Which antiarrhythmic drug to choose after electrical cardioversion: A study on non-valvular atrial fibrillation patients
Which antiarrhythmic drug to choose after electrical cardioversion: A study on non- valvular atrial fibrillation patients
Hye Bin Gwag 0 1 2
Kwang Jin Chun 0 2
Jin Kyung Hwang 0 1 2
Seung-Jung Park 0 1 2
June Soo Kim 0 1 2
Kyoung-Min Park 0 1 2
Young Keun On 0 1 2
0 a Current address: Division of Cardiology, Department of Medicine, College of Medicine, Kangwon National University , Chuncheon , South Korea ¤b Current address: Division of Cardiology, VHS medical center , Seoul , Korea
1 Division of Cardiology, Department of Internal Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 2 Division of Cardiology, Department of Medicine, Kangnam Sacred Heart Hospital, Hallym University Medical Center , Seoul , Korea
2 Editor: Giuseppe Andò, University of Messina , ITALY
The relative efficacy of antiarrhythmic drugs (AADs) after electrical cardioversion are not well established. This study aimed to investigate the efficacies of different AADs for maintaining sinus rhythm (SR) after electrical cardioversion for atrial fibrillation (AF). We selected patients from a retrospective registry including patients admitted for cardioversion between January 2012 and June 2016. The primary outcome was time to AF recurrence during the first year after cardioversion. The secondary outcomes included AF recurrence within 1 month, and first readmission due to heart failure, stroke, or additional non-pharmacological rhythm control. A total of 265 patients were divided into the 4 groups according to AAD type: flecainide (n = 33), propafenone (n = 64), amiodarone (n = 128), and dronedarone (n = 40). During the first year after cardioversion, the AF recurrence-free survival was similar between all AAD groups (69.7% vs. 67.2% vs. 71.9% vs. 80.0%, p = 0.439). About half of all recurrences occurred during the first month. There was no difference in any of the secondary outcomes, although the amiodarone group showed a trend toward more non-pharmacological rhythm control. AAD type was not associated with recurrence in multivariate analysis. In this study, half of all patients received amiodarone after electrical cardioversion. Flecainide, propafenone, amiodarone, and dronedarone showed similar efficacies for maintaining SR after electrical cardioversion. Thus, it might be reasonable to reconsider amiodarone use after cardioversion, since it did not show superior efficacy to the other drugs considered and is associated with potential side effects.
Data Availability Statement: All relevant data are
within the paper and Supporting Information files.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Optimal management of atrial fibrillation (AF) requires careful consideration. In particular,
the relative merit of rhythm control versus rate control remains unsolved. Although recent
randomized trials showed that rate control was not inferior to rhythm control [1±3], rhythm
management is required for patients who have substantial symptoms even with well-controlled
ventricular rate. Thus, rhythm control strategies can be still useful for patients with
symptomatic AF. Electrical cardioversion is one such rhythm control strategy; however, high recurrence
rates after cardioversion have highlighted the need for antiarrhythmic drugs (AADs) [
AADs are widely used for restoration or maintenance of sinus rhythm (SR). However, AADs
have demonstrated only modest efficacy and have limited use because of their side effects,
including pro-arrhythmia. Recent guidelines [6,7] recommend specific AAD types according
to presence or type of concomitant structural heart disease, but the relative efficacy of each
agent has not been well demonstrated. In particular, only a few studies have investigated which
agent is most effective for maintaining SR after electrical cardioversion [
]. Therefore, we
investigated the efficacies of different AADs for maintaining SR after electrical cardioversion
Study design and patients
We selected patients from the retrospective electrical cardioversion registry of Samsung
Medical Center. Consecutive patients admitted to our center between January 2012 and June 2016
for electrical cardioversion due to symptomatic atrial arrhythmia were included in the registry.
