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. 2009 Mar;84(3):234–242. doi: 10.4065/84.3.234

Benefits and Risks of Long-term Amiodarone Therapy for Persistent Atrial Fibrillation: A Meta-analysis

James F Doyle 1,✉, Kwok M Ho 1
PMCID: PMC2664595  PMID: 19252110

Abstract

OBJECTIVE: To assess whether amiodarone, as part of a strategy to achieve sinus rhythm, is safe and effective compared with a placebo or rate control drug in patients with persistent atrial fibrillation (AF) of more than 30 days' duration.

METHODS: Randomized controlled trials comparing amiodarone with a placebo or rate control drug were identified through the EMBASE (January 1, 1988, to October 18, 2008), MEDLINE (January 1, 1966, to October 18, 2008), and Cochrane Controlled Trials Register (second issue 2008) databases with no language restrictions.

RESULTS: Twelve randomized controlled trials that involved a total of 5060 patients with persistent AF were considered. Amiodarone was more effective than a placebo or rate control drug in achieving sinus rhythm (21.3 vs 9.2 per 100 patient-years in sinus rhythm; relative risk [RR], 3.2; 95% confidence interval [CI], 1.9-5.5), and its use was not associated with an increased risk of long-term mortality (4.7 vs 3.9 per 100 patient-years; RR, 0.95; 95% CI, 0.8-1.1; P=.51; I2=0%). Cessation of amiodarone therapy because of intolerable adverse effects was more common compared with a placebo or rate control drug (10.7 vs 1.9 per 100 patient-years; RR, 3.0; 95% CI, 1.4-6.2; P<.001; I2=70%), but amiodarone was not associated with an increased incidence of hospitalizations (RR, 1.1; 95% CI, 0.6-2.1; P=.77; I2=90%).

CONCLUSION: Amiodarone, as part of a strategy to achieve and maintain sinus rhythm, appears to be safe and effective in patients with persistent AF. However, some patients may not tolerate the adverse effects of this agent.

Amiodarone was more effective than a placebo or rate control drug in achieving sinus rhythm, and its use was not associated with an increased risk of long-term mortality; cessation of amiodarone therapy because of intolerable adverse effects was more common compared with a placebo or rate control drug, but amiodarone was not associated with an increased incidence of hospitalizations.

AF = atrial fibrillation; CI = confidence interval; RR = relative risk

Atrial fibrillation (AF) is the most prevalent arrhythmia that requires treatment, with an incidence doubling in each decade of life from 55 years of age to a peak of 35 new cases per 1000 persons per year between the ages of 85 and 94 years.1,2 Besides inducing intolerable symptoms, AF is associated with serious complications, such as systemic embolism, hemodynamic dysfunction, and tachycardia-mediated cardiomyopathy, resulting in a 2-fold increase in mortality compared with the general population.3-5

There are 2 fundamental principles in the management of persistent AF. First, anticoagulation is needed to reduce the risk of thromboembolism. Second, either ablation therapies or pharmacological agents are needed to control the rate or rhythm to reduce the symptoms of AF.6,7 Although ablation therapies can be effective in some patients, these therapies may not be appropriate for all patients, and pharmacological treatments will continue to have an important place in the management of AF.7 The optimal pharmacological strategy to treat AF has been analyzed extensively in the past 10 years by a number of large randomized controlled studies. The overall results showed that the rhythm control strategy is not superior to the rate control strategy in terms of mortality.8-11 However, many of these trials used a variety of antiarrhythmic drugs in the rhythm control strategy, and as such, whether a particular antiarrhythmic agent is superior to or worse than a rate control drug remains uncertain.

Amiodarone, a potent antiarrhythmic drug that is useful for both atrial and ventricular arrhythmia, has a combination of β-blockade, calcium channel blockade, and class III antiarrhythmic effects. In patients with acute-onset AF and also with impaired left ventricular function, amiodarone or digoxin has been recommended because of a minimal negative inotropic effect.6 In patients with persistent AF, amiodarone has been shown to be effective in achieving and maintaining sinus rhythm (50%-70%) in some studies.12-14 However, amiodarone has serious systemic adverse effects; furthermore, amiodarone has been suggested to be associated with an increase in mortality in patients with severe acute or chronic heart failure.15-17

Although a meta-analysis on benefits and risks of long-term amiodarone therapy exists,18 the conclusion of this meta-analysis was limited by 2 factors. First, the meta-analysis included only 673 patients from 4 randomized controlled studies, which limits its statistical power to make any firm conclusion. Second, the marked difference in the duration of follow-up of patients in the included randomized controlled studies was not considered because the outcomes were analyzed only by proportion of patients instead of incidence of events. As such, the benefits and risks of long-term amiodarone treatment in patients with persistent AF remain uncertain. We hypothesized that amiodarone, as part of a strategy to achieve sinus rhythm, is safe and more effective than a rate control drug for persistent AF. In the current meta-analysis, we investigated the effects of long-term amiodarone therapy on mortality, rhythm control, incidence of hospitalization, and drug intolerance leading to withdrawal of treatment in patients with persistent AF of more than 30 days' duration.

