U N S O L IC I T E D R EV I E W
Administration of Antiarrhythmic Drugs to Maintain Sinus Rhythm After Catheter Ablation for Atrial Fibrillation: A Meta-Analysis Xiuli Xu, Choumi T. Alida & Bo Yu Department of Cardiology, The First Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
Keywords Antiarrhythmic drugs; Atrial fibrillation; Catheter ablation; Meta-analysis. Correspondence B. Yu, Department of Cardiology, The First Hospital Affiliated to China Medical University, No. 155, Nanjing North Street, Heping, Shenyang, Liaoning 110001, China. Tel.: +86-24-83282691; Fax: +86-24-83283673; E-mail: [email protected]
doi: 10.1111/1755-5922.12133
SUMMARY Background: Whether the short-term administration of antiarrhythmic drugs (AADs) to maintain sinus rhythm following catheter ablation (CA) for atrial fibrillation (AF) can prevent the recurrence of AF is still a matter of debate. We searched the PubMed database and the Cochrane Library, and compiled a list of retrieved articles. We included only randomised controlled trials(RCTs) that compared any AADs against control (placebo or no treatment) or other AADs following CA for AF. Statistical analysis of the odds ratio (OR) and corresponding 95% confidence interval (CI) were used to determine the overall effect of both outcomes. The Mantel–Haenszel method was used to pool data of the outcomes of AF recurrence into fixed effect model meta-analyses. Aims: We performed a systematic review to determine the effectiveness of short-term treatment with AADs on the recurrence of AF after CA. Results: Six RCTs were included in this study, with a total of 814 patients. Postprocedural temporary administration of AADs in patients after CA for AF reduced the early recurrence of AF (antiarrhythmic drug 103 patients [25.3%], control 162 patients [39.8%]; OR 0.47 [95% CI 0.34–0.64]; v2 = 3.77; P = 0.58; I2 = 0%). No significant difference in patients after CA for AF in the late recurrence of AF (antiarrhythmic drug 148 patients [36.5%], control 171 patients [42.5%]; OR 0.77 [95% CI 0.57–1.03]; v2 = 3.15; P = 0.68; I2 = 0%). The heterogeneity was zero in both analyses. Conclusion: Although the continued administration of AADs after CA for AF can decrease early atrial tachycardias (ATa), this treatment does not prevent late ATa.
Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with increased morbidity and mortality related to stroke, other embolic complications, and heart failure [1,2]. Pharmacological therapy is the mainstay of treatment for AF, but currently available antiarrhythmic drugs (AADs) have limited effectiveness and safety [3–5]. In the past decade, catheter ablation (CA) has emerged as an effective strategy to control cardiac rhythm in patients with symptomatic and drugrefractory AF and its use in clinical practice has been growing gradually [6–10]. Nevertheless, patients undergoing CA frequently experience atrial tachyarrhythmias (ATa) after ablation. Therefore, the empirical administration of AADs following CA for AF has been popular for the purpose of preventing recurrence of AF or alleviating the symptoms. Whether rhythm maintenance with the temporary use of AADs following CA can prevent the recurrence of AF is still a matter of debate. Due to the clinical importance of this issue for this commonly performed therapeutic intervention and the lack of definitive findings from individual published reports, we sought to systematically review the litera-
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ture and perform a meta-analysis of available studies to determine the effectiveness of the concomitant use of AADs after ablation on the recurrence of AF.
Method Eligibility Criteria We selected only randomized controlled trials (RCTs) that included patients who had AF of any type and duration and in whom sinus rhythm had been restored using CA and compared short-term treatment immediately after ablation with any AADs against controls (placebo or no treatment or drugs). We excluded studies that did not address the treatment of AF patients with AADs following CA for AF, studies for which the full text could not be obtained, and studies published in languages other than English. The primary outcome was defined as the occurrence of any ATa (AF, atrial flutter or atrial tachycardia) lasting more than 30 second [11]. Generally speaking, the early recurrence of atrial fibrillation (ERAF) was defined as the occurrence of ATa within the
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X. Xu et al.
first 3 months after ablation, also called the “blank period,” otherwise defined as late recurrence of atrial fibrillation (LRAF).
