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* From the Cardiology Department (Drs. Vardas, Kochiadakis, Igoumenidis, Simantirakis, and Chlouverakis) and the Unit of Toxicology (Dr. Tsatsakis), Heraklion University Hospital, Crete, Greece.
Correspondence to: Panos E. Vardas, MD, PhD, Cardiology Department, Heraklion University Hospital, PO Box 1352 Stavrakia, Heraklion, Crete, Greece; e-mail: cardio{at}med.uoc.gr
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Prospective, randomized, controlled clinical study.
Setting: Tertiary cardiac referral center.
Patients: Two-hundred eight consecutive patients (102 men; mean [± SD] age, 65 ± 10 years) with atrial fibrillation.
Interventions: One-hundred eight patients received amiodarone, and 100 patients received placebo treatment. Patients randomized to amiodarone received 300 mg IV for 1 h, and then 20 mg/kg for 24 h. They were also given 600 mg/d orally, divided into three doses, for 1 week, and thereafter 400 mg/d for 3 weeks. Patients randomized to placebo treatment received an identical amount of saline solution IV over 24 h, and oral placebo treatment for 1 month.
Measurements and results: Baseline clinical characteristics were similar in the two groups. Conversion to sinus rhythm was achieved in 87 of 108 patients (80.05%) who received amiodarone, and in 40 of 100 patients (40%) in the placebo group (p < 0.0001). Statistical analysis showed that the duration of the arrhythmia and the size of the left atrium affected both the likelihood of conversion to sinus rhythm and the time to conversion in both groups. No side effects requiring discontinuation of treatment were observed in either group.
Conclusions: Amiodarone appears to be safe and effective in the termination of atrial fibrillation. However, extreme cases with a large left atrium and long-lasting arrhythmia need long-term therapy.
Key Words: amiodarone • atrial fibrillation • cardioversion • left atrial diameter
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present prospective, randomized, controlled study, we aimed to assess the effectiveness and safety of amiodarone as a first-choice drug in the treatment of patients with atrial fibrillation of either long or short duration, administered during the loading phase in a combination of IV and oral doses. The combined method of administration was chosen in order to achieve a rapid onset of action by means of an initial IV dose, and to assess the role of the long-term administration of oral amiodarone in the conversion of atrial fibrillation in cases resistant to the short-term treatment.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Study Protocol
The study was approved by the Ethics Committee of the hospital.
After giving informed consent, patients were randomized to receive
either amiodarone or placebo treatment. Patients randomized to
amiodarone received 300 mg IV for 1 h, and then 20 mg/kg for
24 h. In addition, they were given 600 mg/d orally, divided into
three doses, for the first week, and thereafter 400 mg/d for 3 weeks.
Patients in the placebo group received an identical amount of saline
solution the first day. They also took three placebo tablets per day
for 1 week and two per day for 3 weeks. Digoxin, 0.5 mg IV initially,
followed by 0.25 mg at 2 h and 0.25 mg every 6 h thereafter,
was administered for 24 h to all patients who had not previously
received it. Subsequently, the digoxin dose was adjusted to maintain
therapeutic serum concentrations in all patients.
To prevent thromboembolic episodes in all patients who had atrial fibrillation lasting > 48 h, or of unknown onset, and who were not already taking anticoagulant medication, acenocoumarol (international normalized ratio, 2–3) was given for > 21 days before cardioversion was attempted. This treatment was continued for 21 days after successful cardioversion, or indefinitely when cardioversion was not achieved.
Monitoring and Follow-up
During the first 24 h, while the drug was being
administered IV, all patients were kept in the coronary care unit under
continuous monitoring of ECG and BP. They were then kept under
observation in the Cardiology Department for at least another 2 days
before being discharged from the hospital. Patients were evaluated in
the clinic after completion of 30 days of treatment.
Before the patient’s entry into the study and at the 30-day follow-up visit, a full history was taken and the following examinations were carried out: physical assessment, 12-lead ECG, chest roentgenogram, and tests of thyroid and liver function.
Blood samples were taken for the measurement of plasma amiodarone, desethylamiodarone, and digoxin immediately after cardioversion was achieved, or at 1 h, 24 h, and 30 days if treatment was unsuccessful. Serum levels of amiodarone were determined using high-performance liquid chromatography. Digoxin serum levels were determined by radioimmunoassay.
One- and two-dimensional echocardiographic examinations were used to determine left atrial size and left ventricular ejection fraction (LVEF), and were performed in all patients either within 24 h after conversion or at the end of the study period. All echocardiographic recordings were reviewed by two experienced operators.
Definition of Terms
Atrial fibrillation was considered chronic when its duration was
at least 1 month, and of recent onset when its duration was < 24 h.
