Long-Term Efficacy of Amiodarone Therapy for the Prevention of

Recurrence of Paroxysmal Atrial Fibrillation

Analysis Based on Patient Characteristics
Takashi Komatsu,1 MD, Hideaki Tachibana,1 MD, Yoshihiro Sato,1 MD, Mahito Ozawa,1 MD,
Fusanori Kunugita,1 MD, and Motoyuki Nakamura,1 MD
Summary
There is little information available on factors affecting the long-term prevention of paroxysmal atrial fibrillation
(AF) in the Japanese population. A total of 71 patients (49 men, mean age, 68 8 years) with paroxysmal AF refractory
to 2 class I antiarrhythmic drugs received oral amiodarone (50-200 mg/day). All patients were observed for more than
12 months (mean follow-up period, 47 26 months) and were analyzed on the basis of patient profiles. The percentage
of patients with AF recurrence despite amiodarone therapy was 54% in all patients. In multivariate logistic regression
analysis adjusted for age and sex, the following factors were associated with preventive efficacy for AF recurrence: left
ventricular ejection fraction (LVEF) (relative risk [RR] 0.933, 95% confidence interval [CI] 0.877-0.993, P = 0.029),
asymptomatic AF (RR 0.068, CI 0.005-0.870, P = 0.039), and AF occurring irrespective of circadian variation (RR
0.115, CI 0.013-0.988, P = 0.049). The percentage of patients with conversion to permanent AF despite amiodarone
therapy was 31% in all patients. In multivariate logistic regression analysis adjusted for age and sex, asymptomatic AF
(RR 0.085, CI 0.010-0.732, P = 0.025) was the only factor associated with preventive efficacy for conversion to permanent AF. Amiodarone appears to be effective in maintaining sinus rhythm, especially in patients with impaired left ventricular function. In contrast, amiodarone appears to be refractory in those with asymptomatic AF or AF occurring irrespective of circadian variation. (Int Heart J 2011; 52: 212-217)
Key words: Atrial fibrillation, Amiodarone, Prevention, Ejection fraction, Symptom

ccording to a large-scale epidemiological survey performed in western countries, atrial fibrillation (AF) is
an independent risk factor for cardiovascular death,
and the risk of such death is 2-3 times higher in patients with
AF than in those with sinus rhythm.1) AF is often encountered
in routine medical practice and is an arrhythmia that should be
actively treated and controlled, because it not only causes cardiovascular complications, including thromboembolism and
heart failure,2) but also decreases survival in patients with impaired left ventricular function.3) The number of patients with
AF in the United States exceeded 5 million in 2000 and is expected to increase two to threefold over the next 50 years.4) In
Japan, the population is aging rapidly and the prevalence of AF
among elderly persons aged 70 years or older is already around
3%. This is expected to increase to about 4.5% over the next
20 years.5)
We have previously reported a therapeutic limitation with
class I antiarrhythmic drugs (AAD) in preventing recurrence
of AF.6) In Japan, amiodarone (a class III antiarrhythmic drug)
has been used to maintain sinus rhythm only in patients with
paroxysmal and obstructive hypertrophic cardiomyopathy, although two large clinical trials have reported that the efficacy
of amiodarone in preventing recurrence of paroxysmal and

persistent AF is superior to that of class I antiarrhythmic drugs

and dl-sotalol.7,8) The Japanese Circulation Society (JCS)
Guidelines9) recommend that amiodarone be used as first-line
therapy for preventing recurrence of paroxysmal AF associated
with underlying heart disease and impaired cardiac function.
However, there has been little information relating to clinical
profiles that are suitable for amiodarone therapy from which to
estimate the long-term efficacy of this drug in Japanese patients with paroxysmal AF. In the present study, we therefore
examined the long-term efficacy of amiodarone therapy for the
prevention of AF recurrence in patients with paroxysmal AF
on the basis of patient clinical profiles.

