lation 50 years on. Nature 2002;415:219-26. tiarrhythmic Therapy in Congestive Heart Copyright © 2007 Massachusetts Medical Society.
11. Roden DM. Antiarrhythmic drugs: Failure. N Engl J Med 1995;333:77-82.