The remaining cases were considered as persistent atrial fibrillation.
For the precise determination of the onset of atrial fibrillation, we took into account the electrocardiographically proven time of onset (for patients treated in our clinic), or the clearly determined time of onset of symptoms such as palpitations, dyspnea, chest congestion (for those patients who came to the emergency department). When the precise time of onset could not be determined (12 patients), the duration of the arrhythmia was considered to be 48 h, and these patients received anticoagulation therapy for 21 days before cardioversion was attempted.
Treatment was considered successful if conversion to sinus rhythm was achieved within the study period. In patients who did not convert to sinus rhythm, conversion was attempted using other antiarrhythmic drugs or current cardioversion.
Statistical Analysis
Patients eligible for the study were allocated to treatment
using a computer-generated random number algorithm; t tests
and 
2 tests were used for continuous and
categorical variables, respectively, to ascertain that the two patient
groups were comparable with respect to potentially important predictors
of conversion, including sex, age, left atrial size, LVEF, duration of
atrial fibrillation, baseline heart rate, baseline systolic BP, and
underlying heart disease.
The analysis then proceeded in two phases. First, we checked at the univariate level which factors were significantly associated with conversion, by comparing the appropriate parameters between patients who converted and those who did not. Following the univariate screen, we employed a multivariate step-wise logistic regression analysis of the significant univariate factors, with conversion outcome as the dependent variable, to determine which of them contained independent prognostic value in predicting conversion. The thresholds for entry into and removal from the model were 5% and 10%, respectively. Time-specific conversion rates were also computed at 1 h (the end of the loading phase), at 24 h (when IV administration was stopped), and after 30 days of treatment. A p value < 5% was the criterion for significance throughout.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Between 24 h and 30 days after the start of continuous oral administration, another 21 amiodarone-treated patients had converted to sinus rhythm, 5 of them before their discharge from the hospital. No more of the patients in the placebo group converted. Thus, by the end of the 30 days, 87 of the amiodarone group (80.5%) and 40 of the control group (40%) had converted to sinus rhythm (odds ratio, 6.21; 95% CI, 3.33 to 11.57; p < 0.0001).
The blood concentrations of amiodarone were sufficiently high at 1 h, and 1 month later had decreased progressively. Conversely, the levels of desethylamiodarone showed a gradual increase during this period (Table 2 ). There was no difference in the plasma levels of amiodarone, desethylamiodarone, or digoxin between patients who converted and those who did not at any of the time points (data not shown).
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2 = 37.1, 64.6, and 22.5,
respectively; p < 0.0001 for all). In Table 7
, the estimated probabilities (percent) of conversion by duration and
left atrial size in the two groups are displayed, as computed by
multiple logistic regression. Patients with recent-onset atrial
fibrillation had excellent chances of converting, regardless of left
atrial size, while the latter factor became more important as the
duration of the arrhythmia increased.
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2 = 73.5, 43.6,
and 13.5, respectively; p < 0.0001 for all).
Adverse Effects of Amiodarone
A significant decrease in systolic BP (< 90 mm Hg) was observed
in 12 patients during the first hour of IV drug administration. All
patients did well after IV fluids, and no additional treatment was
required.
Phlebitis over the site of amiodarone infusion was observed in 17 patients. In all cases, the administration was continued at a more central site.
No adverse effects necessitating drug discontinuation occurred. There were no proarrhythmic events, either in patients who converted to sinus rhythm or in those who remained in atrial fibrillation.
No side effects were observed in the placebo group during either the IV or the oral administration.
Conversion During Further Follow-up
After the end of the study period, 16 of the 21 nonresponders to
amiodarone agreed to undergo electrical cardioversion; 13 of
these procedures (81%) were successful. The 60 nonconverters in the
placebo group were first given other medication than amiodarone in a
further attempt at chemical cardioversion, in accordance with our
standard practice. Of these, 23 subsequently converted (9 with
procainamide, 8 with propafenone, and 6 with flecainide). Twenty-four
of the 37 patients who did not convert with drug treatment consented to
electrical cardioversion; 18 of these patients (75%) were successfully
cardioverted.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When considering the above, however, it is important to keep in mind that those patients with a large left atrium and a long-lasting arrhythmia are precisely those for whom pharmaceutic conversion is most desirable, since their spontaneous conversion rate is extremely low (Tables 5 , 6) . Thus, for these difficult patients, amiodarone may be of great benefit.
In contrast, patients with a small left atrium and/or short-lasting atrial fibrillation have a very high spontaneous conversion rate, so the relative benefit of amiodarone is smaller. This is clearly shown if we consider cases with recent-onset atrial fibrillation and left atrial size < 41 mm: although amiodarone is likely to cause conversion to sinus rhythm in almost all patients (99.7%), we might expect that 9 of 10 would convert spontaneously.
