Association between Ablation Technology and Asymptomatic Cerebral Injury Following Atrial Fibrillation Ablation LIU GUIJIAN, M.D.,* ZHU WENQING, M.D.,† WANG XINGGANG, M.D.,* YU YING, M.D.,* LI MINGHUI, PH.D.,* XIE YEQING, PH.D.,* CHEN RUIZHEN, PH.D.,* and GE JUNBO, PH.D.*,† From the *Key Laboratory of Viral Heart Diseases, Ministry of Public Health, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; and †Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Background: Asymptomatic cerebral injury (ACI) detected by diffusion-weighted magnetic resonance imaging (MRI) following atrial fibrillation (AF) ablation has been reported recently. The purpose of this study was to provide an overview of the incidence of ACI detected by MRI following AF ablation and to explore the association between ablation technology and ACI by systematically reviewing published trials. Methods and Results: PubMed, Web of Science, and the Cochrane Library Databases were systematically searched for studies exploring ACI detected by MRI following AF ablation. Incidence of ACI, odds ratios, and 95% confidence intervals (CIs) were pooled. We identified 21 eligible studies. The combined ACI incidence across all studies was 15.9% (95% CI: 0.124–0.202). We also did a subgroup analysis stratified by different technologies. The incidence of ACI stratified by ablation technology was 13.0%, 27.6%, 12.5%, 17.3%, and 32.6% of the irrigated radiofrequency (RF), multielectrode-phased RF pulmonary vein ablation catheter (PVAC), cryoballoon, laser balloon, and nMARQTM groups, respectively. Conclusions: The incidence of ACI following AF ablation with PVAC was higher than with other technologies. Uninterrupted oral anticoagulant (OAC) during the procedure could lower the incidence of ACI. It seems prudent not to interrupt OACs during the procedure. In addition, intraprocedural activated clotting time was associated with ACI. Different MRI diagnostic criteria for ACI also influenced the results. To facilitate the future research, a generally accepted definition for silent cerebrovascular ischemia suitable to different kinds of MRI is needed. (PACE 2014; 37:1378–1391) atrial fibrillation, asymptomatic cerebral injury, incidence, magnetic resonance imaging, catheter ablation, ablation technology
Introduction Catheter ablation has become an effective therapy for patients with symptomatic and drugrefractory atrial fibrillation (AF). Recently, however, asymptomatic cerebral injury (ACI) detected by diffusion-weighted magnetic resonance imaging (MRI) following AF ablation has been reported. The incidence of ACI detected by MRI after AF ablation varies from 1.7%1 to 52.2%.2
The authors have no financial relationships, or conflicts of interest to disclose. Address for reprints: Chen Ruizhen, PH.D., and Zhu Wenqing, M.D., Key Laboratory of Viral Heart Diseases, Ministry of Public Health, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, No.180, Fenglin Road, Xuhui District, Shanghai 200032, China. Fax: 86021-6422-3006; e-mail: [email protected] and [email protected] Received December 5, 2013; revised April 23, 2014; accepted April 27, 2014. doi: 10.1111/pace.12432
Several studies3–7 compared the different ablation technologies and reported the incidence of ACI changed according to the technology used. It was found that compared with the conventional irrigated radiofrequency (RF) or cryoballoon, multielectrode-phased RF pulmonary vein ablation catheter (PVAC)3,4 increased the risk of ACI. Nevertheless, since most of the studies included a relatively small number of patients and the results were not consistent, we thus performed a meta-analysis including the previous studies about ablation technology and ACI. Methods Literature Search We searched the PubMed, Web of Science, and the Cochrane Library Databases from inception through September 9, 2013 for studies involving MRI-detected ACI after ablation of AF. The search was performed with the term “atrial fibrillation” and “ablation” and “MRI.” No restrictions were imposed. Moreover, secondary
©2014 Wiley Periodicals, Inc. 1378
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ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
Figure 1. Flow diagram of study selection.
