Previous studies have reported that steroids may reduce the risk of atrial fibrillation (AF) recurrence after catheter ablation, but data regarding this issue have been controversial. Therefore, we conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies to ascertain the association of steroids and AF recurrence after ablation. PubMed, Embase, and Cochrane online databases were searched from inception to December 2017. The primary outcome of the meta-analysis was short-term or long-term AF recurrence following a single ablation procedure with or without the use of steroids. Both fixed- and random-effects models were used to calculate the overall effect estimates. Eight studies (four RCTs and four observational studies), with a total 992 patients, were included in the present study. Our meta-analysis shows that steroid use was associated with reduced AF occurrence at 3 months (odd ratio (OR) = 0.53, 95% confidence interval (CI) = 0.31–0.90, P=0.02) and 12–14 months (OR = 0.67, 95% CI = 0.47–0.95, P=0.02) after radiofrequency (RF) catheter ablation (RFCA). No clear benefit was observed for AF recurrence at 2–3 days, 1 or 24 months of follow-up. Steroid use was associated with decreased risk of early AF recurrence 3 and 12–14 months after ablation. No clear relationship was observed for 2–3 days, 1 and 24 months of follow-up and further data are needed to clarify these results.

Introduction

Atrial fibrillation (AF) is the commonest cardiac rhythm disorder observed in clinical practice but it is challenging to cure [1,2]. Radiofrequency (RF) catheter ablation (RFCA) is an effective treatment for drug-refractory symptomatic paroxysmal or persistent AF patients. However, there are still opportunities for recurrence of AF, especially within the first few weeks after ablation [3]. The relationship between inflammation process and the development of AF has been widely studied [4,5].

Recent study has found that the early recurrence of AF after ablation is associated with an inflammatory response to the ablation itself [6]. Halonen et al. [7] showed that hydrocortisone can reduce the incidence of AF after cardiac surgery by preventing inflammatory reactions. Some studies suggested that treatment with steroids after AF ablation is effective for negating AF recurrence by preventing post-ablation inflammatory responses, whereas others have reported no significant benefit. Moreover, the effectiveness of steroids for prevention of AF recurrence may vary at different time points after ablation [8–15]. Given these conflicting findings, we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) and observational studies to ascertain the impact of steroids on preventing AF recurrence after RFCA.

Methods

Search strategy

PubMed, Embase, and Cochrane online databases were searched from their inception to December 2017. The following search string: (hormone or steroid or corticosteroid or glucocorticoid or hydrocortisone or methylprednisolone) and (‘radiofrequency ablation’ or ‘pulmonary vein isolation’ or ‘catheter ablation’ or ‘radiofrequency catheter ablation’) and ‘atrial fibrillation’ were used to identify all the published articles. Searches were not restricted by language. Reference lists of retrieved articles were scanned manually for additional studies.

Study selection

Inclusion criteria were: (i) the study design was randomized controlled trials (RCTs) or cohort studies, (ii) human subjects, (iii) included the characteristics of study patients, (iv) assessed the effect of steroids on AF recurrence after RFCA. Two reviewers (M.L. and M.G.) independently identified duplicates, and then they conducted the initial screening of all titles or abstracts and evaluated all potentially relevant articles based on full-text reviews. Any disagreements between the two investigators were resolved by discussion with a senior reviewer (T.L.).

Quality evaluation

In order to limit the heterogeneity secondary to differences amongst study designs, the quality of each study was evaluated to exclude those studies classified as ‘low quality’. This meta-analysis included four RCT studies and four cohort studies. The quality of observational study was assessed using the Newcastle–Ottawa scale (NOS), and NOS ≥ 7 was considered as a high-quality study. We used Cochrane bias risk tools for quality assessment of RCT study, and finally assigned a judgment of high, low, or unclear risk of material bias for each study. Our NOS analysis for observational studies demonstrated that three studies had high quality scores of ≥ 7 [9–11] with one study having a moderate score [15] (Table 3). Cochrane bias risk tool for assessing RCTs demonstrated that all four were high-quality studies (Supplementary Figure S1).

Flow diagram of study selection process

Data extraction

Two reviewers extracted data from the eligibility studies according to standard data extraction forms. We extracted and analyzed odd ratios (ORs)/HRs/RRs values and the corresponding 95% confidence intervals (CIs) to evaluate the association between steroids and AF recurrence after RFCA. At the same time, the following data were also collected from each study: study characteristics (first author’s last name, year of publication, origin of the studied population, study population, number of patients, follow-up duration, diagnosis and detection methods of AF recurrence, ablation, dose and type of steroids in the steroids group) and patient characteristics (age, male, percentage of paroxysmal AF, hypertension, diabetes, heart failure, antiarrhythmic, echocardiographic parameters, the procedure time of catheter ablation, superior vena cava (SVC) isolation). Any disagreements between the two reviewers (M.L. and M.G.) were resolved by discussion with a senior reviewer (T.L.).

Statistical analysis

Review Manager (version 5.3) was used for statistical analysis. P<0.05 was considered to be statistically significant. Categorical data were described in percentages and continuous variables were reported as mean and S.D. Results of AF recurrence after RFCA were presented as OR and 95% CI. Heterogeneity was evaluated with Chi-square tests and I2, and I2 ≥ 50% was considered to indicate significant heterogeneity. If I2 < 50% then a fixed-effects model was used, otherwise the random-effects model was used. Subgroup analyses were based on study design (cohort study and RCT study).