Another factor, which affects the conversion rate of amiodarone, is the duration of treatment. According to our findings and those of other researchers, the longer the duration of amiodarone treatment, the higher the conversion rate. Kerin et al6 noted an increase in the conversion rate from 44% at 24 h to 67% after 9 months of amiodarone administration. This is probably related to the progressive increase we observed in serum desethylamiodarone levels. The finding of Tieleman et al,5 that for conversion of atrial fibrillation, plasma concentrations of desethylamiodarone are more important than those of the parent compound, further reinforces this hypothesis.
Treatment Duration
According to our results, the time required before amiodarone
treatment is successful is affected by factors such as the duration of
the atrial fibrillation and the size of the left atrium. The larger the
left atrium and the longer the duration of the arrhythmia, the longer
the treatment necessary to produce the desired result. In fact, all of
our patients who converted and had chronic atrial fibrillation, as well
as more than half of those with left atrial size > 46 mm, needed
long-term therapy with amiodarone.
It should be noted that left atrial size and arrhythmia duration are the most important independent predictors of short-term conversion (< 1 h), with treatment relegated to third place. This can also be seen from the fact that the difference between the conversion rates of amiodarone and placebo for the first hour following the start of treatment barely reaches statistical significance. From a practical point of view, this means that where rapid conversion to sinus rhythm is required, amiodarone is likely to be of little assistance and other means of conversion should be sought.
Comparison With Previous Studies
Studies of Recent-Onset Atrial Fibrillation:
The results of
our own study were more encouraging than any previously reported (Table 8
).8
10
13
14
15
16
According to our findings, patients with
atrial fibrillation lasting < 24 h had a high probability of
conversion (> 95%) with amiodarone regardless of the left atrial
size.
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Studies of Long-Lasting Atrial Fibrillation: For long-lasting atrial fibrillation, our conversion results were also higher than those reported for chemical agents in previous studies (Table 8) .5 6 7 17 Only electrical cardioversion shows a higher conversion rate and works faster in these patients. However, that technique requires general anesthesia or heavy sedation. In addition, there is a potential risk of myocardial damage, ventricular tachyarrhythmia, or thromboembolism. It must be admitted that our good results were probably largely due to the long duration of treatment. It is indicative that no patient with chronic atrial fibrillation converted during the first 24 h: all required treatment for a longer period.
This is troublesome from one point of view, since the main goal of an antiarrhythmic agent in atrial fibrillation should be rapid conversion to sinus rhythm. However, in patients with long-lasting arrhythmia, the need for immediate cardioversion is rarely great. Furthermore, in these patients, cardioversion must in any case be delayed until after 21 days of anticoagulation treatment, so that delayed cardioversion would not appear to be a significant problem. To our knowledge, the only other drug for which the conversion rate for chronic atrial fibrillation has been found to increase with time is propafenone18 ; whether the same may hold true for other drugs remains to be confirmed.
Safety
In our study, although we used high doses of amiodarone and
achieved high serum levels, the side effects observed were relatively
few. This was probably due to the method of administration of the drug.
By using a combination of oral and IV administration during the initial
loading phase, we avoided most of the side effects associated with each
route.
Although amiodarone is a drug that has been implicated in many cardiac and noncardiac side effects, it has been proven that the majority of side effects are related to the dose and the duration of treatment19 20 21 22 ; it thus seems likely that the duration of amiodarone treatment in our study was not, in general, sufficient for the development of side effects.
Study Implications
Our results show that amiodarone is an effective and safe means
for the treatment of atrial fibrillation and could be used as a drug of
first choice, provided that rapid conversion is not required.
For short-duration atrial fibrillation, amiodarone is of great benefit, especially in extreme cases with a large left atrium. However, it appears that large doses of amiodarone, leading to high serum levels of amiodarone and desethylamiodarone, are necessary in order to achieve a good result. Although such large doses over a short time increase the risk of side effects, a combination of IV and oral administration seems to achieve the desired high serum levels, while minimizing the risk of side effects from both methods of administration.
For long-lasting atrial fibrillation, amiodarone appears to be a very promising agent for the restoration of sinus rhythm, although long-term therapy is needed in order to achieve a high conversion rate. It may be inferred from our findings and from those of Kerin et al,6 that the longer the duration of treatment, the higher the conversion rate. On the other hand, it must be admitted that the long-term administration of amiodarone also increases the risk of side effects, and this must be taken into account.
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Footnotes |
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Received for publication April 27, 1999. Accepted for publication December 28, 1999.
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