source documents were identified by manual search of reference lists of review articles, original publications, and editorials. Study Selection and Data Collection Studies that were included in our metaanalysis should meet the following criteria: (1) human subjects. (2) Catheter ablation for AF was performed. (3) Cerebral MRI was performed after the ablation procedure for every subject. When multiple studies shared the same subject population, we included only the most recent study. Studies were excluded if they were available as abstracts only because abstracts would not contain enough information to qualify for our meta-analysis. Two investigators (G.J.L and W.Q.Z) independently screened each citation for inclusion. Two reviewers (G.J.L and W.Q.Z) independently reviewed the full-text articles of potentially relevant studies to determine their eligibility. Discrepancies between them were resolved by discussion with the entire group. We extracted the following data from the included studies: publication year, the first author, geographic area, number of patients, the baseline characteristics of
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the study population, features of the study design, and the technology of ablation of AF, catheter ablation strategy, the data we need in our metaanalysis. Quality Assessment We assessed non-randomized control trials (non-RCTs) using key study design components presented in the Newcastle-Ottawa Scale. If the study population included both paroxysmal atrial fibrillation (PAF) and persistent AF, we considered the representativeness of the study population was adequate and gave two stars. If the study population included PAF only, we would give one star. If a study only performed postprocedural cerebral MRI and did not perform preprocedural cerebral MRI, we considered the case definition was not adequate. We assessed RCTs using the Jadad scale.8 Considering the Jadad scale neglected concealment of allocation, we modified the Jadad scales slightly. We assigned scores from 0 to 6 based on the following: (1) Was the study described as randomized? (2) Was the study described as double-blind? (3) Was there a description of withdrawals and dropouts? (4) If the method
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to generate the sequence of randomization was described and it was appropriate. (5) If the method of double blinding was described and it was appropriate. (6) If the investigators are unlikely to know in advance the allocation of each subject. We gave a score of 1 point for each “yes” and 0 points for each “no.” If the key point mentioned above was not described in the studies, we considered that the key point was not conducted.
Study Characteristics
Data Analysis Continuous variables are presented as mean ± standard deviation or median with first and third quartiles (Q1/Q3). Categorical data were expressed as counts or percentages. The incidences of ACI and corresponding 95% confidence intervals (CIs) were calculated for each cohort by extracting raw proportions. Summary of incidence estimates and corresponding 95% CIs were generated using a fixed-effects or random-effects model that was determined by the magnitude of heterogeneity. The odds ratios (ORs) and corresponding 95% CIs were calculated with fourfold table using data from the included studies and then were pooled. Heterogeneity was evaluated using the I2 statistic and χ 2 test. If the I2 value was above 50% and the P value was less than 0.10 in the χ 2 test, heterogeneity was assumed. In case of statistical heterogeneity, data were pooled using the randomeffects model, Otherwise the fixed-effects model was used. Sensitivity analysis and subgroup analysis were performed to identify the source of heterogeneity. Meta-regression analyses were conducted to determine whether the incidence of ACI was modulated by prespecified factors. All differences were considered significant at P < 0.05. A funnel plot was used to assess publication bias. Date analysis was conducted using the Comprehensive Meta-Analysis software Version 2.0 (Biostat, Englewood, NJ, USA).
Incidence
Results Literature Search Our electronic database search yielded 508 potentially relevant abstracts. Manual search further identified five relevant publications. After screening, we reviewed the full text of 25 reports. Of these articles, two9,10 were excluded because of a later report from the same subject population; two11,12 which did not meet our inclusion criterion were also excluded. Consequently, 21 trials were finally selected in this meta-analysis. The results of the search and selection process are shown in Figure 1.
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The 21 included studies were published between 2006 and 2014 involving a total of 1,786 patients. Their general characteristics are summarized in Tables I and II. Of those, 16 studies2–7,13–23 were from the European countries, three24–26 from Japan. Eighteen studies1–7,13–16,19–25 were prospective in design, two17,26 were respective, and one18 was cross-sectional. The results of quality assessment were presented in Table III.