Methods
Subjects: The subjects were 71 patients (49 men and 22 wom-

en, average age, 68 9 years) who had symptoms such as palpitations and electrocardiographic evidence of AF corresponding to those symptoms. All patients visited the hospital every 2
to 4 weeks and were followed-up for more than one year.
Noninvasive examinations, including chest X-rays, exercise testing, and transthoracic echocardiography were per-

From the 1 Division of Cardiology, Department of Internal Medicine and Memorial Heart Center, Iwate Medical University School of Medicine, Iwate, Japan.
Address for correspondence: Takashi Komatsu, MD, Division of Cardiology, Department of Internal Medicine and Memorial Heart Center, Iwate Medical University
School of Medicine, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.
Received for publication November 29, 2010.
Revised and accepted February 28, 2011.
212

Vol 52
No 4

AMIODARONE FOR PAROXYSMAL ATRIAL FIBRILLATION

formed in all patients, while pulmonary function tests, computed tomographic examination of the brain and chest, and
cardiac catheterization were performed at the discretion of the
attending physician. Patients with severe bradyarrhythmia (sick
sinus syndrome, atrioventricular block, or intraventricular conduction disorder), with hepatic or renal dysfunction associated
with laboratory abnormalities, women with childbearing potential, and patients receiving concomitant T-type calcium antagonists were excluded from the study. This study was conducted between June 1997 and August 2009, and the mean observation period was 47 26 months.
Defibrillation protocol and antiarrhythmic drug therapy:

When AF had persisted for less than 48 hours, defibrillation

was attempted immediately by drug therapy or electrical defibrillation under intravenous anesthesia with thiopental in accordance with the American Heart Association (AHA) guidelines.10) If AF had persisted for more than 48 hours in patients
who were not on anticoagulant therapy, transesophageal
echocardiography was performed to confirm that there was no
left atrial thrombus or spontaneous echo contrast, after which
defibrillation was performed and anticoagulant therapy with
warfarin was added. If the patients were already receiving anticoagulant therapy, electrical defibrillation was performed after
their PT-INR was confirmed to be between 1.6 and 3.0.
According to the protocol for preventing the recurrence
of AF by AAD, patients with a left ventricular ejection fraction
of more than 40% on echocardiography underwent medical or
electrical defibrillation to restore sinus rhythm, and were subsequently randomized by the envelope method to either class
Ia or Ib AAD (disopyramide 300 mg/day, aprindine 60 mg/day,
or cibenzoline 300 mg/day) as first-line therapy. Patients were
observed carefully for recurrence of AF, and if this was detected during follow-up, defibrillation was repeated at that time.
Patients were subsequently randomized to receive either class
Ic AAD (flecainide 150 mg/day or pilsicainide 150 mg/day) or
bepridil (150 mg/day) as second-line therapy, and were observed carefully for recurrence. If AF recurred in patients on
second-line therapy, amiodarone was administered if patient
consent was obtained. In patients who withheld consent, a drug
from Class I AAD that had not been used already was administered as third-line therapy. Patients whose left ventricular
ejection fraction was less than 40% on transthoracic echocardiography underwent electrical defibrillation to restore sinus
rhythm, and were subsequently treated with either aprindine
(60 mg/day) or bepridil (150 mg/day) as first- or second-line
therapy. If AF recurred despite such therapy, amiodarone was
administered as a third-line drug at a starting dose of 400 mg/
day for two weeks. After the initial loading phase, the maintenance dose of 50-200 mg/day was adjusted while the efficacy
and side effects were monitored. The amiodarone dose was decreased at a rate of 50 mg/day step by step if recurrence of AF
was not observed for 6 or 12 months. Patients were hospitalized for at least 2 weeks while undergoing initial amiodarone
loading and follow-up was conducted 1 month after discharge,
and then at intervals of 1-3 months. Baseline 12-lead ECG,
echocardiography, thyroid and liver function tests, pulmonary
function tests, ophthalmologic examination, and chest X-rays
were performed for most patients before amiodarone therapy.
Twelve-lead ECG was performed several times during the initial loading phase and also at each outpatient visit. Thyroid and
liver function testing, pulmonary function testing, and chest X-