Results

Patient baseline characteristics

A flow diagram detailing the search and study selection process is illustrated in Figure 1. Three hundred and eighty-nine citations were initially retrieved from PubMed, Embase, and the Cochrane online database. Thirty-six records were discarded as duplicates. Subsequent records including 8 animal studies, 32 case reports, 84 review articles, and 218 irrelevant studies were also excluded accordingly. Subsequently, we excuded 3 records [16–18] of duplicated data by reading 11 full-text articles. In the end, a total of eight studies involving 992 patients between 2010 and 2016 met our selection criteria for inclusion [8–15]. The baseline characteristics of all patients are summarized in Tables 1 and 2, respectively. Seven of eight studies [8–11,13–15] examined outcomes of AF patients undergoing RFCA. The follow-up period varied from 6 to 38 months. It is worth noting that different steroids, including hydrocortisone, dexamethasone, prednisone, and methylprednisolone were used in these studies. Furthermore, the steroid administration method also varied between articles.

Table 1
Characteristics of studies included in the meta-analysis
First author, year Design Country Study population Number of patients (n) S/C Follow-up (month) The variety of steroids Dosage and use time Ablation Diagnosis of AF recurrence Methods of AF detection 
Krishnan, 2010 [15Cohort study U.S.A. AF who underwent RFCA 37/31 NR Dexamethasone Iv 11.9 ± 4.6 mg/day during hospitalization NR Any AF > 10 min during hospitalization Continuous electrocardiographic monitoring 
Kim Y.R., 2012 [12RCT NR NR 56/56 Methylprednisolone Iv 0.5 mg/kg for post-procedural day 1 and orally 12 mg/day for post-procedural days 2–5 NR Atrial tachyarrhythmia Holter monitoring 
Won, 2013 [11Cohort study Korea Drug-resistant AF who underwent RFCA 89/120 12 Hydrocortisone Iv 100 mg within 30 min after RFCA 3.5-mm irrigated-tip catheter, 50°C, 25–35 W Any episode of AF or AT of at least 30 s Holter monitoring ECGs 
         Intensive questioning regarding any arrhythmia related 
Andrade, 2013 [10Prospective cohort study Canada Drug resistant AF who underwent RFCA 45/45 12 Hydrocortisone Iv 250 mg after transseptal access 3.5-mm irrigated-tip catheter, 43°C, 30–35 W, 17–30 ml/min, on the posterior wall, 20–25 W, 17 ml/min Symptomatic electrocardiographically documented AF or AFL, or AT, at least ≥ 30 s Routine transtelephonic
Monitoring
Clinical assessment
Holter monitoring
ECGs 
Koyama, 2010 [8RCT, DB Japan Drug resistant AF who underwent RFCA 60/65 14 Hydrocortisone and prednisonlone Iv hydrocortisone 2 mg/kg in the day of PVI and orally prednisonlone 0.5 mg/kg/day for 3 days after PVI 8-mm distalelectrode
52°C, 30–35 W 
ECG showed AF, irrespective of symptoms Holter monitoring
ECGs
Intensive questioning regarding any arrhythmia related
Electrocardiographic monitoring 
Kim D.R., 2015 [9Cohort study Korea Drug resistant AF who underwent RFCA L 95/ M 97/95 24 Low: hydrocortisone
Moderate: methylprednisolone 
Low: Iv 100 mg within 30 min after RFCA
Moderate: Iv 125 mg within 30 min after RFCA 
3.5-mm irrigated-tip catheter
50°C, 25–35 W 
Any episode of AF or AT of at least 30 s Holter monitoring
ECGs 
Kim Y.R., 2015 [13RCT, DB Korea AF who underwent RFCA 64/74 24 Methylprednisolone Iv 0.5 mg/kg before the femoral vein puncture and orally 12 mg/day for the following 4 days 3.5-mm irrigated-tip catheter
43°C, 30 W 
Any episode of AF/AFL/AT of at least 30 s ECGs Telemetry monitoring
Handheld ECG device
Holter monitoring 
Iskandar, 2016 [14RCT U.S.A. AF who underwent RFCA 30/30 12 Prednisone Orally three doses of 60 mg Q day prior to the procedure NR NR Event monitoring 
First author, year Design Country Study population Number of patients (n) S/C Follow-up (month) The variety of steroids Dosage and use time Ablation Diagnosis of AF recurrence Methods of AF detection 
Krishnan, 2010 [15Cohort study U.S.A. AF who underwent RFCA 37/31 NR Dexamethasone Iv 11.9 ± 4.6 mg/day during hospitalization NR Any AF > 10 min during hospitalization Continuous electrocardiographic monitoring 
Kim Y.R., 2012 [12RCT NR NR 56/56 Methylprednisolone Iv 0.5 mg/kg for post-procedural day 1 and orally 12 mg/day for post-procedural days 2–5 NR Atrial tachyarrhythmia Holter monitoring 
Won, 2013 [11Cohort study Korea Drug-resistant AF who underwent RFCA 89/120 12 Hydrocortisone Iv 100 mg within 30 min after RFCA 3.5-mm irrigated-tip catheter, 50°C, 25–35 W Any episode of AF or AT of at least 30 s Holter monitoring ECGs 
         Intensive questioning regarding any arrhythmia related 
Andrade, 2013 [10Prospective cohort study Canada Drug resistant AF who underwent RFCA 45/45 12 Hydrocortisone Iv 250 mg after transseptal access 3.5-mm irrigated-tip catheter, 43°C, 30–35 W, 17–30 ml/min, on the posterior wall, 20–25 W, 17 ml/min Symptomatic electrocardiographically documented AF or AFL, or AT, at least ≥ 30 s Routine transtelephonic
Monitoring
Clinical assessment
Holter monitoring
ECGs 
Koyama, 2010 [8RCT, DB Japan Drug resistant AF who underwent RFCA 60/65 14 Hydrocortisone and prednisonlone Iv hydrocortisone 2 mg/kg in the day of PVI and orally prednisonlone 0.5 mg/kg/day for 3 days after PVI 8-mm distalelectrode
52°C, 30–35 W 
ECG showed AF, irrespective of symptoms Holter monitoring
ECGs
Intensive questioning regarding any arrhythmia related
Electrocardiographic monitoring 
Kim D.R., 2015 [9Cohort study Korea Drug resistant AF who underwent RFCA L 95/ M 97/95 24 Low: hydrocortisone
Moderate: methylprednisolone 
Low: Iv 100 mg within 30 min after RFCA
Moderate: Iv 125 mg within 30 min after RFCA 
3.5-mm irrigated-tip catheter
50°C, 25–35 W 
Any episode of AF or AT of at least 30 s Holter monitoring
ECGs 
Kim Y.R., 2015 [13RCT, DB Korea AF who underwent RFCA 64/74 24 Methylprednisolone Iv 0.5 mg/kg before the femoral vein puncture and orally 12 mg/day for the following 4 days 3.5-mm irrigated-tip catheter
43°C, 30 W 
Any episode of AF/AFL/AT of at least 30 s ECGs Telemetry monitoring
Handheld ECG device
Holter monitoring 
Iskandar, 2016 [14RCT U.S.A. AF who underwent RFCA 30/30 12 Prednisone Orally three doses of 60 mg Q day prior to the procedure NR NR Event monitoring 