Overall Incidence
The combined ACI incidence across all studies was 15.9% (95% CI: 0.124–0.202). Substantial heterogeneity across all studies was observed (I2 = 77%, P < 0.01); we thus used a randomeffects model (Fig. 2). To identify the source of heterogeneity, we also did subgroup analyses presented in Table IV. In 12 studies,2–5,7,13,15,16,18–22 oral anticoagulation therapy was interrupted before ablation, whereas five studies1,14,17,22,25 continued oral anticoagulation therapy throughout the procedure. In the subgroup analysis based on the procedural anticoagulation protocol, the incidence is lower in the uninterrupted group (0.155; 95% CI: 0.097–0.237) compared to the discontinued group (0.169; 95% CI: 0.119–0.234). Of the included studies, one study6 conducted cerebral examination with two types of MRI (1.5-Tesla and 3.0-Tesla), one study7 with 1.0Tesla MRI, 16 studies1,3–5,13–23,25 with 1.5-Tesla MRI, one study2 with 3.0-Tesla MRI, and two studies24,26 did not supply relevant information. We conducted a subgroup analysis stratified by the type of MRI. The pooled incidence of ACI detected by 1.5-Tesla MRI was 0.157 (95% CI: 0.119– 0.205). We also did a subgroup analysis stratified by single versus multicenter. The incidence was 12.3% in multicenter group and 16.5% in singlecenter group. In our meta-regression, prespecified factors that we investigated were mean age and female. Both of them failed to show a statistically significant interaction with ACI incidence in the meta-regression analysis. Irrigated RF Ablation Catheter
A total of 15 studies3–7,13,15,16,18–20,22,24–26 including 1,102 patients reported data on ACI incidence in patients receiving irrigated RF catheter ablation. Among them, ACI was detected by MRI in 135 patients. The highest incidence7 was 24.2% (95% CI: 0.13–0.42) and the lowest incidence26 was 3.3% (95% CI: 0.01–0.12). Using a fixed-effects model (I2 = 16.7%, Pheterogeneity = 0.266), the pooled incidence of ACI in patients
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2006 Germany
2010 Italy
2010 Germany
2010 Germany
2011 Germany
2011 International
2011 International
2011 Germany
2012 Japan
2012 Germany
Lickfett et al.19
Gaita et al.13
Schrickel et al.20
Schwarz et al.21
Deneke et al.18
Gaita et al.3
Herrera Siklody et al.4
Neumann et al.5
Kaseno et al.26
Rillig et al.16
Region
Year
Author
October 2014 70
60
89
74
108
86
21
53
232
20
Number of Patients
Ablation Technology Ablation Strategy
Prospective nest Irrigated RF ablation PVI case-control study Prospective Irrigated RF ablation PVI or PVI plus multicenter cohort linear lesions plus study atrial defragmentation Prospective nested Irrigated RF ablation PVI case-control study Prospective cohorts Irrigated RF ablation PVI study or cryoballoon A cross-sectional PVAC or irrigated RF PVI or PVI plus study ablation linear lesions plus CFAE Quasi-experiment Irrigated RF ablation PVI or PVAC or cryoballoon Prospective Irrigated RF ablation PVI multicenter or cryoballoon or cohorts study PVAC Quasi-experiment Cryoballoon or PVI or PVI plus irrigated RF linear lesions ablation catheter Retrospective cohort Irrigated RF ablation PVI study Quasi-experiment Irrigated RF ablation PVI
Study Design
Baseline Characteristics of Studies Included
Table I.
1
–
1
1
1
1
1–7
–
1
1†
Preprocedure
Continued
1
1
1
1–2
1
1–2
2–4
1
1
1
Postprocedure
The Timing of Cerebral MRI Conducted (Days) ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
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1382
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2013 Japan
2013 International
2013 Germany
2013 Germany 2014 Germany
Sakamoto et al.25
Verma1 et al.
Wieczorek et al.17
Wieczorek et al.14 Deneke et al.23 120 43
37
60
70
99
131
210
37
80 86
Number of Patients Irrigated RF ablation Irrigated RF ablation or cryoballoon or laser balloon Cryoballoon or RF balloon Irrigated RF ablation
Ablation Technology
PVI
PVI PVI
Ablation Strategy
Prospective nested CFAE or PVI plus case-control study CFAE Prospective nested Irrigated RF ablation PVI or PVI plus case-control study linear lesions plus CFAE RCT Irrigated RF ablation PVI or laser balloon or cryoballoon Prospective nested Irrigated RF ablation PVI or PVI plus case-control study CFAE Prospective, PVAC PVI multicenter, cohort study Retrospective nested PVAC PVI case-control study RCT PVAC PVI Prospective cohorts nMARQTM PVI study
RCT
RCT Quasi-experiment
Study Design
1 1
1 1
1
2
57% 63% NA
52 ± 10 60 ± 8 58 ± 10 59 ± 13 52 ± 12 54.2 ± 9.2 60 ± 9 59 ± 12 58 ± 8 56 ± 10 61 ± 9 >66 (64/67) 56 (47/63) NA
64.5 (55/69) 60.5 (56/68) 53 ± 10 57 ± 12
Male
Age
50% 60% 100% 100%
100% 61% 59% 100% 89% NA 58% 68% 100% 100% 62% 100% 78% NA
PAF
75% 64% 60% 52%
50% 52% 48% 83% 47% 35% NA NA 42% 48% 55% 57% 55% NA
HTN
8% 9% 20% 9%
NA 0% 5% NA NA 4.3% NA NA NA NA NA 0% 5% NA
DM
0% 14% NA NA
NA NA NA 33% 2% 4.3% NA NA NA NA NA 14% 10% NA
CAD
Baseline Characteristics of Patients in the Studies
Table II.