All patients underwent transesophageal echocardiographic examination before cardioversion
to detect thrombus in the left atrial appendage, and anticoagulation was performed for at least
3 weeks in cases of persistent AF or AF with unknown duration before cardioversion.
Pretreatment with AAD was left to the physician's discretion. Patients who met any of the
following criteria were excluded from the analysis: 1) moderate or severe mitral stenosis; 2) previous
history of percutaneous mitral balloon valvuloplasty, mitral valve repair, or other valve surgery;
3) congenital heart disease, except for a small atrial or ventricular septal defect; 4) sinus rhythm
restoration before cardioversion; 5) thrombus or sludge in the cardiac chamber; 6) previous
rhythm control for AF including cardioversion, radiofrequency ablation, or operation; 7) atrial
tachyarrhythmia other than AF; or 8) failed cardioversion. Eligible patients were classified into
groups according to prescribed AAD type.
Data collection and clinical outcomes
Clinical and laboratory data were collected by a trained study coordinator using a standardized
case report form and protocol. The Institutional Review Board at Samsung Medical Center
approved the study protocol (IRB No. 2017-05-022-002). Decisions regarding AAD type and
concurrent beta-blocker or calcium channel blocker use were made by the respective
physicians. The dose of AAD was maintained in patients on previous AAD therapy, while
AADnaïve patients were treated with the usual starting dose of twice daily administration of
flecainide 50mg, propafenone 300mg, amiodarone 200mg, or dronedarone 400mg until the first
visit at the clinic. In cases of recurrence, the dose was usually doubled unless the patient was
complaining of any side effects. Anticoagulation was continued for at least 4 weeks after
cardioversion, and a choice of anticoagulant type (non-vitamin K oral anticoagulant vs. warfarin)
was based upon contraindications of each drug and patients preference. All patients were
treated with anticoagulants during the first 4 weeks, and treatment was continued at the
discretion of physicians. Follow-up visits were routinely performed at 1, 3, 6, and 12 months after
electrical cardioversion, with additional visits in the case of any symptom of AF recurrence.
The primary outcome was time to AF recurrence during the first year after electrical
cardioversion. The secondary outcomes included AF recurrence within 1 month and first readmission
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due to heart failure, stroke, or additional non-pharmacological rhythm control (including
repeated cardioversion, radiofrequency ablation, or operation). Date of AF recurrence was
assessed by electrocardiogram or electrocardiographic monitorings. Left ventricular systolic
dysfunction was defined as left ventricular ejection fraction < 50%.
Continuous variables are presented as median and interquartile range or mean ± standard
deviation, whereas categorical variables are presented as number and percentage. Continuous
variables were compared between groups using the Kruskal-Wallis test. Categorical data were
compared between groups using Fisher's exact test or the Chi-square test, as appropriate. For
outcome analysis, event-free survival was estimated by the Kaplan-Meier method and
compared with the log-rank test. A Cox proportional hazards model was used to adjust for baseline
differences between the groups, and variables with a p value < 0.1 were used for adjustment.
All tests were two-sided, and a p value < 0.05 was considered statistically significant. IBM
SPSS Statistics software version 23 (IBM Corporation, Armonk, NY, USA) was used for
Baseline clinical characteristics
A total of 286 patients were eligible for this study. We excluded patients with no follow-up
after cardioversion (n = 2) or unanalyzable electrocardiograms (n = 1). Patients who were not
on any AAD (n = 8), patients who were on pilsicainide (n = 3), and patients who were on
sotalol (n = 7) were also excluded because of their small numbers. Of the final 265 patients, 33
(12.5%) were being treated with flecainide, 64 (24.2%) with propafenone, 128 (48.3%) with
amiodarone, and 40 (15.1%) with dronedarone (Fig 1). The patient baseline clinical
characteristics are shown in Table 1. The amiodarone group had the highest percentage of males, while
the flecainide group had the lowest (92.2% vs. 69.7%, p = 0.007 between the 2 groups). Patients
on amiodarone had the highest prevalence of cardiomyopathy and of left ventricular systolic
dysfunction; however, there were no statistically significant differences between propafenone
and amiodarone group, with the exception of the presence of cardiomyopathy (0% vs. 13.3%,
p = 0.001). The amiodarone and dronedarone groups showed higher incidence of coronary
artery disease than the propafenone group (p = 0.006 and p = 0.020, respectively). Concurrent
use of beta-blockers was more frequent in the flecainide group than in the other groups
(p < 0.001). The left atrial volume indexes were similar between the groups, except that the
propafenone group had a smaller volume index than the amiodarone group (41.6 [36.1±49.8]
vs. 47.5 [40.4±56.2], p = 0.001).