METHODS

We performed independent searches of the Cochrane Controlled Trials Register (2008 issue 2), EMBASE (January 1, 1988, to October 18, 2008), and MEDLINE (January 1, 1966, to October 18, 2008) databases. Exploded medical subject heading terms used were atrial fibrillation, supraventricular arrhythmia, or supraventricular tachyarrhythmia with amiodarone. The search was then limited to any clinical trial, letter, editorial, review, or randomized controlled trial. The reference lists of any relevant studies were further searched to identify suitable trials. There were no language restrictions in the searches.

Selection Criteria and Validity Assessment

We included trials that compared amiodarone with a placebo or rate control drug to treat persistent AF (>30 days' duration) in adult patients. Trials that evaluated the effects of amiodarone on AF (<30 days) or compared amiodarone with another rhythm control antiarrhythmic agent (eg, flecainide, ibutilide) were excluded. The data, design, and quality of the study were assessed independently by the authors. The quality of the study assessed included blinding, allocation concealment, intention to treat, and randomization. The grading of allocation concealment was based on the Cochrane approach: adequate, uncertain, or clearly inadequate. When information on the study data was insufficient, we wrote to the senior authors for further clarifications. The senior author of 1 included trial replied to our request and provided the mortality data of the trial.19 No disagreements occurred between the 2 independent reviewers (J.F.D., K.M.H.) in the data extracted.

Outcomes of Interest

The primary end point of the current meta-analysis was all-cause mortality. Secondary end points were rhythm control at the end of the study period, treatment withdrawal because of intolerance of the study drug's adverse effects, and incidence of all-cause hospitalizations from either adverse effects or electrical cardioversion during the study period.

Statistical Analyses

Because different trials had different follow-up periods, we analyzed the incidence of all the outcomes per patient-year and report the results as the incidence rate per 100 patient-years. The difference in outcomes between amiodarone and the placebo or rate control group is reported as relative risks (RRs) with 95% confidence intervals (CIs) in the forest plots, using a fixed-effect model or a random-effects model for those end points with significant heterogeneity. The presence of heterogeneity among trials was assessed by the χ2 test and I2 statistics. P<.05 was regarded as statistically significant. Data were analyzed by Review Manager (RevMan, version 5.0; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Comprehensive Meta-Analysis (version 2.2.034, 2006; Biostat, Englewood, NJ).

Sensitivity Analyses and Publication Bias

The effect of different follow-up periods among different trials on the heterogeneity of the pooled results was assessed by repeating the analysis using the proportion of patients with the outcome rather than the incidence of the outcome per patient-year. The effect of amiodarone on mortality and conversion to sinus rhythm in patients with left ventricular dysfunction (ejection fraction <40%) was assessed by restricting the analysis to studies that recruited only these patients. A sensitivity analysis of double-blind studies was performed to assess whether the quality of the studies would have affected the results.

A funnel plot was used to assess publication bias, using the proportion of patients who achieved sinus rhythm at the end of the study period as an end point. The trim-and-fill method was used to assess whether any potential publication bias would have changed the results significantly.

RESULTS

Twelve studies from 9 different countries met the inclusion criteria and were subject to meta-analysis (Figure 1).19-30 All 12 randomized controlled trials were published in English. Four trials were unblinded, 2 trials were single-blinded, and 6 trials were double-blinded. Eight studies compared amiodarone with a rate control drug, either a β-blocker or digoxin, and 4 trials compared amiodarone with a placebo. Although all trials were prospective, subgroup analyses were performed without prior definition in some studies. All 12 studies reported that baseline characteristics, including concomitant medical therapy such as angiotensin-converting enzyme inhibitors, among the study groups were comparable. The detailed characteristics of the included studies are described in the Table.

FIGURE 1.

FIGURE 1.

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Trial inclusion and exclusion criteria for the meta-analysis. AF = atrial fibrillation.

TABLE.

Characteristics of Included Trialsa

graphic file with name 234tbl.jpg

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Assessment of Primary End Point

Twelve studies that involved a total of 5060 patients reported data on all-cause mortality. No mortality was reported in 5 of the smallest pooled studies (Figure 2). The use of amiodarone, as part of a strategy to achieve sinus rhythm, was not associated with a change in mortality compared with a placebo or rate control drug (4.7 vs 3.9 per 100 patient-years; RR, 0.95; 95% CI, 0.8-1.1; P=.51; I2=0%). No significant heterogeneity was found in this result among the trials.

FIGURE 2.