65 (65/65) 65 (60/65) 62 ± 4 63 ± 5
NA NA NA 57 ± 5 60 ± 9 NA NA NA NA NA NA 63 (59/63) 60 (57/64) NA
LVEF
288.5 ± 31.4 276.5 ± 36 286 ± 21 333 ± 24
NA 269 ± 28 282 ± 32 NA NA NA 347 ± 84 325 ± 87 312 ± 44 306 ± 53 NA 313 (280/339) 301 (277/322) NA
Intraprocedural Mean ACT ACT (Seconds)
Continued
discontinue
Discontinue (dabigatran) uninterrupted (warfarin) Discontinue
Discontinue Discontinue
Discontinue
Discontinue Discontinue
Discontinue
Discontinue Discontinue
OAC during the Procedure
ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
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October 2014 No ACI ACI No ACI ACI No ACI ACI No ACI All subject ACI No ACI ACI No ACI All subjects
All subjects ACI No ACI ACI
Subjects
± ± ± ± ± ± ± ± ± ± ± ± ± 10 8 8 6 10 8 11 9.7 3 2 8 9 12
78% 75% 70% NA NA 20% 23% 68% 90% 67% 68% 73% 60%
63% 69% 52% 88%
63 ± 9 64 (58/68) 63 (56/69) 62 ± 11
60 64 59 66 64 63 60 60.3 64 57 61 59 64
Male
Age
55% 38% 64% 100% 100% 20% 63% 87% 100% 100% NA NA 65%
23% 100% 100% 38%
PAF
49% 63% 56% 91% 68% 70% 52% 48% 30% 22% 62% 64% NA
66% 56% 52% 65%
HTN
14% 13% 5% 5% 7% 10% 6.7% 7% NA NA NA NA NA
9% 19% 10% 23%
DM
6% 19% 21% 23% 17% 0 20% 3% NA NA NA NA NA
8% 19% 24% 12%
CAD
No ACE 54 ± 3 53 ± 4 60 ± 10 59 ± 7 61 ± 11 64 ± 10 NA 58 ± 2 57 ± 1 62 ± 9 64 ± 5 62 ± 9
64 ± 7 NA NA ACE
LVEF
287 ± 30 335 ± 45 345 ± 32 274 ± 75 311 ± 180 323 ± 32 339 ± 43 405 ± 116 293 ± 20 260 ± 14 321 ± 31 331 ± 19 334 ± 78
NA 294 (270/308) 293 (259/329) 277 ± 22
Intraprocedural Mean ACT ACT (Seconds)
Discontinue(33%)
Uninterrupted
Uninterrupted Uninterrupted
Uninterrupted
Discontinue
Uninterrupted
Discontinue (dabigatran) Uninterrupted (warfarin)
NA Discontinue
OAC during the Procedure
Continuous data are presented as mean ± SD or median (Q1/Q3). ACI = asymptomatic cerebral injury; ACT = activated clotting time; AF = atrial fibrillation; CAD = coronary artery disease; DM = diabetes mellitus; HTN = hypertension; LVEF = left ventricular ejection; NA = no available; OAC = oral anticoagulant; PAF = paroxysmal atrial fibrillation.
Deneke et al. (2014)23
Wieczorek et al. (2013)14
Verma et al. (2013)1 Wieczorek et al. (2013)17
Sakamoto et al. (2013)25
Schmidt et al. (2013)7
Martinek et al. (2013 )22
Ichiki (2013)24
Wissner et al. (2013 )6 Herm et al. (2013)2
Study
Continued
Table II.
GUIJIAN, ET AL.
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Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Study Herm2 Schmidt7
Jadad Score 3 3
Clear Definition of Study Population
Yes Yes Yes Yes Cross-sectional Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes
Is It a Prospective Study No Yes No Yes Yes Yes Yes Yes Yes No Yes No Yes No Yes Yes Yes
Jadad Score 3 3
Is the Case Definition Adequate
Representativeness of the Study Population
Yes Yes Yes NA Yes Yes Yes Yes Yes Yes Yes Yes NA Yes Yes Yes Yes
Independent Blind Assessment of MRI
MRI = magnetic resonance imaging; NA = no available; RCT = randomized control trial. If the study population included both paroxysmal atrial fibrillation and persistent AF, we considered the representativeness of the study population was adequate and gave two stars. If the study population included paroxysmal atrial fibrillation only, we would give one star.
Lickfett (2006)19 Gaita (2010)13 Schrickel (2010)20 Schwarz (2010)21 Deneke (2011)18 Gaita (2011)3 Herrera Siklody (2011)4 Neumann (2011)5 Rillig (2012)16 Kaseno (2012)26 Wissner (2014)6 Ichiki (2013)24 Martinek (2013)22 Sakamoto (2013)25 Verma (2013)1 Wieczorek (2013)17 Deneke23 (2014) RCT Study Scaglione (2012)15 Wieczorek (2013)14
Study
Non-RCT
Quality Assessment
Table III.