Search Strategy We searched the PubMed database and the Cochrane Library (until October 2014) using the following terms: (Atrial fibrillation OR fibrillation, atrial OR [(atrial OR atrium OR auricular) AND fibrillat*]) AND (radiofrequency catheter ablation OR ablation, catheter) AND (anti-arrhythmia agents OR antiarrhythmic drugs OR anti-arrhythmi* OR anti-arrhythm* OR pharmacologic* OR therapeutic use OR flecainide OR amiodarone OR dronedarone OR sotalol OR propafenone OR ibutilide). We also checked the reference lists of the retrieved studies, meta-analyses, and general reviews on AF.
Data Extraction and Validity Assessment Studies that met the inclusion criteria were assessed by one reviewer and verified by another. Data collected included the year of publication, study size, patients with AF, follow-up period, demographic characteristics, and comorbidities. All disagreements were solved by discussion and consensus. The modified Jadad seven-point scale to evaluate the quality of RCT was applied; this scale scored a maximum of two points for randomization, two points for allocation concealment, two points for blinding, and one point for the description of withdrawal and drop out [12]. v2 and I2 were used to assess the statistical heterogeneity among the selected studies. The I2 statistics represents the proportion of variation in the treatment estimate which is not related to sampling error. When I2 was >50%, statistical heterogeneity was presumed.
Data Synthesis The statistical analyses were conducted using the RevMan 5.3 software (The Cochrane Collaboration, Oxford, UK). Dichotomous results were analyzed using the Mantel–Haenszel method. Odds ratio (OR) and its 95% confidence interval (CI) were calculated.
Results From a total of 2248 references identified, we assessed 26 articles in more detail. Six studies fulfilled the inclusion criteria and presented usable data, involving a total of 814 patients. All studies were RCTs [13–18]. Data not provided in the main articles were sought from the study by Roux et al. [19]. Figure 1 illustrates the results of the search strategy. Five RCTs scored high on the modified Jadad scale and one scored low. The type of AF most frequently studied was paroxysmal AF. The percentage of male patients was greater than that of female patients, except in one trial. The proportion of patients having underlying heart disease, as defined in each study, varied widely from 30.6% to 91%; furthermore, the mean left ventricular ejection fraction was >50%. No significant difference was found between the AADs and the control groups with regard to the baseline characteristics of patients in individual studies. Table 1 details the baseline charac-
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2248 publications identified and screened
2 additional studies identified through the reference list
2097 excluded based on title and/or abstract
125 excluded 115 did not meet inclusion criteria 6 controlled but nonrandomised 151 records screened
4 comments
11 randomised but not for allocation to antiarrhythmic drugs 2 letters 26 full-text articles were assessed for eligibility
1 not meet inclusion criteria 1 no comparison arm
2 had same data source 1 non-English publication 11 potentially appropriate randomised controlled trials to be included
1 subject not meeting inclusion criteria 1 no full text
6 citations fulfilled inclusion criteria
Figure 1 Flow diagram of the selection process of eligible articles.
teristics of the eligible studies. Table 2 summarizes their data and conclusions. To determine the overall effect, a meta-analysis was performed and the calculated OR for ERAF was 0.95 (95% CI: 0.86–1.05) (Figure 2). The OR for LRAF was 0.99 (95% CI: 0.87–1.13) (Figure 3). The postprocedural temporary administration of AADs after CA for AF reduced the ERAF (AADs 103 patients [25.3%], control 162 patients [39.8%]; OR 0.47 [95% CI 0.34–0.64]; v2 = 3.77; P = 0.58; I2 = 0%). In contrast, this treatment did not reduce the LRAF (AADs 148 patients [36.5%], control 171 patients [42.5%]; OR 0.77 [95% CI 0.57–1.03]; v2 = 3.15; P = 0.68; I2 = 0%). Figures 2 and 3 summarize the total number of patients, the contribution of each study, the results of the pooled analyses, and the heterogeneity of the study populations. Heterogeneity was found to be zero in both analyses. A funnel plot for the publication bias analysis was not determined because this type of analysis is not recommended when fewer than 10 studies are analyzed [20].