213

rays were used to access the adverse effects of amiodarone

therapy at week 2, months 1 and 3, and then every 6 months
after initiation. Ophthalmologic examination was performed
every 6 months.
Two to four weeks after commencement of or alteration
in an oral antiarrhythmic drug, standard 12-lead ECG and ambulatory 24-hour monitoring were recorded in all patients. In
addition, at every visit to our outpatient clinic, maintenance or
otherwise of sinus rhythm was confirmed with the use of a
portable ECG monitor (IEC-1101 Heart Mate, Nihon Kohden Corporation). Whenever palpitations occurred, an ambulatory 24-hour monitoring was recorded at the discretion of the
attending physician to determine whether AF had recurred or
not.
Definitions: Based on symptoms and ambulatory 24-hour
monitoring, paroxysmal AF was defined as transient AF terminating spontaneously within 1 week of onset.11) The history of
AF was the period from the initial episode of AF to the time of
the initiation of antiarrhythmic therapy. Permanent AF was defined as AF that was refractory to pharmacological and electrical cardioversion and did not convert to sinus rhythm for a period greater than 6 months. Asymptomatic AF was defined as
an AF episode in which patients had none of the symptoms associated with arrhythmia such as palpitations, dizziness, chest
discomfort or syncope, or heart failure symptoms such as dyspnea, edema, orthopnea, or paroxysmal nocturnal dyspnea at
initial hospital visit.12) Cerebral thromboembolism was diagnosed in all cases based on typical neurological symptoms and
the development of a new low-density lesion greater than 3
mm on brain computed tomographic examination or magnetic
resonance imaging, which was performed in all patients. Hypertension was defined according to the Japanese Society of
Hypertension Guidelines for the Management of Hypertension
(JSH 2009).13) Diabetes mellitus was diagnosed if fasting venous blood glucose was 126 mg/dL or hemoglobin A1C was
6.5%. Onset of paroxysmal AF was classified as the diurnal
(07:00 to 17:00), nocturnal (17:00 to 07:00 next morning), or
mixed type (AF occurring irrespective of circadian variation)
based on standard 12-lead ECG and ambulatory 24-hour monitoring findings. In patients with AF at the time of hospital visits, classification was based on the time when symptoms commenced. 14) Recurrence of AF was not determined from
subjective symptoms, but was defined as the time when ECG
first revealed AF during antiarrhythmic drug therapy. In the
pulmonary function test, we regarded FEV1.0 70% as a diagnostic criterion for chronic obstructive pulmonary disease.
Risk factors for thromboembolism regarding CHADS2 scores
were defined as a history of cerebral infarction or transient
ischemic attack, hypertension, diabetes mellitus, coronary artery disease, or recent heart failure.10)
Statistical analysis: Continuous data are expressed as the mean
standard deviation (SD). Between-group comparisons were
performed using the Mann-Whitney U-test for continuous variables and the chi-square test for noncontinuous variables. The
independent predictors for recurrence and conversion to the
permanent form of paroxysmal AF were analyzed by multivariate logistic regression analysis. In all of these tests, P values <
0.05 were identified as significant differences.

214

Int Heart J
July 2011

KOMATSU, ET AL

Results
Comparison of subject baseline profiles estimated by preventive
efficacy of AF recurrence: The percentage of patients with and

without AF recurrence during amiodarone therapy was 54% (n

= 38 patients, group I) and 46% (n = 33 patients, group II), respectively, in all 71 patients during the follow-up period. The
incidence of asymptomatic AF was significantly higher in
group I (24%) than in group II (3%) (P < 0.05, Table I). The
incidence of concomitant RAAS inhibitors was significantly
lower in group I (24%) than in group II (64%) (P < 0.05, Table
II). In contrast, left ventricular ejection fraction (LVEF) was
significantly higher in group I (65.9 13.0%) than in group II
(57.6 14.0%) (P < 0.05, Table II). Other demographic data
showed no significant differences.
Predictors of preventive efficacy for AF recurrence during amiodarone therapy: Multivariate logistic regression analysis ad-

justed for age and sex revealed that LVEF (relative risk 0.933,
95% confidence interval 0.877-0.993, P = 0.029), asymptomatic AF (0.068, 0.005-0.870, P = 0.039), and AF occurring

Table I. Patient Characteristics I

Group I
(n = 38)
Age (years)
Male : female
Smoking
Hypertension
Diabetes mellitus
Dyslipidemia
Hyperuricemia
Alcohol habits
Organic heart disease
Organic pulmonary disease
Non-valvular AF
Asymptomatic AF
CHADS2 score

Group II
(n = 33)

68.0 8.1
67.9 8.4
28 : 10
21 : 12
14 (37%)
6 (18%)
15 (39%)
13 (39%)
7 (18%)
3 (9%)
4 (11%)
5 (15%)
2 (5%)
3 (9%)
19 (50%)
13 (39%)
18 (47%)
19 (58%)
0 (0%)
2 (6%)
34 (89%)
29 (88%)
9 (24%)
1 (3%)
1.32 1.23 1.18 1.04

P
0.963
0.443
0.114
0.999
0.320
0.724
0.658
0.474
0.477
0.213
0.999
0.016
0.626

AF indicates atrial fibrillation.