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Figure 2. Forest plot of random-effects meta-analysis of the incidence of asymptomatic brain injury. I2 = 77%, Pheterogeneity < 0.01. CI = confidence interval. Table IV. Subgroup Analysis Group Study Design Multicenter Single-center OAC Uninterrupted Discontinue MRI 1.5 Tesla
No of Included Studies
Incidence 95%CI
P
I2
Pheterogenity
3 18
0.123 (0.067–0.218) 0.165 (0.125–0.216)
Background: Asymptomatic cerebral injury (ACI) detected by diffusion-weighted magnetic resonance imaging (MRI) following atrial fibrillation (AF) ablation has been reported recently. The purpose of this study was to provide an overview of the incidence of ACI detected by MRI following AF ablation and to explore the association between ablation technology and ACI by systematically reviewing published trials. Methods and Results: PubMed, Web of Science, and the Cochrane Library Databases were systematically searched for studies exploring ACI detected by MRI following AF ablation. Incidence of ACI, odds ratios, and 95% confidence intervals (CIs) were pooled. We identified 21 eligible studies. The combined ACI incidence across all studies was 15.9% (95% CI: 0.124–0.202). We also did a subgroup analysis stratified by different technologies. The incidence of ACI stratified by ablation technology was 13.0%, 27.6%, 12.5%, 17.3%, and 32.6% of the irrigated radiofrequency (RF), multielectrode-phased RF pulmonary vein ablation catheter (PVAC), cryoballoon, laser balloon, and nMARQTM groups, respectively. Conclusions: The incidence of ACI following AF ablation with PVAC was higher than with other technologies. Uninterrupted oral anticoagulant (OAC) during the procedure could lower the incidence of ACI. It seems prudent not to interrupt OACs during the procedure. In addition, intraprocedural activated clotting time was associated with ACI. Different MRI diagnostic criteria for ACI also influenced the results. To facilitate the future research, a generally accepted definition for silent cerebrovascular ischemia suitable to different kinds of MRI is needed. (PACE 2014; 37:1378–1391) atrial fibrillation, asymptomatic cerebral injury, incidence, magnetic resonance imaging, catheter ablation, ablation technology
Introduction Catheter ablation has become an effective therapy for patients with symptomatic and drugrefractory atrial fibrillation (AF). Recently, however, asymptomatic cerebral injury (ACI) detected by diffusion-weighted magnetic resonance imaging (MRI) following AF ablation has been reported. The incidence of ACI detected by MRI after AF ablation varies from 1.7%1 to 52.2%.2
The authors have no financial relationships, or conflicts of interest to disclose. Address for reprints: Chen Ruizhen, PH.D., and Zhu Wenqing, M.D., Key Laboratory of Viral Heart Diseases, Ministry of Public Health, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, No.180, Fenglin Road, Xuhui District, Shanghai 200032, China. Fax: 86021-6422-3006; e-mail: [email protected] and [email protected] Received December 5, 2013; revised April 23, 2014; accepted April 27, 2014. doi: 10.1111/pace.12432
Several studies3–7 compared the different ablation technologies and reported the incidence of ACI changed according to the technology used. It was found that compared with the conventional irrigated radiofrequency (RF) or cryoballoon, multielectrode-phased RF pulmonary vein ablation catheter (PVAC)3,4 increased the risk of ACI. Nevertheless, since most of the studies included a relatively small number of patients and the results were not consistent, we thus performed a meta-analysis including the previous studies about ablation technology and ACI. Methods Literature Search We searched the PubMed, Web of Science, and the Cochrane Library Databases from inception through September 9, 2013 for studies involving MRI-detected ACI after ablation of AF. The search was performed with the term “atrial fibrillation” and “ablation” and “MRI.” No restrictions were imposed. Moreover, secondary
©2014 Wiley Periodicals, Inc. 1378
October 2014
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ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
Figure 1. Flow diagram of study selection.
source documents were identified by manual search of reference lists of review articles, original publications, and editorials. Study Selection and Data Collection Studies that were included in our metaanalysis should meet the following criteria: (1) human subjects. (2) Catheter ablation for AF was performed. (3) Cerebral MRI was performed after the ablation procedure for every subject. When multiple studies shared the same subject population, we included only the most recent study. Studies were excluded if they were available as abstracts only because abstracts would not contain enough information to qualify for our meta-analysis. Two investigators (G.J.L and W.Q.Z) independently screened each citation for inclusion. Two reviewers (G.J.L and W.Q.Z) independently reviewed the full-text articles of potentially relevant studies to determine their eligibility. Discrepancies between them were resolved by discussion with the entire group. We extracted the following data from the included studies: publication year, the first author, geographic area, number of patients, the baseline characteristics of
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the study population, features of the study design, and the technology of ablation of AF, catheter ablation strategy, the data we need in our metaanalysis. Quality Assessment We assessed non-randomized control trials (non-RCTs) using key study design components presented in the Newcastle-Ottawa Scale. If the study population included both paroxysmal atrial fibrillation (PAF) and persistent AF, we considered the representativeness of the study population was adequate and gave two stars. If the study population included PAF only, we would give one star. If a study only performed postprocedural cerebral MRI and did not perform preprocedural cerebral MRI, we considered the case definition was not adequate. We assessed RCTs using the Jadad scale.8 Considering the Jadad scale neglected concealment of allocation, we modified the Jadad scales slightly. We assigned scores from 0 to 6 based on the following: (1) Was the study described as randomized? (2) Was the study described as double-blind? (3) Was there a description of withdrawals and dropouts? (4) If the method
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to generate the sequence of randomization was described and it was appropriate. (5) If the method of double blinding was described and it was appropriate. (6) If the investigators are unlikely to know in advance the allocation of each subject. We gave a score of 1 point for each “yes” and 0 points for each “no.” If the key point mentioned above was not described in the studies, we considered that the key point was not conducted.