Discussion In this first systematic review and meta-analysis of the effectiveness of AADs on the incidence of recurrence of AF after ablation, we demonstrated that subsequent AAD treatment had an favorable influence by decreasing the ERAF after CA but did not lower the rate of late ATa. This finding may have significant implications
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Table 1 Baseline characteristics of patients in eligible studies Hayashi et al. (2014) [13] AF type No. of pts Mean age (SD) Men (%) Hypertension (%) Valvular disease (%) CHD (%) LAD (mm) (SD) LVEF (%) Treatment group
Follow-up (SD) (month) Jadad score
Gu et al. (2012) [14]
Leong-Sit et al. (2011) [15,19]
Turco et al. (2007) [16]
Brignole et al. (2002) [17]
Darkner et al. (2014) [18]
PAF (71%), PeAF (29%) 126 63 (11) 77 63
PeAF
PAF
PAF
PAF (50%)
123 59.5 (9.5) 55 54.5
110 55.5 (8.5) 71 91
PAF (60%), PeAF (40%) 107 57 (10) 64.5 57
137 68 (8) 42.3 30.6
212 61 83 39.6
NR
0.8
NR
6
11
NR
NR 38 (5.5) 68.5 (8.5) Initial 3 months postablation: flecainide, 143 (19) mg/day; no AAD
5.7 42 (6.5) 61.5 (7.5) The first 6 weeks after ablation: propafenone 150 mg TID or flecainide 100 mg BID, sotalol 80 mg BID or dofetilide 500 g BID; no AAD
5 48 (6) NR 71% were treated with amiodarone, 19% with flecainide, 6% with propafenone, and 4% with sotalol; no treatment
16 NR NR The first 6 months: amiodarone (200 mg/day), sotalol (120–240 mg/day), propafenone (450–900 mg/day), flecainide (100–200 mg/day) and combinations of these; no drug
6.6 44 (7) 50.5 (8.5) The first 8 weeks: amiodarone 400 mg BID for 13 days, then 200 mg BID for 2 weeks finally and 200 mg QD for 4 weeks; placebo
17 (9)
8.9 46.6 (3.25) 56 (7.2) Initial 2 months: both AAD type Ic (propafenone 150 mg/d t.i.d) and type III (amiodarone 600 mg/day for 2 weeks, 400 mg/day for the next 2 weeks, 200 mg daily thereafter); one AAD (type Ic OR III) 12
6
12
12–24
6
3
4
5
5
5
5
AAD, antiarrhythmic drug; AF, atrial fibrillation; LVEF, left ventricular ejection fraction; CHD, coronary heart disease; NR, not reported; LAD, left atrium diameter; No. of pts, number of patients; PAF, paroxysmal atrial fibrillation; PeAF, persistent atrial fibrillation; SD, standard deviation.
Table 2 Summary of data and conclusions from eligible studies Studies
AADs (n)
Control (n)
Hayashi et al. (2014) [13]
62
63
Gu et al. (2012) [14]
62
61
Leong-Sit et al. (2011) [15,19] Turco et al. (2007) [16] Brignole et al. (2002) [17] Darkner et al. (2014) [18]
53
57
54 68 108
53 69 104
Primary endpoint
Conclusion
Any ATa lasting for ≥ 30 second during the first 3 months Any episode of symptomatic or asymptomatic ATa lasting for ≥ 30 second Freedom from asymptomatic or symptomatic ATa The absence of ATa lasting >30 second Prevent the development of permanent AF Any documented ATa lasting 30 second
Did not reduce the early and late ATa Decreased early ATa but did not prevent late ATa Decreased early ATa but did not prevent ATa at 6 months Did not lower the rate of AF recurrences Reduced the risk of development of permanent AF Did not significantly reduce the recurrence of ATa at the 6-month follow-up
AADs, antiarrhythmic drugs; AF, atrial fibrillation; ATa, atrial tachyarrhythmias.