During the first year after cardioversion, AF recurred in 189 patients (71.3% of the total
population), with the highest recurrence rate (80.0%) in patients treated with dronedarone (Fig 2
and Table 2). Log-rank tests between the AAD groups did not reveal any statistically
significant differences, although the propafenone and amiodarone groups tended to have lower AF
recurrence rates compared to the dronedarone group (p = 0.095 and p = 0.173, respectively,
p > 0.5 for the others) (Fig 2). The clinical outcomes are summarized in Table 2 and Fig 3.
After adjusting for baseline differences and using dronedarone as a reference, Cox regression
analysis did not reveal any association between AAD group and AF recurrence. Only the
amiodarone group showed a tendency to be associated with more non-pharmacological
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Fig 1. Study population. AAD indicates antiarrhythmic drug; ECG, electrocardiogram; MS, mitral stenosis; MVR, mitral valve replacement; PMV, percutaneous mitral
balloon valvuloplasty. AADs in the grey box were included in the final analysis.
rhythm control (hazard ratio 2.25, 95% confidential interval 0.93±5.45, p = 0.074). The rate of
anticoagulation therapy at 1 year after cardioversion was lower in the amiodarone group than
the propafenone group (75.8% vs. 89.1%, p = 0.034), while there were no differences between
the other groups (S1 Table).
In the present study, we investigated the relative efficacies of AADs for maintaining SR after
electrical cardioversion. The major findings of this study were: (1) the recurrence rate was
71.4% during the first year after electrical cardioversion, with approximately half of all
recurrences occur within the first month; and (2) no AAD showed superior efficacy compared to
the others, although amiodarone did show a tendency for greater additional rhythm control.
Setting aside the debate about whether rhythm control or rate control is a better strategy,
cardioversion is still a useful option for patients with symptomatic AF. However, SR
maintenance after cardioversion is challenging, with recurrence rates ranging from 63±84% in the
first year [
]. While several types of AADs are available, their efficacies are modest at best,
and they are associated with undesirable side effects. Therefore, safety has been proposed to be
more important than efficacy when choosing the type of AAD [6,7]. Nevertheless, data
regarding the relative efficacy of AADs would provide additional information for guiding AAD
choice. Although some studies have focused on this subject, none was a prospective
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Values are presented as median (interquartile range), mean±SD, or number (percentage).
AAD = antiarrhythmic drug; AF = atrial fibrillation; COPD = chronic obstructive pulmonary disease; LA = left atrial; LVEF = left ventricular ejection fraction;
PAOD = peripheral arterial occlusive disease; RASB = renin-angiotensin receptor blocker.
Echocardiographic measurements were not available for 3 patients in the flecainide group and 2 patients in the amiodarone group.