Abbreviations: AT, atrial flutter; DB, double blind; ECG, electrocardiogram; Iv, intravenous injection; NR, not reported; PVI, pulmonary vein isolation; S/C, steroid group/control group.

Table 2
Patients’ characteristics of studies included in the meta-analysis
First author, year Age (years), S/C Male S/C n (%) Paroxysmal AF, S/C, n (%) Hypertension S/C, n (%) Diabetes S/C, n (%) HF S/C, n (%) Antiarrhythmic drugs, S/C, n (%) 
       Class Ic Class III 
Krishnan, 2010 55 ± 10* 51 (75)* 38 (56)* NR NR 8 (12)* NR NR 
Kim Y.R., 2012 NR NR NR NR NR NR NR NR 
Won, 2013 55 ± 11/55 ± 11 70 (78)/94 (78) 50 (56)/57 (48) 38 (45)/52 (44) 4 (5)/16 (14) 2 (2)/4 (3) 53 (60)/70 (58) 27 (30)/45 (38) 
Andrade, 2013 58.4 ± 9.5* (57.4 ± 10.5/59.5 ± 8.3) 33 (72)/31 (69) 45 (100)/45 (100) 11 (24)/16 (36) 0 (0)/3 (7) NR NR NR 
Koyama, 2010 60.7 ± 9.6* (59.8 ± 8.7/61.5 ± 10.3) 48 (80)/52 (80) 60 (100)/65 (100) 36 (55.4)/29 (44.6) NR NR 41 (68.3)/39 (60.0) 23 (38.3)/33 (50.8) 
Kim D.R., 2015 L56 ± 9/M56 ± 10/56 ± 10 L80 (84)/M82 (84)/80 (85) L58 (63)/M61 (64)/60 (63) L46 (48)/M49 (52)/40 (42) L6 (6)/M13 (14)/10 (10) L3 (3)/M5 (5)/2 (2) L61 (64)/M61 (63)/54 (57) L23 (24)/M30 (31)/39 (41) 
Kim Y.R., 2015 56 ± 10* (56 ± 9/56 ± 10) 51 (79.7)/50 (67.6) 138* 21 (32.8)/27 (36.5) 8 (12.5)/10 (13.5) 8 (12.5)/3 (4.1) 43 (68.4)/54 (73.3) 7 (10.5)/16 (22.2) 
Iskandar, 2016 63 ± 7* NR 60 (100)* NR NR NR NR NR 
First author, year Age (years), S/C Male S/C n (%) Paroxysmal AF, S/C, n (%) Hypertension S/C, n (%) Diabetes S/C, n (%) HF S/C, n (%) Antiarrhythmic drugs, S/C, n (%) 
       Class Ic Class III 
Krishnan, 2010 55 ± 10* 51 (75)* 38 (56)* NR NR 8 (12)* NR NR 
Kim Y.R., 2012 NR NR NR NR NR NR NR NR 
Won, 2013 55 ± 11/55 ± 11 70 (78)/94 (78) 50 (56)/57 (48) 38 (45)/52 (44) 4 (5)/16 (14) 2 (2)/4 (3) 53 (60)/70 (58) 27 (30)/45 (38) 
Andrade, 2013 58.4 ± 9.5* (57.4 ± 10.5/59.5 ± 8.3) 33 (72)/31 (69) 45 (100)/45 (100) 11 (24)/16 (36) 0 (0)/3 (7) NR NR NR 
Koyama, 2010 60.7 ± 9.6* (59.8 ± 8.7/61.5 ± 10.3) 48 (80)/52 (80) 60 (100)/65 (100) 36 (55.4)/29 (44.6) NR NR 41 (68.3)/39 (60.0) 23 (38.3)/33 (50.8) 
Kim D.R., 2015 L56 ± 9/M56 ± 10/56 ± 10 L80 (84)/M82 (84)/80 (85) L58 (63)/M61 (64)/60 (63) L46 (48)/M49 (52)/40 (42) L6 (6)/M13 (14)/10 (10) L3 (3)/M5 (5)/2 (2) L61 (64)/M61 (63)/54 (57) L23 (24)/M30 (31)/39 (41) 
Kim Y.R., 2015 56 ± 10* (56 ± 9/56 ± 10) 51 (79.7)/50 (67.6) 138* 21 (32.8)/27 (36.5) 8 (12.5)/10 (13.5) 8 (12.5)/3 (4.1) 43 (68.4)/54 (73.3) 7 (10.5)/16 (22.2) 
Iskandar, 2016 63 ± 7* NR 60 (100)* NR NR NR NR NR 
Table 2
Patients’ characteristics of studies (continued)
First author, year Catheter ablation, S/C SVC isolation S/C, n (%) Echocardiographic parameters, S/C 