for the management of patients undergoing radiofrequency CA, particularly considering the increasing number of patients with AF on chronic therapy with AADs postablation. In recent years, the hope that CA could take the place of conventional pharmacological therapy for AF has been replaced by the belief that the benefits of the combined approach of AADs and CA could outweigh those of ablation alone [21–23]. The number
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of studies on continuous administration of AADs after CA of AF is scarce. The great majority of studies found that the treatment of AADs following the procedure could prevent ERAF rather than LRAF [13–16,19,24]. As demonstrated, most recurrences occurred in the initial 6 months after ablation, but even after 1 year, an annual recurrence rate of 5–9% has been described [25]. O0 Donnell et al. [26] found that a delayed cure of AF can be found in a
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Figure 2 Comparison of patients on AADs and control patients with regard to ERAF postablation. AADs, antiarrhythmic drugs; ERAF, early recurrence of atrial fibrillation.
Figure 3 Comparison of patients on AADs and control patients with regard to LRAF postablation. AADs, antiarrhythmic drugs; LRAF, late recurrence of atrial fibrillation.
significant number of patients despite an ERAF after focal pulmonary vein ablation, which is most prevalent in patients with persistent AF and structural and electric abnormalities of the atrium. In contrast, Caia et al. [27] reported that ERAF was one of the independent predictors of LRAF. An agreement on the contribution of ERAF to the effectiveness of the procedure for AF could not be reached. In addition, the use of AADs during the initial months after CA may also be indicated in cases of macro-reentrant left atrial tachycardias, which account for 10% of arrhythmias during the “blank period,” and most likely increase the percentage of patients who developed asymptomatic episodes of AF [28]. Thus, the evaluation of the actual effectiveness of AADs on ERAF was incomplete. As previously described, ERAF is a common finding that is not implicitly related to a failure of CA [29–31]. Almost half of the patients experiencing these arrhythmias during the first month postablation will not have any subsequent arrhythmia during long-term follow-up because these arrhythmias tend to resolve spontaneously during the “blank period” [32,33]. In view of this observation, it is difficult to distinguish the contribution of AADs from those of self-restoration and auto-adjustment of the cardiac system as to sustained sinus rhythm. What is more, whether patients with AF previously not responsive to AADs may have a positive response to antiarrhythmic agents after the ablation procedure remains in question. Several studies comparing CA to AADs for the treatment of recurrent atrial arrhythmia suggest that repeat ablation is superior to AADs [34,35]. Given the high cost and potential postprocedural complications of repeat CA, promoting sinus rhythm postablation through the administration of AADs becomes important. The problem is that the notion of the appropriate selection, the proper dosage, and the duration of treatment with AADs after ablation differs. In routine clinical practice, temporary treatment with AADs for the maintenance of sinus rhythm may be somewhat beneficial, at least in some categories of patients.
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As mentioned above, it was hard to weigh the advantages and disadvantages of the continuous administration of AADs for AF patients after CA. On the basis of our study, the administration of AADs for sustaining sinus rhythm after CA for AF appears to be unnecessary with regard to preventing AF recurrence. However, this evidence is based on a limited number of studies and patients. Additional data would be needed to consolidate the conclusion of our study.
Strength and Limitation An extensive survey of the medical literature was performed to help guarantee the representation of all currently available data from studies that met our predefined inclusion criteria. All eligible studies were RCTs. There was no significant difference in heterogeneity of the patient populations between studies. This meta-analysis of pertinent medical literature presents several limitations. (1) Not all RCTs included in this meta-analysis were blinded. (2) Although the overall conclusions of the meta-analyses are consistent, variability was present among individual study results. These differences may be attributable to differences in patient risk profiles, ablation procedures, ablation catheter, physician experience, and selection and dosage of AADs. (3) Given the limitations of the available studies, additional data from a large multicentre randomized study are needed.
Conclusion Meta-analysis of currently available studies demonstrated that concomitant administration of AADs within initial months after CA for AF may decrease early ATa but does not prevent late ATa.
Conflict of Interest The authors declare no conflict of interest.