(n = 128)
randomized trial. Furthermore, direct comparison between all AAD types could not be
performed, since previous randomized trials conducted head-to-head comparison between two
AAD groups or between an AAD group and a placebo group [9±12]. One review and a recent
prospective cohort study presented the relative efficacies of different AADs for prevention of
recurrent AF after electrical cardioversion [
]. The review reported amiodarone as the most
effective agent (Peto odds ratio 0.19 [0.14±0.27]). Similarly, the cohort study concluded that
amiodarone seemed to be superior to the other AADs, even in patients without structural
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Fig 2. Kaplan-Meier curve for recurrence of atrial fibrillation during the first year after electrical cardioversion according to
antiarrhythmic drug type. AF indicates atrial fibrillation; AAD, antiarrhythmic drug. P value as calculated by the log-rank test
between the 4 AAD groups. `No AAD group' is shown for reference only.
heart disease. In contrast to these studies, all AADs included in the present study showed
similar efficacy for maintaining SR. The difference between our results and theirs might resulted
be due to differences in study design, study population, or specific study limitations. The
review was based on previously published data lacking randomized trials and the author's
personal experience. In the other study, only patients without structural heart disease were
included, and analyses did not adjust for baseline differences in each AAD group, even though
Values are presented as n (%).
²P value refers to the difference among the groups as assessed by the chi-square test.
AAD = antiarrhythmic drug; AF = atrial fibrillation; CI = confidence interval; HR = hazard ratio; RF = radiofrequency.
One-month ECG was not available for 1 patient in the propafenone, 11 patients for the amiodarone group, and 1 patient for the dronedarone group.
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Fig 3. Cox proportional hazards model for atrial fibrillation recurrence and additional rhythm control. The dronedarone group was used as a reference group.
Adjusted covariates included sex, cardiomyopathy, chronic obstructive lung disease, coronary artery disease, beta-blocker use, and left atrial volume index. AF indicates
atrial fibrillation; CI, confidence interval; HR, hazard ratio.
AAD use was not randomized. The recurrence rates were only compared for each time period;
moreover, amiodarone only had a trend of better efficacy compared to the other class 1c
agents, without statistically significant difference (p = 0.09).
Since amiodarone use as first-line treatment has been limited due to possible extracardiac
side effects, it has been recommended to reserve this drug for specific situations such as
concomitant heart failure. However, similar to previous studies, amiodarone was the most
frequently prescribed drug in our study (48.1%). In the previous prospective registry study, 55%
of all patients were treated with amiodarone, even though the study population consisted of
patients without structural heart disease. The reason why amiodarone was the most commonly
used agent in these studies is unclear. We postulate that amiodarone was the second-line
treatment in these studies, because it is likely that electrical cardioversion was attempted in patients
who were refractory to their previous first-line treatment. In our study, the rate of de novo
AAD use was significantly lower in the amiodarone group than in all other groups (22.7% in
the amiodarone, 90.9% in the flecainide group, 37.5% in the propafenone group, and 45% in
the dronedarone group, p < 0.001). Therefore, the antiarrhythmic efficacy of amiodarone
could have been underestimated due to potential bias by including more patients refractory to
first-line therapy in the amiodarone group. Of note, a recent large retrospective study
comparing the efficacies of different first-line AADs in AF patients demonstrated that amiodarone
showed the best efficacy for prevention of AF recurrence . This finding might be explained
by the same rationale as described above. For this reason, we performed a subgroup analysis
targeting only patients on de novo AADs. The prevalence of heart failure, left ventricular
systolic dysfunction, cardiomyopathy, and concomitant beta-blocker use was higher in the
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amiodarone group than in all other AAD groups. There was no difference in AF
recurrencefree survival rate between the groups, and AAD type was not associated with AF recurrence,
even after multivariate adjustment (S1 Fig). However, the multivariate analysis was
underpowered due to the small number of patients on de novo therapy (30 patients with flecainide, 24
with propafenone, 29 with amiodarone, and 18 with dronedarone). Because amiodarone is
preferred for patients with structural heart disease or heart failure, there is a possibility of
underestimated efficacy of amiodarone. We also cannot rule out other unmeasured
confounding factors influencing both prescription of amiodarone and recurrence of AF.