 Total duration of procedure, min Total fluoroscopytime, min Duration of RF ablation, min  LAD, mm LVDED, mm LVEF, % 
Krishnan, 2010 NR NR NR NR 40.7 ± 6.8* NR NR 
Kim Y.R., 2012 NR NR NR NR NR NR NR 
Won, 2013 188 ± 45/201 ± 52 47 ± 21/48 ± 16 82 ± 28/89 ± 32 4 (5)/7(6) 43 ± 5/41 ± 6 50 ± 4/50 ± 4 63 ± 7/63 ± 8 
Andrade, 2013 176 ± 49* (169 ± 35/182 ± 60) 39 ± 16* (35 ± 8/42 ± 20) 53 ± 20* (58 ± 21/48 ± 19) NR 38.0 ± 5.7* (37.5 ± 5.8/38.5 ± 5.6) NR NR 
Koyama, 2010 205.1 ± 34.3* (200.8 ± 35.6/209.1 ± 32.6) 81.4 ± 24.4* (81.4 ± 22.3/82.6 ± 24.3) 48.1 ± 17.6* (47.9 ±15.8/48.2 ± 19.3) 4 (6.6)/3 (4.6) 38.3 ± 7.4* (37.6 ± 7.1/38.9 ± 7.7) 48.3 ± 4.9* (48.4 ± 5.3/48.3 ± 4.5) 64.4 ± 8.8* (66.1 ± 7.3/62.8 ± 9.8) 
Kim D.R., 2014 L182 ± 46/M168 ± 40/192 ± 52 L58 ± 19/M43 ± 13/48 ± 16 L77 ± 27/M68 ± 23/86 ± 24 L2 (2)/M14 (15)/6 (7) L41 ± 5/M42 ± 7/42 ± 6 L49 ± 5/M50.6 ± 4/52 ± 8 L64 ± 7/M62 ± 9/61 ± 6 
Kim Y.R., 2015 377 ± 97* (363 ± 94/390 ± 99) 37 ± 8* (37 ± 9/38 ± 8) 123 ±38* (118 ± 38/127 ± 38) 6 (9.4)/8 (10.8) 41.6 ± 6.2* (40.9 ± 5.8/42.2 ± 6.5) 142.5 ± 33.7* (142.2 ± 37.7/142.7 ± 30.9) 59.5 ± 6.6* (57.8 ± 8.7/ 60.5 ± 6.1) 
Iskandar, 2016 NR NR 56 ± 10.65/51 ± 13.53 NR NR NR NR 
First author, year Catheter ablation, S/C SVC isolation S/C, n (%) Echocardiographic parameters, S/C 
 Total duration of procedure, min Total fluoroscopytime, min Duration of RF ablation, min  LAD, mm LVDED, mm LVEF, % 
Krishnan, 2010 NR NR NR NR 40.7 ± 6.8* NR NR 
Kim Y.R., 2012 NR NR NR NR NR NR NR 
Won, 2013 188 ± 45/201 ± 52 47 ± 21/48 ± 16 82 ± 28/89 ± 32 4 (5)/7(6) 43 ± 5/41 ± 6 50 ± 4/50 ± 4 63 ± 7/63 ± 8 
Andrade, 2013 176 ± 49* (169 ± 35/182 ± 60) 39 ± 16* (35 ± 8/42 ± 20) 53 ± 20* (58 ± 21/48 ± 19) NR 38.0 ± 5.7* (37.5 ± 5.8/38.5 ± 5.6) NR NR 
Koyama, 2010 205.1 ± 34.3* (200.8 ± 35.6/209.1 ± 32.6) 81.4 ± 24.4* (81.4 ± 22.3/82.6 ± 24.3) 48.1 ± 17.6* (47.9 ±15.8/48.2 ± 19.3) 4 (6.6)/3 (4.6) 38.3 ± 7.4* (37.6 ± 7.1/38.9 ± 7.7) 48.3 ± 4.9* (48.4 ± 5.3/48.3 ± 4.5) 64.4 ± 8.8* (66.1 ± 7.3/62.8 ± 9.8) 
Kim D.R., 2014 L182 ± 46/M168 ± 40/192 ± 52 L58 ± 19/M43 ± 13/48 ± 16 L77 ± 27/M68 ± 23/86 ± 24 L2 (2)/M14 (15)/6 (7) L41 ± 5/M42 ± 7/42 ± 6 L49 ± 5/M50.6 ± 4/52 ± 8 L64 ± 7/M62 ± 9/61 ± 6 
Kim Y.R., 2015 377 ± 97* (363 ± 94/390 ± 99) 37 ± 8* (37 ± 9/38 ± 8) 123 ±38* (118 ± 38/127 ± 38) 6 (9.4)/8 (10.8) 41.6 ± 6.2* (40.9 ± 5.8/42.2 ± 6.5) 142.5 ± 33.7* (142.2 ± 37.7/142.7 ± 30.9) 59.5 ± 6.6* (57.8 ± 8.7/ 60.5 ± 6.1) 
Iskandar, 2016 NR NR 56 ± 10.65/51 ± 13.53 NR NR NR NR 

* means the data of all populations. Abbreviations: HF, heart failure; LAD, left atrial diameter; LVDED, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; NR, not reported; S/C, steroid group/control group.