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ª 2015 John Wiley & Sons Ltd
Administration of Antiarrhythmic Drugs to Maintain Sinus Rhythm After Catheter Ablation for Atrial Fibrillation: A Meta-Analysis Xiuli Xu, Choumi T. Alida & Bo Yu Department of Cardiology, The First Hospital Affiliated to China Medical University, Shenyang, Liaoning, China
Keywords Antiarrhythmic drugs; Atrial fibrillation; Catheter ablation; Meta-analysis. Correspondence B. Yu, Department of Cardiology, The First Hospital Affiliated to China Medical University, No. 155, Nanjing North Street, Heping, Shenyang, Liaoning 110001, China. Tel.: +86-24-83282691; Fax: +86-24-83283673; E-mail: [email protected]
doi: 10.1111/1755-5922.12133
SUMMARY Background: Whether the short-term administration of antiarrhythmic drugs (AADs) to maintain sinus rhythm following catheter ablation (CA) for atrial fibrillation (AF) can prevent the recurrence of AF is still a matter of debate. We searched the PubMed database and the Cochrane Library, and compiled a list of retrieved articles. We included only randomised controlled trials(RCTs) that compared any AADs against control (placebo or no treatment) or other AADs following CA for AF. Statistical analysis of the odds ratio (OR) and corresponding 95% confidence interval (CI) were used to determine the overall effect of both outcomes. The Mantel–Haenszel method was used to pool data of the outcomes of AF recurrence into fixed effect model meta-analyses. Aims: We performed a systematic review to determine the effectiveness of short-term treatment with AADs on the recurrence of AF after CA. Results: Six RCTs were included in this study, with a total of 814 patients. Postprocedural temporary administration of AADs in patients after CA for AF reduced the early recurrence of AF (antiarrhythmic drug 103 patients [25.3%], control 162 patients [39.8%]; OR 0.47 [95% CI 0.34–0.64]; v2 = 3.77; P = 0.58; I2 = 0%). No significant difference in patients after CA for AF in the late recurrence of AF (antiarrhythmic drug 148 patients [36.5%], control 171 patients [42.5%]; OR 0.77 [95% CI 0.57–1.03]; v2 = 3.15; P = 0.68; I2 = 0%). The heterogeneity was zero in both analyses. Conclusion: Although the continued administration of AADs after CA for AF can decrease early atrial tachycardias (ATa), this treatment does not prevent late ATa.
Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with increased morbidity and mortality related to stroke, other embolic complications, and heart failure [1,2]. Pharmacological therapy is the mainstay of treatment for AF, but currently available antiarrhythmic drugs (AADs) have limited effectiveness and safety [3–5]. In the past decade, catheter ablation (CA) has emerged as an effective strategy to control cardiac rhythm in patients with symptomatic and drugrefractory AF and its use in clinical practice has been growing gradually [6–10]. Nevertheless, patients undergoing CA frequently experience atrial tachyarrhythmias (ATa) after ablation. Therefore, the empirical administration of AADs following CA for AF has been popular for the purpose of preventing recurrence of AF or alleviating the symptoms. Whether rhythm maintenance with the temporary use of AADs following CA can prevent the recurrence of AF is still a matter of debate. Due to the clinical importance of this issue for this commonly performed therapeutic intervention and the lack of definitive findings from individual published reports, we sought to systematically review the litera-
242
Cardiovascular Therapeutics 33 (2015) 242–246
ture and perform a meta-analysis of available studies to determine the effectiveness of the concomitant use of AADs after ablation on the recurrence of AF.
Method Eligibility Criteria We selected only randomized controlled trials (RCTs) that included patients who had AF of any type and duration and in whom sinus rhythm had been restored using CA and compared short-term treatment immediately after ablation with any AADs against controls (placebo or no treatment or drugs). We excluded studies that did not address the treatment of AF patients with AADs following CA for AF, studies for which the full text could not be obtained, and studies published in languages other than English. The primary outcome was defined as the occurrence of any ATa (AF, atrial flutter or atrial tachycardia) lasting more than 30 second [11]. Generally speaking, the early recurrence of atrial fibrillation (ERAF) was defined as the occurrence of ATa within the
ª 2015 John Wiley & Sons Ltd
X. Xu et al.
first 3 months after ablation, also called the “blank period,” otherwise defined as late recurrence of atrial fibrillation (LRAF).