Table II. Patient Characteristics II

Group I
(n = 38)
AF history (months)
RAAS inhibitors
Statin
RAAS inhibitors & Statin
Time of onset;
Diurnal : nocturnal : mixed
At baseline;
LVDd (mm)
LAD (mm)
LVEF (%)
Antiplatlet therapy
None
Aspirin
Warfarin

Group II
(n = 33)

24.5 40.7 12.7 21.7

11 (29%)
21 (64%)
5 (13%)
5 (15%)
0 (0%)
2 (6%)

irrespective of circadian variation (0.115, 0.013-0.988, P =

0.049) were associated with preventive efficacy for AF recurrence (Table III).
Comparison of subject baseline profiles estimated by preventive
efficacy of conversion to permanent AF: The percentage of pa-

tients with and without conversion to permanent AF during

amiodarone therapy was 31% (n = 22 patients, Group III) and
69% (49 = patients, Group IV), respectively, in all 71 patients
during the follow-up period. The incidences of diabetes mellitus and asymptomatic AF were significantly higher in Group
III (32% and 36%, respectively) than in Group IV (6% and
4%, respectively) (both P < 0.05, Table IV). The incidence of
concomitant RAAS inhibitor use was significantly lower in
Group III (18%) than in Group IV (57%) (P < 0.05, Table V).
In contrast, left ventricular ejection fraction (LVEF) was significantly higher in Group III (67.8 12.4%) than in Group IV
(59.4 14.1%) (P < 0.05, Table V). Other demographic data
showed no significant differences.
Predictors of preventive efficacy for conversion to permanent
AF during amiodarone therapy: Multivariate logistic regres-

sion analysis adjusted for age and sex showed that asymptomatic AF (0.085, 0.010-0.732, P = 0.025) was associated with
preventive efficacy for conversion to permanent AF only (Table
VI).
Adverse effects: The incidence of intolerable noncardiac effects resulting in withdrawal of the drug during oral amiodar-

Table III. Multivariate Predictors of Preventive Efficacy for Recurrence

of Atrial Fibrillation
Variable

Odds ratio (95%CI)

LVEF (%)
Asymptomatic AF
Onset with mixed type AF
RAAS inhibitors
LVDd (mm)
LAD (mm)
Statin
CHADS2 score
AF history (months)
Organic heart disease
Diabetes mellitus

0.933 (0.877-0.993)
0.068 (0.005-0.870)
0.115 (0.013-0.988)
2.452 (0.595-10.10)
0.945 (0.857-1.043)
0.949 (0.854-1.055)
0.409 (0.340-14.20)
1.158 (0.654-2.051)
1.003 (0.985-1.022)
0.813 (0.197-3.351)
0.977 (0.110-8.707)

0.029
0.039
0.049
0.214
0.263
0.332
0.409
0.614
0.739
0.774
0.984

LVDd indicates left ventricular end-diastolic dimension; LAD, left atrial

dimension; and LVEF, left ventricular ejection fraction.

0.144
0.004
0.100
0.213

2 : 0 : 36

3 : 4 : 26

0.221

46.3 7.1
36.9 6.4
65.9 13.0

47.5 6.5
38.4 5.1
57.6 14.0

0.475
0.286
0.012

7 (18%)
9 (24%)
22 (58%)

8 (24%)
3 (9%)
22 (67%)

0.574
0.123
0.474

AF indicates atrial fibrillation; RAAS, renin angiotensin aldosterone system; LVDd, left ventricular end-diastolic dimension; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; and ANP, atrial natriuretic peptide.

Figure 1. Rates of successful prevention of recurrence of atrial fibrillation

during amiodarone therapy.

Vol 52
No 4

215

AMIODARONE FOR PAROXYSMAL ATRIAL FIBRILLATION

Table IV. Patient Characteristics III
Group III
(n = 22)

Age (years)
Male : female
Smoking
Hypertension
Diabetes mellitus
Dyslipidemia
Hyperuricemia
Alcohol habits
Organic heart disease
Organic pulmonary disease
Non-valvular AF
Asymptomatic AF
CHADS2 score

Group IV
(n = 49)

67.3 8.9
68.4 7.9
16 : 6
33 : 16
8 (36%)
12 (24%)
8 (36%)
20 (41%)
7 (32%)
3 (6%)
3 (14%)
6 (12%)
1 (5%)
4 (8%)
10 (45%)
22 (45%)
9 (41%)
28 (57%)
0 (0%)
2 (4%)
20 (91%)
43 (88%)
8 (36%)
2 (4%)
1.64 1.43 1.08 0.95

Table VI. Multivariate Predictors of Preventive Efficacy for Conversion

to Permanent Atrial Fibrillation
P
0.661
0.784
0.394
0.397
0.008
0.999
0.999
0.999
0.460
0.999
0.999
0.001
0.058