Study Characteristics
Data Analysis Continuous variables are presented as mean ± standard deviation or median with first and third quartiles (Q1/Q3). Categorical data were expressed as counts or percentages. The incidences of ACI and corresponding 95% confidence intervals (CIs) were calculated for each cohort by extracting raw proportions. Summary of incidence estimates and corresponding 95% CIs were generated using a fixed-effects or random-effects model that was determined by the magnitude of heterogeneity. The odds ratios (ORs) and corresponding 95% CIs were calculated with fourfold table using data from the included studies and then were pooled. Heterogeneity was evaluated using the I2 statistic and χ 2 test. If the I2 value was above 50% and the P value was less than 0.10 in the χ 2 test, heterogeneity was assumed. In case of statistical heterogeneity, data were pooled using the randomeffects model, Otherwise the fixed-effects model was used. Sensitivity analysis and subgroup analysis were performed to identify the source of heterogeneity. Meta-regression analyses were conducted to determine whether the incidence of ACI was modulated by prespecified factors. All differences were considered significant at P < 0.05. A funnel plot was used to assess publication bias. Date analysis was conducted using the Comprehensive Meta-Analysis software Version 2.0 (Biostat, Englewood, NJ, USA).
Incidence
Results Literature Search Our electronic database search yielded 508 potentially relevant abstracts. Manual search further identified five relevant publications. After screening, we reviewed the full text of 25 reports. Of these articles, two9,10 were excluded because of a later report from the same subject population; two11,12 which did not meet our inclusion criterion were also excluded. Consequently, 21 trials were finally selected in this meta-analysis. The results of the search and selection process are shown in Figure 1.
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The 21 included studies were published between 2006 and 2014 involving a total of 1,786 patients. Their general characteristics are summarized in Tables I and II. Of those, 16 studies2–7,13–23 were from the European countries, three24–26 from Japan. Eighteen studies1–7,13–16,19–25 were prospective in design, two17,26 were respective, and one18 was cross-sectional. The results of quality assessment were presented in Table III.
Overall Incidence
The combined ACI incidence across all studies was 15.9% (95% CI: 0.124–0.202). Substantial heterogeneity across all studies was observed (I2 = 77%, P < 0.01); we thus used a randomeffects model (Fig. 2). To identify the source of heterogeneity, we also did subgroup analyses presented in Table IV. In 12 studies,2–5,7,13,15,16,18–22 oral anticoagulation therapy was interrupted before ablation, whereas five studies1,14,17,22,25 continued oral anticoagulation therapy throughout the procedure. In the subgroup analysis based on the procedural anticoagulation protocol, the incidence is lower in the uninterrupted group (0.155; 95% CI: 0.097–0.237) compared to the discontinued group (0.169; 95% CI: 0.119–0.234). Of the included studies, one study6 conducted cerebral examination with two types of MRI (1.5-Tesla and 3.0-Tesla), one study7 with 1.0Tesla MRI, 16 studies1,3–5,13–23,25 with 1.5-Tesla MRI, one study2 with 3.0-Tesla MRI, and two studies24,26 did not supply relevant information. We conducted a subgroup analysis stratified by the type of MRI. The pooled incidence of ACI detected by 1.5-Tesla MRI was 0.157 (95% CI: 0.119– 0.205). We also did a subgroup analysis stratified by single versus multicenter. The incidence was 12.3% in multicenter group and 16.5% in singlecenter group. In our meta-regression, prespecified factors that we investigated were mean age and female. Both of them failed to show a statistically significant interaction with ACI incidence in the meta-regression analysis. Irrigated RF Ablation Catheter