Search Strategy We searched the PubMed database and the Cochrane Library (until October 2014) using the following terms: (Atrial fibrillation OR fibrillation, atrial OR [(atrial OR atrium OR auricular) AND fibrillat*]) AND (radiofrequency catheter ablation OR ablation, catheter) AND (anti-arrhythmia agents OR antiarrhythmic drugs OR anti-arrhythmi* OR anti-arrhythm* OR pharmacologic* OR therapeutic use OR flecainide OR amiodarone OR dronedarone OR sotalol OR propafenone OR ibutilide). We also checked the reference lists of the retrieved studies, meta-analyses, and general reviews on AF.
Data Extraction and Validity Assessment Studies that met the inclusion criteria were assessed by one reviewer and verified by another. Data collected included the year of publication, study size, patients with AF, follow-up period, demographic characteristics, and comorbidities. All disagreements were solved by discussion and consensus. The modified Jadad seven-point scale to evaluate the quality of RCT was applied; this scale scored a maximum of two points for randomization, two points for allocation concealment, two points for blinding, and one point for the description of withdrawal and drop out [12]. v2 and I2 were used to assess the statistical heterogeneity among the selected studies. The I2 statistics represents the proportion of variation in the treatment estimate which is not related to sampling error. When I2 was >50%, statistical heterogeneity was presumed.
Data Synthesis The statistical analyses were conducted using the RevMan 5.3 software (The Cochrane Collaboration, Oxford, UK). Dichotomous results were analyzed using the Mantel–Haenszel method. Odds ratio (OR) and its 95% confidence interval (CI) were calculated.
Results From a total of 2248 references identified, we assessed 26 articles in more detail. Six studies fulfilled the inclusion criteria and presented usable data, involving a total of 814 patients. All studies were RCTs [13–18]. Data not provided in the main articles were sought from the study by Roux et al. [19]. Figure 1 illustrates the results of the search strategy. Five RCTs scored high on the modified Jadad scale and one scored low. The type of AF most frequently studied was paroxysmal AF. The percentage of male patients was greater than that of female patients, except in one trial. The proportion of patients having underlying heart disease, as defined in each study, varied widely from 30.6% to 91%; furthermore, the mean left ventricular ejection fraction was >50%. No significant difference was found between the AADs and the control groups with regard to the baseline characteristics of patients in individual studies. Table 1 details the baseline charac-
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Postablation Use of Antiarrhythmic Drug
2248 publications identified and screened
2 additional studies identified through the reference list
2097 excluded based on title and/or abstract
125 excluded 115 did not meet inclusion criteria 6 controlled but nonrandomised 151 records screened
4 comments
11 randomised but not for allocation to antiarrhythmic drugs 2 letters 26 full-text articles were assessed for eligibility
1 not meet inclusion criteria 1 no comparison arm
2 had same data source 1 non-English publication 11 potentially appropriate randomised controlled trials to be included
1 subject not meeting inclusion criteria 1 no full text
6 citations fulfilled inclusion criteria
Figure 1 Flow diagram of the selection process of eligible articles.
teristics of the eligible studies. Table 2 summarizes their data and conclusions. To determine the overall effect, a meta-analysis was performed and the calculated OR for ERAF was 0.95 (95% CI: 0.86–1.05) (Figure 2). The OR for LRAF was 0.99 (95% CI: 0.87–1.13) (Figure 3). The postprocedural temporary administration of AADs after CA for AF reduced the ERAF (AADs 103 patients [25.3%], control 162 patients [39.8%]; OR 0.47 [95% CI 0.34–0.64]; v2 = 3.77; P = 0.58; I2 = 0%). In contrast, this treatment did not reduce the LRAF (AADs 148 patients [36.5%], control 171 patients [42.5%]; OR 0.77 [95% CI 0.57–1.03]; v2 = 3.15; P = 0.68; I2 = 0%). Figures 2 and 3 summarize the total number of patients, the contribution of each study, the results of the pooled analyses, and the heterogeneity of the study populations. Heterogeneity was found to be zero in both analyses. A funnel plot for the publication bias analysis was not determined because this type of analysis is not recommended when fewer than 10 studies are analyzed [20].