Variable

Odds ratio (95%CI)

Asymptomatic AF
RAAS inhibitors
LVEF (%)
Onset with mixed type AF
Diabetes mellitus
LVDd (mm)
Statin
CHADS2 score
LAD (mm)
AF history (months)
Organic heart disease

0.085 (0.010-0.732)
4.963 (0.745-33.08)
0.953 (0.890-1.021)
0.124 (0.006-2.536)
0.312 (0.031-3.120)
0.944 (0.841-1.060)
2.466 (0.314-19.34)
0.764 (0.403-1.449)
0.961 (0.852-1.084)
0.997 (0.978-1.016)
1.262 (0.250-6.357)

0.025
0.098
0.171
0.175
0.322
0.333
0.390
0.410
0.516
0.736
0.778

LVDd indicates left ventricular end-diastolic dimension; LAD, left atrial

dimension; and LVEF, left ventricular ejection fraction.

AF indicates atrial fibrillation.

Table V. Patient Characteristics IV

AF history (months)
RAAS inhibitors
Statin
RAAS inhibitors & Statin
Time of onset;
Diurnal : nocturnal : mixed
At baseline;
LVDd (mm)
LAD (mm)
LVEF (%)
Antiplatlet therapy
None
Aspirin
Warfarin

Group III
(n = 22)

Group IV
(n = 49)

25.9 36.8
4 (18%)
4 (18%)
0 (0%)

15.9 31.9
28 (57%)
6 (12%)
2 (4%)

0.247
0.004
0.488
0.999

1 : 0 : 21

4 : 4 : 41

0.286

46.0 7.4
37.5 6.6
67.8 12.4

47.3 6.6
37.7 5.6
59.4 14.1

0.468
0.875
0.019

4 (18%)
6 (27%)
12 (55%)

11 (22%)
6 (12%)
32 (65%)

0.763
0.170
0.435

AF indicates atrial fibrillation; RAAS, renin angiotensin aldosterone system; LVDd, left ventricular end-diastolic dimension; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; and ANP, atrial natriuretic peptide.

one therapy was 5.6% in all cases during the mean follow-up
period of 47 26 months. We did not experience any fatal adverse events, although amiodarone therapy was discontinued
because of pulmonary toxicity in 3 cases and skin eruption in 1
case.

Discussion
Pharmacological effects of amiodarone: The pharmacological

effects of amiodarone on single myocardial cells include inhibition of the Ito, Iks, Ik1, and Ikach channels as well as the
IKur channel specific to atrial muscle cells, which results in
prolongation of the atrial refractory period.15,16) While the current density of the Ito and Iks channels varies depending on the
site within the myocardial tissue, which contributes to the nonuniformity of action potential duration over the myocardium,
amiodarone blocks these channels to decrease the nonuniformity of the atrial refractory period15) and also has beta-blocking
and If-channel blocking activities.17) These properties make

Figure 2. Rates of successful prevention of conversion to permanent atrial

fibrillation during amiodarone therapy.

this drug a multichannel blocker. Some reports have indicated

that amiodarone not only has potent antiarrhythmic effects but
also exerts beneficial effects on cardiac hemodynamics. Because of its alpha- and beta-sympathetic blocking actions,18,19)
its inhibition of the production of cytokines such as tumor
necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and
monocyte chemoattractant protein (MCP)-1,20,21) its antioxidant
property to inhibit the generation of active oxygen,22) and its
inotropic action via increased intracellular Ca concentrations
due to its Na-K pump inhibitory effect,23) amiodarone is expected to provide therapeutic effects in patients with AF where
onset is closely related to cardiac hemodynamic deterioration.
Clinical effects of amiodarone: In patients with impaired cardiac function, it has been reported that the prevalence of AF increases as the severity of heart failure increases.24) Class I antiarrhythmic drugs, which are widely used in Japan, have a
negative inotropic effect and it has therefore been reported that
long-term treatment with such drugs is associated with worsened prognosis in patients with AF who have impaired left
ventricular function.25) In contrast, amiodarone is believed to
have a minimal negative inotropic effect and fewer proarrhythmic effects than other class I antiarrhythmic drugs.26) Moreover, it has been reported that two years of amiodarone therapy
improved left ventricular ejection fraction in patients with congestive heart failure participating in a large-scale controlled