FIGURE 2.

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Effect of amiodarone on incidence of all-cause mortality per patient-year follow-up. AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CHF-STAT = Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy; CI = confidence interval; PIAF = Pharmacological Intervention in Atrial Fibrillation; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; RR = relative risk.

Assessment of Secondary End Points

Eleven studies that involved a total of 5044 patients reported data on the number of patients in sinus rhythm at the end of the study period (Figure 3). Amiodarone was associated with significant improvement in achieving and maintaining sinus rhythm compared with a placebo or rate control drug (21.3 vs 9.2 per 100 patient-years in sinus rhythm; RR, 3.2; 95% CI, 1.9-5.5; I2=96%). Nine studies that involved a total of 3176 patients reported data on drug withdrawal due to intolerance of the study drug's adverse effects (Figure 4). Amiodarone was associated with a much higher risk of withdrawal from the study compared with a placebo or rate control drug (10.7 vs 1.9 per 100 patient-years; RR, 3.0; 95% CI, 1.4-6.2; P<.001; I2=70%). However, significant heterogeneity was found in these 2 secondary outcomes.

FIGURE 3.

FIGURE 3.

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Effect of amiodarone on conversion to sinus rhythm per patient-year follow-up. AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CHF-STAT = Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy; CI = confidence interval; PIAF = Pharmacological Intervention in Atrial Fibrillation; RR = relative risk; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial.

FIGURE 4.

FIGURE 4.

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Rate of drug withdrawal per patient-year follow-up. AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CHF-STAT = Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy; CI = confidence interval; PIAF = Pharmacological Intervention in Atrial Fibrillation; RR = relative risk.

Five studies that involved a total of 2932 patients reported data on incidence of all-cause hospitalizations. The use of amiodarone, as part of a strategy to achieve sinus rhythm, was not associated with a higher incidence of all-cause hospitalizations compared with the use of a placebo or rate control drug (32.1 vs 25.7 per 100 patient-years; RR, 1.1; 95% CI, 0.6-2.1; P=.77; I2=90%) (Figure 5).

FIGURE 5.

FIGURE 5.

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Rate of all-cause hospitalizations per patient-year follow-up. AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CI = confidence interval; PIAF = Pharmacological Intervention in Atrial Fibrillation; RR = relative risk.

Sensitivity Analyses

Analyzing the results by using the proportion of patients instead of the incidence rate as an outcome did not change the effects of amiodarone on mortality or heterogeneity in the results of achieving sinus rhythm or intolerance to the study drug. This latter result suggested that the variable follow-up periods among the studies were not an explanation for the heterogeneity in these outcomes (Figure 6).

FIGURE 6.

FIGURE 6.

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Conversion to sinus rhythm using proportion of patients instead of incidence rate as an end point. AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; CHF-STAT = Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy; CI = confidence interval; PIAF = Pharmacological Intervention in Atrial Fibrillation; RR = relative risk; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial.

Restricting the analysis to 6 double-blinded studies did not change the effects of amiodarone on mortality (RR, 0.98; 95% CI, 0.61-1.58; P=.93; I2=53%) or conversion to sinus rhythm (RR, 3.07; 95% CI, 1.89-5.00; P<.001; I2=53%). Similarly, no change was found in the effects of amiodarone on mortality (RR, 0.97; 95% CI, 0.83-1.15; P=.75; I2=0%) or achieving sinus rhythm (RR, 2.81; 95% CI, 1.95-4.05; P<.001; I2=25%) when the analysis was restricted to 3 studies that solely studied patients with left ventricular dysfunction.

The funnel plot suggested the presence of a publication bias, favoring amiodarone in achieving sinus rhythm in the published small randomized controlled trials (Figure 7). Using the trim-and-fill method, the effect of amiodarone on achieving sinus rhythm was slightly more conservative (RR, 2.39; 95% CI, 1.61-3.54).

FIGURE 7.

FIGURE 7.

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Use of rhythm control as an end point shows the possibility of a publication bias. RR = relative risk.

DISCUSSION

This meta-analysis shows that use of amiodarone, as part of a strategy to achieve sinus rhythm, in the treatment of persistent AF (>30 days' duration) appears to be safe and effective. However, this strategy was associated with a significant incidence of withdrawal of treatment because of adverse effects.