Table 3
NOS quality evaluation for cohort studies
First author, year Selection Comparability Outcome Total 
 Representativeness of the exposed cohort Selection of the non-exposed cohort Ascertainment of exposure Demonstration that outcomes were not present at the start of study Comparability on the basis of the design or analysis Assessment of outcome Adequate follow-up duration Adequacy of follow-up of cohorts Score 
Krishnan, 2010 ★ ★ ★ ★ ★ 
Won, 2013 ★ ★ ★ ★ ★ (age, sex)
★ (paroxysmal AF) 
★ ★ 
Andrade, 2013 ★ ★ ★ ★ ★ (age, sex)
★ (paroxysmal AF) 
★ ★ 
Kim D.R., 2015 ★ ★ ★ ★ ★ (age, sex)
★ (paroxysmal AF) 
★ ★ ★ 
First author, year Selection Comparability Outcome Total 
 Representativeness of the exposed cohort Selection of the non-exposed cohort Ascertainment of exposure Demonstration that outcomes were not present at the start of study Comparability on the basis of the design or analysis Assessment of outcome Adequate follow-up duration Adequacy of follow-up of cohorts Score 
Krishnan, 2010 ★ ★ ★ ★ ★ 
Won, 2013 ★ ★ ★ ★ ★ (age, sex)
★ (paroxysmal AF) 
★ ★ 
Andrade, 2013 ★ ★ ★ ★ ★ (age, sex)
★ (paroxysmal AF) 
★ ★ 
Kim D.R., 2015 ★ ★ ★ ★ ★ (age, sex)
★ (paroxysmal AF) 
★ ★ ★ 

Efficacy of steroids in preventing AF recurrence post-RFCA

As the impact of steroids on AF recurrence after RFCA were reported at different follow-up periods, we evaluated the association between steroid use and AF recurrence post-RFCA at (i) 2–3 days, (ii) 1, (iii) 3, (iv) 12–14, and (v) 24 months, respectively. Only data from the low-dose steroid group in the Kim et al. study were used for this meta-analysis [9].

AF recurrence with steroids 2–3 days after RFCA

Three studies reported AF recurrence 2–3 days after RFCA [8,11,13]. Of these, one was an RCT that showed that steroids reduced AF recurrence [8], whereas the remaining two studies found no observable benefit [11,13]. Though insignificant, pooled analysis of the included studies demonstrated that patients treated with steroids had lower odds of AF recurrence when compared with the control group (OR = 0.46, 95% CI = 0.17–1.24, P=0.13; Figure 2). Similarly, subgroup analyses into two RCTs also showed that steroid use was not significantly associated with decreased risk of AF recurrence [8,13] (OR = 0.31, 95% CI = 0.08–1.16, P=0.08; Figure 2). The overall heterogeneity was low across subgroups (I2 = 39%).

Association between steroids and AF recurrence in 2–3 days after ablation
Figure 2
Association between steroids and AF recurrence in 2–3 days after ablation

Subgroup analysis based on study design was also presented.

Figure 2
Association between steroids and AF recurrence in 2–3 days after ablation

Subgroup analysis based on study design was also presented.

AF recurrence with steroids 1 month following RFCA

Three studies reported AF recurrence 1 month after RFCA [8,11,13]. Our analysis showed that the use of steroids post-RFCA is not associated with an increased risk of 1-month AF recurrence (OR = 0.92, 95% CI = 0.41–2.08, P=0.85; Figure 3). Subsequent analyses based on study design also revealed that steroid therapy was not associated with AF recurrence in 1 month after RFCA, whether in RCTs [8,13] (OR = 0.58, 95% CI = 0.28–1.18, P=0.13; Figure 3) or in the cohort study [11] (OR = 1.68, 95% CI = 0.93–3.06, P=0.09; Figure 3). However, the heterogeneity was found to be high across subgroups (I2 = 80%). To locate the origin of the heterogeneity, sensitivity analysis excluding one study at a time was performed. Doing so did not significantly alter the overall heterogeneity.

Association between steroids and AF recurrence in 1 month after ablation
Figure 3
Association between steroids and AF recurrence in 1 month after ablation

Subgroup analysis based on study design was also presented.

Figure 3
Association between steroids and AF recurrence in 1 month after ablation

Subgroup analysis based on study design was also presented.

AF recurrence with steroids 3 months following RFCA

Six studies reported AF recurrence 3 months after RFCA [9,10,12–15]. Of these, three studies [12,13,15] showed that steroids use reduced the risk of AF recurrence, whereas the remaining three studies [9,10,14] did not find any significant benefit. The pooled analysis of the included studies demonstrated that patients treated with steroids have lower odds of AF recurrence 3 months after RFCA when compared with controls (OR = 0.53, 95% CI = 0.31–0.90, P=0.02; Figure 4). When further subgroup analyses were conducted, steroid use was associated with decreased risk of AF recurrence in RCTs [12–14] (OR = 0.38, 95% CI = 0.22–0.63, P=0.0002; Figure 4) but not in cohort studies [9,10,15] (OR = 0.70, 95% CI = 0.32–1.53, P=0.37, Figure 4). The heterogeneity was low across subgroup (I2= 40%).

Association between steroids and AF recurrence in 3 months after ablation
Figure 4
Association between steroids and AF recurrence in 3 months after ablation

Subgroup analysis based on study design was also presented.

Figure 4
Association between steroids and AF recurrence in 3 months after ablation

Subgroup analysis based on study design was also presented.