A total of 15 studies3–7,13,15,16,18–20,22,24–26 including 1,102 patients reported data on ACI incidence in patients receiving irrigated RF catheter ablation. Among them, ACI was detected by MRI in 135 patients. The highest incidence7 was 24.2% (95% CI: 0.13–0.42) and the lowest incidence26 was 3.3% (95% CI: 0.01–0.12). Using a fixed-effects model (I2 = 16.7%, Pheterogeneity = 0.266), the pooled incidence of ACI in patients
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2006 Germany
2010 Italy
2010 Germany
2010 Germany
2011 Germany
2011 International
2011 International
2011 Germany
2012 Japan
2012 Germany
Lickfett et al.19
Gaita et al.13
Schrickel et al.20
Schwarz et al.21
Deneke et al.18
Gaita et al.3
Herrera Siklody et al.4
Neumann et al.5
Kaseno et al.26
Rillig et al.16
Region
Year
Author
October 2014 70
60
89
74
108
86
21
53
232
20
Number of Patients
Ablation Technology Ablation Strategy
Prospective nest Irrigated RF ablation PVI case-control study Prospective Irrigated RF ablation PVI or PVI plus multicenter cohort linear lesions plus study atrial defragmentation Prospective nested Irrigated RF ablation PVI case-control study Prospective cohorts Irrigated RF ablation PVI study or cryoballoon A cross-sectional PVAC or irrigated RF PVI or PVI plus study ablation linear lesions plus CFAE Quasi-experiment Irrigated RF ablation PVI or PVAC or cryoballoon Prospective Irrigated RF ablation PVI multicenter or cryoballoon or cohorts study PVAC Quasi-experiment Cryoballoon or PVI or PVI plus irrigated RF linear lesions ablation catheter Retrospective cohort Irrigated RF ablation PVI study Quasi-experiment Irrigated RF ablation PVI
Study Design
Baseline Characteristics of Studies Included
Table I.
1
–
1
1
1
1
1–7
–
1
1†
Preprocedure
Continued
1
1
1
1–2
1
1–2
2–4
1
1
1
Postprocedure
The Timing of Cerebral MRI Conducted (Days) ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
1381
1382
October 2014
2013 Japan
2013 International
2013 Germany
2013 Germany 2014 Germany
Sakamoto et al.25
Verma1 et al.
Wieczorek et al.17
Wieczorek et al.14 Deneke et al.23 120 43
37
60
70
99
131
210
37
80 86
Number of Patients Irrigated RF ablation Irrigated RF ablation or cryoballoon or laser balloon Cryoballoon or RF balloon Irrigated RF ablation
Ablation Technology
PVI
PVI PVI
Ablation Strategy
Prospective nested CFAE or PVI plus case-control study CFAE Prospective nested Irrigated RF ablation PVI or PVI plus case-control study linear lesions plus CFAE RCT Irrigated RF ablation PVI or laser balloon or cryoballoon Prospective nested Irrigated RF ablation PVI or PVI plus case-control study CFAE Prospective, PVAC PVI multicenter, cohort study Retrospective nested PVAC PVI case-control study RCT PVAC PVI Prospective cohorts nMARQTM PVI study
RCT
RCT Quasi-experiment
Study Design
1 1
1 1
1
2
57% 63% NA
52 ± 10 60 ± 8 58 ± 10 59 ± 13 52 ± 12 54.2 ± 9.2 60 ± 9 59 ± 12 58 ± 8 56 ± 10 61 ± 9 >66 (64/67) 56 (47/63) NA
64.5 (55/69) 60.5 (56/68) 53 ± 10 57 ± 12
Male
Age
50% 60% 100% 100%
100% 61% 59% 100% 89% NA 58% 68% 100% 100% 62% 100% 78% NA
PAF
75% 64% 60% 52%
50% 52% 48% 83% 47% 35% NA NA 42% 48% 55% 57% 55% NA
HTN
8% 9% 20% 9%
NA 0% 5% NA NA 4.3% NA NA NA NA NA 0% 5% NA
DM
0% 14% NA NA
NA NA NA 33% 2% 4.3% NA NA NA NA NA 14% 10% NA
CAD
Baseline Characteristics of Patients in the Studies
Table II.