216

Int Heart J
July 2011

KOMATSU, ET AL

study27) and that long-term amiodarone therapy for more than

two years prevented the progression of left atrial enlargement
in patients with paroxysmal AF. In this study, left ventricular
ejection fraction was found to be an independent predictor of
recurrent AF after oral amiodarone therapy, and it was shown
that amiodarone therapy would be more effective in preventing
recurrences of AF in patients with reduced cardiac function
than in those with normal cardiac function. On the other hand,
it was difficult to maintain sinus rhythm even after amiodarone
therapy in patients with mixed type AF occurring irrespective
of circadian variation or those with asymptomatic AF, and this
result was consistent with our previously reported long-term
study results on class I antiarrhythmic drugs in such patients
with paroxysmal AF.28) Ueng, et al demonstrated that an independent predictor for the maintenance of sinus rhythm in patients with long-standing persistent AF was left atrial dimension > 40 mm prior to electrical cardioversion at a mean
follow-up period of 270 days.29) Our study, in contrast, showed
that LVDd and LAD in patients with paroxysmal AF refractory
to 2 class I antiarrhythmic drugs were not associated with independent predictors for the preventive efficacy of AF recurrence or conversion to permanent AF at a mean follow-up period of 47 26 months. This inconsistency may have resulted
from differences in the subjects, follow-up periods, mean doses
of amiodarone, and incidence of concomitant RAAS inhibitors
between the two studies.
Tachycardic episodes are easily overlooked in patients
with asymptomatic AF who do not visit medical institutions as
the symptoms are both rare and subjective; it is thus likely that
AF has already been present for a long period of time. Since
the duration of AF leads to a vicious circle of atrial electrophysiologic remodeling, AF tends to recur more frequently
and eventually becomes a chronic (permanent) condition.30) In
a previous study, we reported that failure to convert to sinus
rhythm early after recurrence of AF impaired the subsequent
therapeutic response to antiarrhythmic drugs.31) This finding is
believed to explain why it is more difficult to prevent asymptomatic AF than symptomatic AF. In addition, mixed type AF
occurring irrespective of circadian variation is considered to be
less related to autonomic nerves, but more related to the influence of degeneration or fibrosis of atrial muscles themselves. It
is therefore easy to predict that AF will become increasingly
refractory to antiarrhythmic drug therapy as the myocardial lesion progresses.
In the 1980s, the administration of high doses of amiodarone was identified as a major cause of pulmonary toxicity.32)
The initial large study in 1990 demonstrated the incidence rate
reached 9.1% at 60 months of amiodarone therapy in patients
receiving a daily dose of 400-500 mg.33) It is commonly considered that low-dose amiodarone therapy is safer.34,35) The incidence of amiodarone-induced pulmonary toxicity was recently reported to be 2.1% per year in 500 Japanese patients on
low maintenance doses of less than 200 mg daily,36) which is
not low compared with the 1.8% per year in a meta-analysis of
6,500 American and European patients in placebo-controlled
amiodarone trials.37) Other studies in small numbers of Japanese patients with atrial tachycardia found that 2.7-3.6% of patients receiving amiodarone developed pulmonary toxicity
during mean follow-up periods of 30-36 months.14,38) In the
present study, the incidence of pulmonary toxicity was 1.4%
per year, which is not low in comparison to American and Eu-

ropean data.37) These findings suggested that we should reduce

the incidence of amiodarone-induced pulmonary toxicity because there is no safe dose of amiodarone therapy, at least in
Japanese patients. It is, therefore, important to check suitable
screening tests for their efficacy and adverse effects as soon as
possible to detect pulmonary toxicity during long-term amiodarone therapy.
Limitations: The present study has the following limitations:
First, as this was a retrospective observation study, some bias
may exist in the demographic data of each respective group. It
is believed to be difficult to administer amiodarone to patients
randomly as the first-choice drug for paroxysmal AF in routine
practice in Japan because pulmonary toxic effects such as interstitial pneumonia occur at an incidence of about 2.1% yearly.36) Secondly, recurrence of AF was diagnosed at the time of
detection of AF on ECG. A study using ambulatory 24-hour
monitoring reported that more than half of tachycardic episodes were not recognized by patients with paroxysmal AF
who had obvious symptoms.39) On the other hand, a study using an ambulatory ECG monitor (Cardiophone) reported that
30 to 70% of patients with symptomatic AF developed sinus
tachycardia or premature atrial contraction when they complained of palpitations.40) In other words, present detection
methods based on ECG findings have methodological limitations in accurately detecting AF recurrence. Thirdly, since amiodarone is a multichannel blocker, it is not known which pharmacological action of the drug was effective in each case.
Fourth, since the present study targeted patients with paroxysmal AF only, it was not known how amiodarone was effective
in preventing sustained AF. Lastly, the sample size of the
present study was relatively small.
It will therefore be necessary to conduct a prospective
controlled multicenter study in Japan in order to reevaluate the
efficacy and safety of amiodarone in a larger patient population
with paroxysmal and persistent AF.
Conclusion: Amiodarone appears to be an effective therapy for
patients with impaired left ventricular function and paroxysmal
AF. However, it is less effective in those with asymptomatic
AF or AF occurring irrespective of circadian variation.