We found that long-term use of amiodarone is not associated with an increase in mortality in patients with AF. The effect of amiodarone on mortality remains controversial, especially in patients with acute and chronic heart failure. Recent evidence suggests that amiodarone may be harmful in patients with acute heart failure after myocardial infarction.17 The retrospective analysis of the Carvedilol or Metoprolol European Trial (COMET) also suggested that long-term amiodarone treatment may increase the risk of mortality due to circulatory failure in patients with severe chronic heart failure.31 Furthermore, use of amiodarone was shown to be associated with higher mortality rates compared with use of implanted cardiac defibrillators in patients with advanced heart failure.32 The mechanisms through which amiodarone may potentially increase mortality in patients with AF remain speculative. One hypothesis suggests that amiodarone can induce atrioventricular delay, especially in patients with severe left ventricular failure (ejection fraction <30%).33,34

Dronedarone, a new derivative of amiodarone, was reported to be associated with an increase in mortality in patients with chronic heart failure.15,16,35 Our results showed that the mortality rate in those who received long-term amiodarone therapy was low (4.7 per 100 patient-years). When analysis was restricted to patients with AF and severe heart failure (n=1587), amiodarone was not associated with any increase in mortality compared with a placebo or rate control drug. All the pooled studies reported that concomitant medical therapies among the study groups were comparable, and as such, the possibility of unequal nonantiarrhythmic therapy in achieving equal mortality was highly unlikely. Hence, our results provide some assurance, albeit still limited, that long-term amiodarone treatment appears to be safe in patients with persistent AF, especially if the patients have no heart failure.

A sustained sinus rhythm has been reported to improve quality of life and exercise performance in some patients,36 and these benefits may be particularly important in young patients with AF.37 Our results showed that long-term amiodarone therapy, as part of a strategy to control rhythm, is more effective than a placebo or rate control drug in achieving and maintaining sinus rhythm. These results are consistent with the results of a recent study on the effectiveness of dronedarone in treating persistent AF.38 If amiodarone has no adverse mortality effect and is effective in achieving sinus rhythm, it may be a viable treatment option for patients who have uncontrollable symptoms of AF.

Although amiodarone is more effective than a rate control drug or placebo in achieving sinus rhythm in patients with persistent AF, our results also showed that use of amiodarone was associated with a significant incidence of adverse effects that led to cessation of the treatment. Amiodarone has been associated with multiple systemic adverse effects, including bradycardia, hypothyroidism or hyperthyroidism, pulmonary toxicity, ocular deposits, and liver function derangements. Recent animal and observational studies also suggested that amiodarone may cause renal impairment by reducing renal blood flow.39,40 We noted that one of the pooled studies and also another uncontrolled study showed that the incidence of adverse effects from long-term amiodarone treatment is dose dependent.22,41 A relatively low dose of amiodarone (100 mg/d) appears to be equally effective but with a much lower incidence of adverse effects.

Despite the association of amiodarone with significant systemic adverse effects that led to cessation of the drug, our results showed that amiodarone was not associated with an increase in the incidence of hospitalizations. The causes of hospitalization were reported in 4 of the pooled studies and showed that adverse effects of amiodarone accounted for less than 20% of all reported hospitalizations.21,22,25,27 Therefore, long-term amiodarone therapy, especially at a low dose (100 mg/d), may be cost-effective in patients with intolerant symptoms of persistent AF.42,43

Our study has important limitations. First, although the total sample size of this meta-analysis is not small (N=5060), the number of patients with heart failure is more limited (n=1587). As such, this subgroup analysis has only an 80% power to exclude a 3.2% increase in mortality in patients with AF and heart failure, assuming that the baseline mortality of the rate control group is 4%. Second, crossover among treatment groups occurred in many of the larger studies included in this meta-analysis, which reduced the power of the meta-analysis with the intention-to-treat principle analysis. Third, heterogeneity was found in the results of rhythm control and drug withdrawal in the reported studies. Therefore, the mean estimates of the effects of amiodarone on rhythm control and incidence of drug withdrawal must be interpreted with caution and are not generalizable. We also noted that the methods used to ascertain recurrence of AF in the included studies varied. Most studies used serial electrocardiograms with preceding 24-hour electrocardiographic Holter recordings at follow-up clinics. Paroxysmal recurrences of AF might have been overlooked in some of the patients. Finally, the overall quality of some of the included studies was unsatisfactory, and only 6 studies (50%) were double-blinded. As such, the overall results of this meta-analysis were prone to bias that was incurred from the bias of these original studies. The funnel plot suggests a small publication bias that favors amiodarone in the small randomized controlled studies. After adjusting for this potential publication bias, the effectiveness of amiodarone in achieving sinus rhythm was more conservative than the mean estimate reported in the forest plot.

CONCLUSION

With the limited data available, long-term amiodarone therapy appears to be safe and effective for persistent AF. However, this strategy was associated with a significant intolerance of its adverse effects, leading to cessation of treatment. Whether long-term, low-dose amiodarone therapy (100 mg/d) is more cost-effective and better tolerated than new analogues of amiodarone, such as dronedarone, remains uncertain and merits further investigation.

Acknowledgments

We thank Kevin S. Channer, MD, FRCP, for providing details of his original study.

Footnotes

No financial support was received for this study from pharmaceutical companies or other private companies in the form of grants or award.

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