Discussion In this first systematic review and meta-analysis of the effectiveness of AADs on the incidence of recurrence of AF after ablation, we demonstrated that subsequent AAD treatment had an favorable influence by decreasing the ERAF after CA but did not lower the rate of late ATa. This finding may have significant implications
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Table 1 Baseline characteristics of patients in eligible studies Hayashi et al. (2014) [13] AF type No. of pts Mean age (SD) Men (%) Hypertension (%) Valvular disease (%) CHD (%) LAD (mm) (SD) LVEF (%) Treatment group
Follow-up (SD) (month) Jadad score
Gu et al. (2012) [14]
Leong-Sit et al. (2011) [15,19]
Turco et al. (2007) [16]
Brignole et al. (2002) [17]
Darkner et al. (2014) [18]
PAF (71%), PeAF (29%) 126 63 (11) 77 63
PeAF
PAF
PAF
PAF (50%)
123 59.5 (9.5) 55 54.5
110 55.5 (8.5) 71 91
PAF (60%), PeAF (40%) 107 57 (10) 64.5 57
137 68 (8) 42.3 30.6
212 61 83 39.6
NR
0.8
NR
6
11
NR
NR 38 (5.5) 68.5 (8.5) Initial 3 months postablation: flecainide, 143 (19) mg/day; no AAD
5.7 42 (6.5) 61.5 (7.5) The first 6 weeks after ablation: propafenone 150 mg TID or flecainide 100 mg BID, sotalol 80 mg BID or dofetilide 500 g BID; no AAD
5 48 (6) NR 71% were treated with amiodarone, 19% with flecainide, 6% with propafenone, and 4% with sotalol; no treatment
16 NR NR The first 6 months: amiodarone (200 mg/day), sotalol (120–240 mg/day), propafenone (450–900 mg/day), flecainide (100–200 mg/day) and combinations of these; no drug
6.6 44 (7) 50.5 (8.5) The first 8 weeks: amiodarone 400 mg BID for 13 days, then 200 mg BID for 2 weeks finally and 200 mg QD for 4 weeks; placebo
17 (9)
8.9 46.6 (3.25) 56 (7.2) Initial 2 months: both AAD type Ic (propafenone 150 mg/d t.i.d) and type III (amiodarone 600 mg/day for 2 weeks, 400 mg/day for the next 2 weeks, 200 mg daily thereafter); one AAD (type Ic OR III) 12
6
12
12–24
6
3
4
5
5
5
5
AAD, antiarrhythmic drug; AF, atrial fibrillation; LVEF, left ventricular ejection fraction; CHD, coronary heart disease; NR, not reported; LAD, left atrium diameter; No. of pts, number of patients; PAF, paroxysmal atrial fibrillation; PeAF, persistent atrial fibrillation; SD, standard deviation.
Table 2 Summary of data and conclusions from eligible studies Studies
AADs (n)
Control (n)
Hayashi et al. (2014) [13]
62
63
Gu et al. (2012) [14]
62
61
Leong-Sit et al. (2011) [15,19] Turco et al. (2007) [16] Brignole et al. (2002) [17] Darkner et al. (2014) [18]
53
57
54 68 108
53 69 104
Primary endpoint
Conclusion
Any ATa lasting for ≥ 30 second during the first 3 months Any episode of symptomatic or asymptomatic ATa lasting for ≥ 30 second Freedom from asymptomatic or symptomatic ATa The absence of ATa lasting >30 second Prevent the development of permanent AF Any documented ATa lasting 30 second
Did not reduce the early and late ATa Decreased early ATa but did not prevent late ATa Decreased early ATa but did not prevent ATa at 6 months Did not lower the rate of AF recurrences Reduced the risk of development of permanent AF Did not significantly reduce the recurrence of ATa at the 6-month follow-up
AADs, antiarrhythmic drugs; AF, atrial fibrillation; ATa, atrial tachyarrhythmias.