Acknowledgments
We thank all study participants, and the physicians and medical staff
of Iwate Medical University School who were involved in the study. We
are also deeply grateful for the direction provided by Professor Ken Okumura of Hirosaki University School of Medicine (Aomori, Japan).

References

1. Benjamin EJ, Wolf PA, DAgostino RB, Silbershatz H, Kannel

WB, Levy D. Impact of atrial fibrillation on the risk of death: the
Framingham Heart Study. Circulation 1998; 98: 946-52.
2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987; 147: 1561-4.
3. Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waciawiw MA,
Stevenson LW. Atrial fibrillation is associated with an increased
risk for mortality and heart failure progression in patients with
asymptomatic and symptomatic left ventricular dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricu-

Vol 52
No 4

AMIODARONE FOR PAROXYSMAL ATRIAL FIBRILLATION

lar Dysfunction. J Am Coll Cardiol 1998; 32: 695-703.

4. Miyasaka Y, Barnes ME, Gersh SJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to
2000, and implications on the projections for future prevalence.
Circulation 2006; 114: 119-25.
5. Ohsawa M, Okayama A, Sakata K, et al. Rapid increase in estimated number of persons with atrial fibrillation in Japan: an analysis from national surveys on cardiovascular diseases in 1980, 1990
and 2000. J Epidemiol 2005; 15: 194-6.
6. Komatsu T, Nakamura S, Suzuki O, Horiuchi D, Yomogida K,
Okumura K. Long-term prognosis of patients with paroxysmal
atrial fibrillation depends on their response to antiarrhythmic therapy. Circ J 2004; 68: 729-33.
7. AFFIRM First Antiarrhythmic Drug Substudy Investigators.
Maintenance of sinus rhythm in patients with atrial fibrillation: an
AFFIRM substudy of the first antiarrhythmic drug. J Am Coll
Cardiol 2003; 42: 20-9.
8. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol
for atrial fibrillation. N Engl J Med 2005; 352: 1861-72.
9. Ogawa S, Aizawa Y, Atarashi H, Inoue H, Ohe T, Okumura K, et
al. (The Japanese Circulation Society Joint Study Group) Guidelines for pharmacotherapy of atrial fibrillation. Circ J 2008; 72
(Suppl IV): 1581-638. (Japanese)
10. Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006
Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines and the European Society of Cardiology Committee
for Practice Guidelines Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society.
Circulation 2006; 114: 700-52.
11. Sopher SM, Camm AJ. Atrial fibrillation: maintenance of sinus
rhythm versus rate control. Am J Cardiol 1996; 77: 24A-37A.
(Review)
12. Flaker GC, Belew K, Beckman K, et al. Asymptomatic atrial fibrillation: demographic features and prognostic information from
the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005; 149: 657-63.
13. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of
Hypertension Guidelines for the Management of Hypertension
(JSH2009). Hypertens Res 2009; 32: 3-107.
14. Komatsu T, Tachibana H, Sato Y, Ozawa M, Nakamura M, Okumura K. Efficacy of amiodarone for preventing the recurrence of
symptomatic paroxysmal and persistent atrial fibrillation after cardioversion. Circ J 2007; 71: 46-51.
15. Kodama I, Kamiya K, Toyama J. Amiodarone: ionic and cellular
mechanisms of action of the most promising class III agent. Am J
Cardiol 1999; 84: 20R-28R. (Review)
16. Kamiya K, Nishiyama A, Yasui K, Hojo M, Sanguinetti MC, Kodama I. Short- and long-term effects of amiodarone on the two
components of cardiac delayed rectifier K (+) current. Circulation
2001; 103: 1317-24.
17. Tamura A, Ogura T, Uemura H, et al. Effects of antiarrhythmic
drugs on the hyperpolarization-activated cyclic nucleotide-gated
channel current. J Pharmacol Sci 2009; 110: 150-9.
18. Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Int Med
1995; 122: 689-700. (Review)
19. Kaye DM, Dart AM, Jennings GL, Esler MD. Antiadrenergic effect of chronic amiodarone therapy in human heart failure. J Am
Coll Cardiol 1999; 33: 1553-9.
20. Matsumori A, Ono K, Nishio R, Nose Y, Sasayama S. Amiodarone inhibits production of tumor necrosis factor-alpha by human
mononuclear cells: a possible mechanism for its effect in heart
failure. Circulation 1997; 96: 1386-9.
21. Hirasawa Y, Nakagomi A, Kobayashi Y, Katoh T, Mizuno K.
Short-term amiodarone treatment attenuates the production of

22.
23.