Another interesting observation in our study was the high percentage of male patients. We
postulate that this was partly because of a higher incidence of AF in men. Males have a higher
incidence of AF in all age groups, while the absolute number of patients seems equal in the
elderly population because the incidence of AF and the proportion of females increase with
age. Because most patients in our study were in their 50s and 60s, it is likely that more men
were included than women. A similar trend was observed in previous studies investigating
Korean AF patients undergoing cardioversion (74.0% ~ 80.6% males in total population)
The concept of upstream therapy was introduced to reduce or prevent atrial remodeling,
which perpetuates AF. Several agents such as renin-angiotensin receptor blockers, statins, or
polyunsaturated fatty acids have been studied as part of this therapy [16±18]. As with the
previous studies, the present study does not rule out the possibility that these non-AADs have
antiarrhythmic effects, even though these agents have not yet shown convincing benefits.
Additionally, the results could have been confounded by the effects of other factors, like the
antiarrhythmic effects of beta-blockers and calcium channel blockers [
of concurrent cardiovascular conditions, and/or lifestyle factors (exercise intensity, weight
reduction, smoking, and alcohol intake) [21,22].
Considering all evidence obtained to date, it seems reasonable to reserve amiodarone only
for special situations, since it was not shown to be superior to the other AADs and is associated
with potential side effects. However, the lack of data and the limitations of previous studies
comparing AADs emphasize the need for cautious interpretation of the previous results and
for further randomized trials. In particular, we anticipate that future studies would be of great
use to clinical practice by investigating optimal duration of AAD therapy and AAD choice
following treatment failure.
There were several limitations in this study. First, this was a retrospective single-center
study. Not all patients could be followed-up according to a standardized protocol, and there is
a chance that symptomatic patients could have visited the clinic more frequently. There were
also differences in baseline characteristics between the 4 groups. Even though we conducted
multivariate analysis to adjust for these differences, the possibility of confounding effects
remains. Second, patients on pilsicanide and sotalol were excluded from the study due to their
small numbers. Third, as discussed above, we could not validate the antiarrhythmic effect of
drugs other than AADs. Fourth, we could not assess other clinical outcomes including quality
of life. Lastly, we investigated clinical outcomes during a follow-up duration of one year. While
this time period might seem short, the outcomes would probably not have been much different
with longer follow-up times, considering that most of the recurrences occurred during the first
6 months and reached a plateau thereafter.
In this retrospective study, flecainide, propafenone, amiodarone, and dronedarone showed
similar efficacies for maintaining SR after electrical cardioversion. Since amiodarone did not
show superior efficacy to any other AAD and is associated with potential side effects, it might
be reasonable to reserve amiodarone for special situations. However, our results need to be
interpreted with caution because of the retrospective observational design of the study.
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S1 Table. Anticoagulation therapy after electrical cardioversion.
S1 Fig. Kaplan-Meier curve for recurrence of atrial fibrillation during the first year after
electrical cardioversion according to type of antiarrhythmic drugs (AADs) in patients on
de novo AADs. AF indicates atrial fibrillation; AAD, antiarrhythmic drug. P value as
calculated by the log-rank test between the 4 AAD groups. `No AAD group' is shown for reference
S1 Dataset. Minimal relevant dataset of this study.
Conceptualization: June Soo Kim, Young Keun On.
Data curation: Hye Bin Gwag, Kwang Jin Chun.
Formal analysis: Hye Bin Gwag, Young Keun On.
Investigation: Hye Bin Gwag, Kwang Jin Chun, Jin Kyung Hwang.
Methodology: Hye Bin Gwag, Kwang Jin Chun.
Project administration: Young Keun On.
Resources: Seung-Jung Park, June Soo Kim, Kyoung-Min Park, Young Keun On.
Supervision: June Soo Kim, Young Keun On.
Validation: Jin Kyung Hwang.
Visualization: Hye Bin Gwag, Kwang Jin Chun.
Writing ± original draft: Hye Bin Gwag.
Writing ± review & editing: June Soo Kim, Young Keun On.
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