65 (65/65) 65 (60/65) 62 ± 4 63 ± 5
NA NA NA 57 ± 5 60 ± 9 NA NA NA NA NA NA 63 (59/63) 60 (57/64) NA
LVEF
288.5 ± 31.4 276.5 ± 36 286 ± 21 333 ± 24
NA 269 ± 28 282 ± 32 NA NA NA 347 ± 84 325 ± 87 312 ± 44 306 ± 53 NA 313 (280/339) 301 (277/322) NA
Intraprocedural Mean ACT ACT (Seconds)
Continued
discontinue
Discontinue (dabigatran) uninterrupted (warfarin) Discontinue
Discontinue Discontinue
Discontinue
Discontinue Discontinue
Discontinue
Discontinue Discontinue
OAC during the Procedure
ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
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1384
October 2014 No ACI ACI No ACI ACI No ACI ACI No ACI All subject ACI No ACI ACI No ACI All subjects
All subjects ACI No ACI ACI
Subjects
± ± ± ± ± ± ± ± ± ± ± ± ± 10 8 8 6 10 8 11 9.7 3 2 8 9 12
78% 75% 70% NA NA 20% 23% 68% 90% 67% 68% 73% 60%
63% 69% 52% 88%
63 ± 9 64 (58/68) 63 (56/69) 62 ± 11
60 64 59 66 64 63 60 60.3 64 57 61 59 64
Male
Age
55% 38% 64% 100% 100% 20% 63% 87% 100% 100% NA NA 65%
23% 100% 100% 38%
PAF
49% 63% 56% 91% 68% 70% 52% 48% 30% 22% 62% 64% NA
66% 56% 52% 65%
HTN
14% 13% 5% 5% 7% 10% 6.7% 7% NA NA NA NA NA
9% 19% 10% 23%
DM
6% 19% 21% 23% 17% 0 20% 3% NA NA NA NA NA
8% 19% 24% 12%
CAD
No ACE 54 ± 3 53 ± 4 60 ± 10 59 ± 7 61 ± 11 64 ± 10 NA 58 ± 2 57 ± 1 62 ± 9 64 ± 5 62 ± 9
64 ± 7 NA NA ACE
LVEF
287 ± 30 335 ± 45 345 ± 32 274 ± 75 311 ± 180 323 ± 32 339 ± 43 405 ± 116 293 ± 20 260 ± 14 321 ± 31 331 ± 19 334 ± 78
NA 294 (270/308) 293 (259/329) 277 ± 22
Intraprocedural Mean ACT ACT (Seconds)
Discontinue(33%)
Uninterrupted
Uninterrupted Uninterrupted
Uninterrupted
Discontinue
Uninterrupted
Discontinue (dabigatran) Uninterrupted (warfarin)
NA Discontinue
OAC during the Procedure
Continuous data are presented as mean ± SD or median (Q1/Q3). ACI = asymptomatic cerebral injury; ACT = activated clotting time; AF = atrial fibrillation; CAD = coronary artery disease; DM = diabetes mellitus; HTN = hypertension; LVEF = left ventricular ejection; NA = no available; OAC = oral anticoagulant; PAF = paroxysmal atrial fibrillation.
Deneke et al. (2014)23
Wieczorek et al. (2013)14
Verma et al. (2013)1 Wieczorek et al. (2013)17
Sakamoto et al. (2013)25
Schmidt et al. (2013)7
Martinek et al. (2013 )22
Ichiki (2013)24
Wissner et al. (2013 )6 Herm et al. (2013)2
Study
Continued
Table II.
GUIJIAN, ET AL.
PACE, Vol. 37
PACE, Vol. 37
October 2014
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Study Herm2 Schmidt7
Jadad Score 3 3
Clear Definition of Study Population
Yes Yes Yes Yes Cross-sectional Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes
Is It a Prospective Study No Yes No Yes Yes Yes Yes Yes Yes No Yes No Yes No Yes Yes Yes
Jadad Score 3 3
Is the Case Definition Adequate
Representativeness of the Study Population
Yes Yes Yes NA Yes Yes Yes Yes Yes Yes Yes Yes NA Yes Yes Yes Yes
Independent Blind Assessment of MRI
MRI = magnetic resonance imaging; NA = no available; RCT = randomized control trial. If the study population included both paroxysmal atrial fibrillation and persistent AF, we considered the representativeness of the study population was adequate and gave two stars. If the study population included paroxysmal atrial fibrillation only, we would give one star.
Lickfett (2006)19 Gaita (2010)13 Schrickel (2010)20 Schwarz (2010)21 Deneke (2011)18 Gaita (2011)3 Herrera Siklody (2011)4 Neumann (2011)5 Rillig (2012)16 Kaseno (2012)26 Wissner (2014)6 Ichiki (2013)24 Martinek (2013)22 Sakamoto (2013)25 Verma (2013)1 Wieczorek (2013)17 Deneke23 (2014) RCT Study Scaglione (2012)15 Wieczorek (2013)14
Study
Non-RCT
Quality Assessment
Table III.
ABLATION AND ASYMPTOMATIC CEREBRAL INJURY
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GUIJIAN, ET AL.
Figure 2. Forest plot of random-effects meta-analysis of the incidence of asymptomatic brain injury. I2 = 77%, Pheterogeneity < 0.01. CI = confidence interval. Table IV. Subgroup Analysis Group Study Design Multicenter Single-center OAC Uninterrupted Discontinue MRI 1.5 Tesla
No of Included Studies
Incidence 95%CI
P
I2
Pheterogenity
3 18
0.123 (0.067–0.218) 0.165 (0.125–0.216)