for the management of patients undergoing radiofrequency CA, particularly considering the increasing number of patients with AF on chronic therapy with AADs postablation. In recent years, the hope that CA could take the place of conventional pharmacological therapy for AF has been replaced by the belief that the benefits of the combined approach of AADs and CA could outweigh those of ablation alone [21–23]. The number
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of studies on continuous administration of AADs after CA of AF is scarce. The great majority of studies found that the treatment of AADs following the procedure could prevent ERAF rather than LRAF [13–16,19,24]. As demonstrated, most recurrences occurred in the initial 6 months after ablation, but even after 1 year, an annual recurrence rate of 5–9% has been described [25]. O0 Donnell et al. [26] found that a delayed cure of AF can be found in a
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Figure 2 Comparison of patients on AADs and control patients with regard to ERAF postablation. AADs, antiarrhythmic drugs; ERAF, early recurrence of atrial fibrillation.
Figure 3 Comparison of patients on AADs and control patients with regard to LRAF postablation. AADs, antiarrhythmic drugs; LRAF, late recurrence of atrial fibrillation.
significant number of patients despite an ERAF after focal pulmonary vein ablation, which is most prevalent in patients with persistent AF and structural and electric abnormalities of the atrium. In contrast, Caia et al. [27] reported that ERAF was one of the independent predictors of LRAF. An agreement on the contribution of ERAF to the effectiveness of the procedure for AF could not be reached. In addition, the use of AADs during the initial months after CA may also be indicated in cases of macro-reentrant left atrial tachycardias, which account for 10% of arrhythmias during the “blank period,” and most likely increase the percentage of patients who developed asymptomatic episodes of AF [28]. Thus, the evaluation of the actual effectiveness of AADs on ERAF was incomplete. As previously described, ERAF is a common finding that is not implicitly related to a failure of CA [29–31]. Almost half of the patients experiencing these arrhythmias during the first month postablation will not have any subsequent arrhythmia during long-term follow-up because these arrhythmias tend to resolve spontaneously during the “blank period” [32,33]. In view of this observation, it is difficult to distinguish the contribution of AADs from those of self-restoration and auto-adjustment of the cardiac system as to sustained sinus rhythm. What is more, whether patients with AF previously not responsive to AADs may have a positive response to antiarrhythmic agents after the ablation procedure remains in question. Several studies comparing CA to AADs for the treatment of recurrent atrial arrhythmia suggest that repeat ablation is superior to AADs [34,35]. Given the high cost and potential postprocedural complications of repeat CA, promoting sinus rhythm postablation through the administration of AADs becomes important. The problem is that the notion of the appropriate selection, the proper dosage, and the duration of treatment with AADs after ablation differs. In routine clinical practice, temporary treatment with AADs for the maintenance of sinus rhythm may be somewhat beneficial, at least in some categories of patients.
ª 2015 John Wiley & Sons Ltd
As mentioned above, it was hard to weigh the advantages and disadvantages of the continuous administration of AADs for AF patients after CA. On the basis of our study, the administration of AADs for sustaining sinus rhythm after CA for AF appears to be unnecessary with regard to preventing AF recurrence. However, this evidence is based on a limited number of studies and patients. Additional data would be needed to consolidate the conclusion of our study.
Strength and Limitation An extensive survey of the medical literature was performed to help guarantee the representation of all currently available data from studies that met our predefined inclusion criteria. All eligible studies were RCTs. There was no significant difference in heterogeneity of the patient populations between studies. This meta-analysis of pertinent medical literature presents several limitations. (1) Not all RCTs included in this meta-analysis were blinded. (2) Although the overall conclusions of the meta-analyses are consistent, variability was present among individual study results. These differences may be attributable to differences in patient risk profiles, ablation procedures, ablation catheter, physician experience, and selection and dosage of AADs. (3) Given the limitations of the available studies, additional data from a large multicentre randomized study are needed.
Conclusion Meta-analysis of currently available studies demonstrated that concomitant administration of AADs within initial months after CA for AF may decrease early ATa but does not prevent late ATa.
Conflict of Interest The authors declare no conflict of interest.
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