24.
25.

26.
27.

28.

29.

30.
31.

32.
33.
34.
35.
36.
37.

38.
39.
40.

217

monocyte cytokines and chemokines by C-reactive protein and

improves cardiac function in patients with idiopathic dilated cardiomyopathy and ventricular tachycardia. Circ J 2009; 73: 639-46.
Ide T, Tsutsui H, Kinugawa S, Utsumi H, Takeshita A. Amiodarone protects cardiac myocytes against oxidative injury by its free
radical scavenging action. Circulation 1999; 100: 690-2.
Hensley CB, Bersohn MM, Sarma JS, Singh BN, McDonough
AA. Amiodarone decreases Na, K-ATPase alpha 2 and beta 2 expression specifically in cardiac ventricle. J Mol Cell Cardiol 1994;
26: 417-24.
Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003; 91: 2D-8D. (Review)
Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL,
Hart RG. Antiarrhythmic drug therapy and cardiac mortality in
atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20: 527-32.
Nagai T, Satomi K, Noda T, et al. Relationship between oral amiodarone and inappropriate therapy from an implantable cardioverter
defibrillator. Circ J 2010; 74: 1302-7.
Massie BM, Fisher SG, Radford M, et al. Effect of amiodarone on
clinical status and left ventricular function in patients with congestive heart failure. CHF-STAT Investigators. Circulation 1996; 93:
2128-34.
Komatsu T, Tachibana H, Satoh Y, Ozawa M, Kunigida F, Nakamura M. Efficacy of antiarrhythmic drug therapy in preventing recurrence of atrial fibrillation and long-term cardiovascular prognosis in patients with asymptomatic paroxysmal atrial fibrillation. Int
Heart J 2010; 51: 98-104.
Ueng KC, Tasai TP, Yu WC, et al. Use of enalapril to facilliate sinus rhythm maintenance after external cardioversion of longstanding persistent atrial fibrillation. Results of a prospective and
controlled study. Eur Heart J 2003; 24: 2090-8.
Allessie MA. Atrial electrophysiologic remodeling: another vicious circle? J Cardiovasc Electrophysiol 1998; 9: 1378-93. (Review)
Komatsu T, Satoh Y, Tachibana H, Nakamura M, Horiuchi D,
Okumura K. Randomized crossover study of the long-term effects
of pilsicainide and cibenzoline in preventing recurrence of symptomatic paroxysmal atrial fibrillation: influence of the duration of
arrhythmia before therapy. Circ J 2006; 70: 667-72.
Rakita L, Sobol SM, Mostow N, Vrobel T. Amiodarone pulmonary toxicity. Am Heart J 1983; 106: 906-16. (Review)
Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82: 51-9.
Fraire AE, Guntupalli KK, Greenberg SD, Cartwright J Jr, Chasen
MH. Amiodarone pulmonary toxicity: a multidisciplinary review
of current status. South Med J 1993; 86: 67-77. (Review)
Kowey PR, Friehling TD, Marinchak RA, Sulpizi AM, Stohler JL.
Safety and efficacy of amiodarone. The low-dose perspective.
Chest 1988; 93: 54-9.
Yamada Y, Shiga T, Matsuda N, Hagiwara N, Kasanuki H. Incidence and predictors of pulmonary toxicity in Japanese patients
receiving low-dose amiodarone. Circ J 2007; 71: 1610-6.
Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomized trials. Amiodarone
Trials Meta-Analysis Investigators. Lancet 1997; 350: 1417-24.
Shiga T, Wakaumi M, Imai T, et al. Effect of low-dose amiodarone
on atrial fibrillation or flutter in Japanese patients with heart failure. Circ J 2002; 66: 600-4.
Rho RW, Page RL. Asymptomatic atrial fibrillation. Prog Cardiovasc Dis 2005; 48: 79-87. (Review)
Fukuda Y, Akashi M, Noma S, Mitamura H, Ogawa S. Asymptomatic recurrence of atrial fibrillation -Cardiophone- guided management. Circ J 2003; 67 (Suppl I): 310.