AF recurrence with steroids 12–14 months following RFCA

Five studies reported AF recurrence 12–14 months after RFCA [8–11,14]. Of these, one study [8] demonstrated decreased risk of AF recurrence with the use of steroids with the remaining studies reporting a lack of benefit. Nevertheless, the pooled analysis demonstrated reduced odds of AF recurrence with steroid use (OR = 0.67, 95% CI = 0.47–0.95, P=0.02; Figure 5). Once again, subgroup analyses demonstrated statistically significant reduction in AF recurrence in RCTs [8,14] (OR = 0.51, 95% CI = 0.28–0.92, P=0.02, Figure 5), but not in cohort studies [9–11] (OR = 0.78, 95% CI = 0.51–1.20, P=0.25, I2 = 0%; Figure 5). The heterogeneity was low across subgroups (I2 = 24%).

Association between steroids and AF recurrence in 12–14 months after ablation
Figure 5
Association between steroids and AF recurrence in 12–14 months after ablation

Subgroup analysis based on study design was also presented.

Figure 5
Association between steroids and AF recurrence in 12–14 months after ablation

Subgroup analysis based on study design was also presented.

AF recurrence with steroids 24 months following RFCA

Only one study [13] reported AF recurrence 24 months after RFC but steroid use was not associated with significant difference in AF recurrence whether in univariate (HR = 1.03, 95% CI = 0.58–1.81, P=0.922) or multivariate analysis (HR = 0.97, 95% CI = 0.55–1.71, P=0.918).

Discussion

The main findings of this systematic review and meta-analysis are that steroid use is associated with a decreased risk of AF recurrence 3 and 12–14 months after RFCA. On the other hand, there seems to be no significant association between steroid therapy and risk of AF recurrence in 2–3 days, 1 and 24 months after RFCA.

However, we found a significant heterogeneity, which could have been attributed to the type of AF (paroxysmal/persistent), intensity of ECG monitoring on follow-up, lesion sets deployed, doses of steroids used, and the time points on follow-up at which recurrences were evaluated. This heterogeneity is likely responsible for the conclusion that short-term steroid use decreases AF recurrence at 3 and 12 months, but not at 2–3 days and 1 month. Effective doses or dosing intervals to decrease AF recurrence are not fully established, even in cardiac surgery studies.

Inflammation induced by ablation can promote acute AF recurrence [19], which plays an important role during this period, increasing oxidative stress, promoting fibrosis, and facilitating re-entry [20–23]. It has been demonstrated that colchicine is an effective and safe agent for preventing early AF recurrences after pulmonary vein isolation in patients with paroxysmal AF, associated with reduced CRP and IL-6 levels [24]. The use of steroid to prevent AF has mainly been evaluated in cardiothoracic surgery. Previous meta-analyses have reported that steroid treatment is associated with a decrease in more than 50% postoperative cases [25]. The use of steroids is beneficial in this regard given their anti-inflammatory properties. Indeed, the levels of inflammatory cytokines immediately post-ablation were lower in the steroid group compared with the control group [14]. Moreover, CRP levels 3 days after ablation were lower in the corticosteroid group [8,9]. Furthermore, Koyama et al. [8] reported that AF recurrence 1 month after RFCA was not related to changes in inflammatory markers such as CRP. However, factors other than CRP in the pro-inflammatory signaling cascade can mediate pro-fibrotic changes. Given the main role of inflammation in immediate and early AF recurrence after ablation, treatments targetting this process may have a great potential to ameliorate this adverse event improving prognosis. Steroids can inhibit pro-inflammatory response, suppress VEGF expression and inhibit fibroblast proliferation [26]. These effects can modulate the pro-arrhythmic substrate and reduce conduction defects [27].

The major cause of longer term recurrence may be associated with electrical reconnection between PVs and LA after apparently successful initial isolation. The occurrence of this reconnection results from deficiencies of the index ablation procedure [26]. Rizzo et al. observed that α-lipoic acid (ALA) therapy could reduce inflammation stress, but could not prevent AF recurrence at 12-month follow-up after catheter ablation [28]. In this study, we found that steroid therapy decreased the risk of AF recurrence in 12–14 months after RFCA. However, it seems fairly implausible that steroid use shortly after PVI could prevent re-conduction between the LA and PVs over the long term. First, structural and electrical remodeling takes place within a few hours of AF onset, whereas reverse remodeling after restoration of sinus rhythm occurs much more slowly [29]. The use of steroids may halt electrical or functional remodeling of the atria, thereby permitting reverse remodeling to occur. Second, AF also induces inflammation, which in turn can perpetuate AF [30]. Steroid therapy shortly after RFCA might halt the relationship between inflammation and AF, which may represent a vicious cycle. Third, gaps of sufficient cross-sectional dimensions within linear RF lesions may promote recovery of conduction [31]. Steroids can potentially prevent AF recurrence by suppressing the delayed extension of the RF lesion between the ablation points [12].

Indeed, Andrade et al. [10] suggested that steroids use remained independently associated with the high prevalence of dormant PV conduction unmasked by adenosine. Therefore, a balance of anti-inflammatory action and delayed extension of the RF lesion determines the net pro- or anti-arrhythmic effect of steroids. Moreover, ablation can lead to transient autonomic dysfunction by increasing the sympathetic tone and decreasing the parasympathetic tone [32]. These could promote arrhythmias by both triggered activity and re-entry [33].

Study limitations

Several potential limitations of this meta-analysis should be acknowledged. First, our analysis pooled together both RCTs and cohort studies, but subgroup analyses based on study design were also performed. Second, our study involved a relatively small number of subjects (n=992). Third, the moderate heterogeneity observed was only partially explained by study design, and other factors such as steroid dose may play a role. Steroid dosing was not differentiated in most of the included studies, it was therefore not possible to derive dose–response relationships between steroids and AF recurrence after ablation. Fourth, in most of studies, although we identified AF recurrence by using the ECG and Holter monitoring during follow-up, some asymptomatic intermittent AF events might have been missed. Fifth, less than one-third women were included in the studies. Thereby, data may not be applicable to female patients.

Conclusion

Our meta-analysis suggested that steroid use was associated with a decreased risk of early AF recurrence 3 and 12–14 months after ablation. No clear relationship was observed for 2–3 days, 1 and 24 months of follow-up. Further data are needed to clarify the clinical merit of this intervention in the long term, and provided the dose information of steroid for prevention of AF recurrence.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 81570298, 81270245 (to T.L.)]; the Tianjin Natural Science Foundation [grant number 16JCZDJC34900 (to T.L.)]; and the Clinical Assistant Professorship of the Croucher Foundation of Hong Kong (to G.T.).

Author contribution

M.L. designed the study; drafted and revised the manuscript; performed statistical analysis. M.G. performed statistical analysis and critically revised the manuscript. G.Bazoukis, K.P.L., P.K., G.Bisleri, G.L., B.G., K.H.C.L., and A.B. were responsible for data interpretation and critically revised the manuscript. T.L. was responsible for designing the study; data interpretation, and critically revised the manuscript.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • AF

    atrial fibrillation

  •  
  • CI

    confidence interval

  •  
  • CRP

    C-reaction protein

  •  
  • HR

    hazard ratio

  •  
  • LA

    left atrium

  •  
  • IL-6

    interleukin 6

  •  
  • NOS

    Newcastle–Ottawa scale

  •  
  • OR

    odd ratio

  •  
  • PV

    pulmonary vein

  •  
  • RCT

    randomized clinical trial

  •  
  • RF

    radiofrequency

  •  
  • RFCA

    RF catheter ablation

  •  
  • RR

    relative risk

  •  
  • VEGF

    vascular endothelial growth factor

References

References
1
Cardenas
M.
(
2007
)
Atrial fibrillation
.
Arch. Cardiol. Mex.
77
(
Suppl. 2
),
S2
9-S2-13
[PubMed]
2
Sopher
S.M.
and
Camm
A.J.
(
1996
)
Atrial fibrillation: maintenance of sinus rhythm versus rate control
.
Am. J. Cardiol.
77
,
24a
37a
[PubMed]
3
Oral
H.
,
Knight
B.P.
,
Ozaydin
M.
,
Tada
H.
,
Chugh
A.
and
Hassan
S.
(
2002
)
Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation
.
J. Am. Coll. Cardiol.
40
,
100
[PubMed]
4
Hagiwara
N.
(
2010
)
Inflammation and atrial fibrillation
.
Circ. J.
74
,
246
247
[PubMed]
5
Issac
T.T.
,
Dokainish
H.
and
Lakkis
N.M.
(
2007
)
Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data
.
J. Am. Coll. Cardiol.
50
,
2021
2028
[PubMed]
6
McCabe
J.M.
,
Smith
L.M.
,
Tseng
Z.H.
,
Badhwar
N.
,
Lee
R.J.
and
Scheinman
M.M.
(
2008
)
Protracted CRP elevation after atrial fibrillation ablation
.
Pacing Clin. Electrophysiol.
31
,
1146
1151
[PubMed]
7
Halonen
J.
,
Halonen
P.
,
Järvinen
O.
,
Taskinen
P.
,
Auvinen
T.
and
Tarkka
M.
(
2007
)
Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial
.
JAMA
297
,
1562
1567
[PubMed]
8
Koyama
T.
,
Tada
H.
,
Sekiguchi
Y.
,
Arimoto
T.
,
Yamasaki
H.
and
Kuroki
K.
(
2010
)
Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial
.
J. Am. Coll. Cardiol.
56
,
1463
1472
[PubMed]
9
Kim
D.R.
,
Won
H.
,
Uhm
J.S.
,
Kim
J.Y.
,
Sung
J.H.
and
Pak
H.N.
(
2015
)
Comparison of two different doses of single bolus steroid injection to prevent atrial fibrillation recurrence after radiofrequency catheter ablation
.
Yonsei Med. J.
56
,
324
331
[PubMed]
10
Andrade
J.G.
,
Khairy
P.
,
Nattel
S.
,
Vanella
A.
,
Rivard
L.
and
Guerra
P.G.
(
2013
)
Corticosteroid use during pulmonary vein isolation is associated with a higher prevalence of dormant pulmonary vein conduction
.
Heart Rhythm
10
,
1569
1575
11
Won
H.
,
Kim
J.Y.
,
Shim
J.
,
Uhm
J.S.
,
Pak
H.N.
and
Lee
M.H.
(
2013
)
Effect of a single bolus injection of low-dose hydrocortisone for prevention of atrial fibrillation recurrence after radiofrequency catheter ablation
.
Circ. J.
77
,
53
59
[PubMed]
12
Kim
Y.R.
,
Nam
G.B.
,
Kim
Y.G.
,
Hwang
K.W.
,
Choi
H.O.
and
Kim
S.H.
(
2012
)
The effect of short term steroid therapy for preventing atrial tachyarrhythmias during blanking period after catheter ablation of atrial fibrillation
.
Heart Rhythm
9
,
S343
13
Kim
Y.R.
,
Nam
G.B.
,
Han
S.
,
Kim
S.H.
,
Kim
K.H.
and
Lee
S.
(
2015
)
Effect of short-term steroid therapy on early recurrence during the blanking period after catheter ablation of atrial fibrillation
.
Circ. Arrhythm. Electrophysiol.
8
,
1366
1372
14
Iskandar
S.
,
Afzal
M.
,
Rajasingh
J.
,
Atkins
D.
,
Bommana
S.
and
Umbarger
L.
(
2016
)
Use of oral steroid and its effects on atrial fibrillation recurrence and inflammatory cytokines post ablation-the steroid AF study: a randomized control trial
.
J. Am. Coll. Cardiol.
67
,
674
[PubMed]
15
Sood
N.A.
,
Krishnan
G.M.
,
Coleman
C.I.
,
Kluger
J.
,
Anglade
M.
and
Clyne
C.A.
(
2011
)
Intravenous corticosteroid use is associated with reduced early recurrence of atrial fibrillation immediately following radiofrequency catheter ablation
.
J. Atr. Fibrillation
,
4
,
16
Won
H.
,
Uhm
J.S.
,
Shim
J.
,
Hwang
H.J.
,
Sung
J.H.
and
Kim
J.Y.
(
2012
)
Prevention of atrial fibrillation recurrence with single bolus injection of low dose corticosteroid after radiofrequency catheter ablation
.
Heart Rhythm
9
,
S277
17
Macle
L.
,
Andrade
J.
,
Vanella
A.
,
Nattel
S.
,
Rivard
L.
,
Guerra
P.G.
et al. 
(
2013
)
Prevalence and characteristics of spontaneous and adenosine induced acute PV reconnection associated with IV corticosteroid use during pulmonary vein isolation
.
Circulation
,
128
,
Suppl. 22
,
Abstract 9461
18
Belhassen
B.
(
2010
)
Corticosteroid therapy after catheter ablation of atrial fibrillation for an authentic “blanking period”
.
J. Am. Coll. Cardiol.
56
,
1472
1475
19
Koyama
T.
,
Sekiguchi
Y.
,
Tada
H.
,
Arimoto
T.
,
Yamasaki
H.
and
Kuroki
K.
(
2009
)
Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation
.
Am. J. Cardiol.
103
,
1249
1254
[PubMed]
20
Smit
M.D.
,
Maass
A.H.
,
De Jong
A.M.
,
Muller Kobold
A.C.
,
Van Veldhuisen
D.J.
and
Van Gelder
I.C.
(
2012
)
Role of inflammation in early atrial fibrillation recurrence
.
Europace
14
,
810
817
[PubMed]
21
Tse
G.
,
Yan
B.P.
,
Chan
Y.W.
,
Tian
X.Y.
and
Huang
Y.
(
2016
)
Reactive oxygen species, endoplasmic reticulum stress and mitochondrial dysfunction: the link with cardiac arrhythmogenesis
.
Front. Physiol.
7
,
313
[PubMed]
22
Tse
G.
,
Lai
E.T.
,
Lee
A.P.
,
Yan
B.P.
and
Wong
S.H.
(
2016
)
Electrophysiological mechanisms of gastrointestinal arrhythmogenesis: lessons from the heart
.
Front. Physiol.
7
,
230
[PubMed]
23
Tse
G.
,
Lai
E.T.
,
Yeo
J.M.
,
Tse
V.
and
Wong
S.H.
(
2016
)
Mechanisms of electrical activation and conduction in the gastrointestinal system: lessons from cardiac electrophysiology
.
Front. Physiol.
7
,
182
[PubMed]
24
Deftereos
S.
,
Giannopoulos
G.
,
Kossyvakis
C.
,
Efremidis
M.
,
Panagopoulou
V.
and
Kaoukis
A.
(
2012
)
Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: a randomized controlled study
.
J. Am. Coll. Cardiol.
60
,
1790
1796
[PubMed]
25
Marik
P.E.
and
Fromm
R.
(
2009
)
The efficacy and dosage effect of corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a systematic review
.
J. Crit. Care
24
,
458
463
[PubMed]
26
Andrade
J.G.
,
Khairy
P.
,
Verma
A.
,
Guerra
P.G.
,
Dubuc
M.
and
Rivard
L.
(
2012
)
Early recurrence of atrial tachyarrhythmias following radiofrequency catheter ablation of atrial fibrillation
.
Pacing Clin. Electrophysiol.
35
,
106
116
27
Tse
G.
and
Yeo
J.M.
(
2015
)
Conduction abnormalities and ventricular arrhythmogenesis: the roles of sodium channels and gap junctions
.
Int. J. Cardiol. Heart Vasc.
9
,
75
82
28
Sardu
C.
,
Santulli
G.
,
Santamaria
M.
,
Barbieri
M.
,
Sacra
C.
,
Paolisso
P.
et al. 
(
2017
)
Effects of α-lipoic acid on multiple cytokines and biomarkers and recurrence of atrial fibrillation within one year of catheter ablation
.
Am. J. Cardiol.
119
,
1382
1386
[PubMed]
29
Allessie
M.
,
Ausma
J.
and
Schotten
U.
(
2002
)
Electrical, contractile and structural remodeling during atrial fibrillation
.
Cardiovasc. Res.
54
,
230
246
[PubMed]
30
Marcus
G.M.
,
Smith
L.M.
,
Glidden
D.V.
,
Wilson
E.
,
McCabe
J.M.
and
Whiteman
D.
(
2008
)
Markers of inflammation before and after curative ablation of atrial flutter
.
Heart Rhythm
5
,
215
221
[PubMed]
31
Perez
F.J.
,
Wood
M.A.
and
Schubert
C.M.
(
2006
)
Effects of gap geometry on conduction through discontinuous radiofrequency lesions
.
Circulation
113
,
1723
1729
[PubMed]
32
Hsieh
M.H.
,
Chiou
C.W.
,
Wen
C.H.
,
Wu
C.H.
,
Tai
C.T.
and
Tsai
C.F.
(
1999
)
Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins
.
Circulation
100
,
2237
2243
[PubMed]
33
Tse
G.
(
2015
)
Mechanisms of cardiac arrhythmias
.
J. Arrhythmia
32
,
75
81
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

Supplementary data