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. 2020 Oct 1;15(10):e0239339. doi: 10.1371/journal.pone.0239339

Slit-based irrigation catheters can reduce procedure-related ischemic stroke in atrial fibrillation patients undergoing radiofrequency catheter ablation

Yun Gi Kim 1, Jaemin Shim 1,*, Ki Yung Boo 1, Do Young Kim 1, Kwang-No Lee 1, Jong-Il Choi 1, Young-Hoon Kim 1
Editor: Giuseppe Coppola2
PMCID: PMC7529237  PMID: 33002011

Abstract

Open irrigation ablation catheters are now the standard in radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Among various irrigation catheters, laser-cut slit-based irrigation system (Cool Flex and FlexAbility) has a unique design to cool the catheter tip more efficiently. We aimed to assess the safety of slit-based irrigation catheters regarding prevention of procedure-related ischemic complication in AF patients undergoing RFCA. The analysis was performed with Korea University Medicine Anam Hospital RFCA registry. Procedure-related ischemic complication was defined as ischemic stroke or transient ischemic attack (TIA) occurring within 30 days after RFCA. Patients were divided into 3 groups: non-irrigation, hole-based irrigation, and slit-based irrigation catheter groups. A total of 3,120 AF patients underwent first RFCA. Non-irrigation, non-slit-based irrigation, and slit-based irrigation catheters were used in 290, 1,539, and 1,291 patients, respectively. As compared with non-irrigation and non-slit-based irrigation catheter groups, slit-based irrigation catheter group had significantly older age, higher prevalence of non-paroxysmal AF, large left atrial size, and decreased left atrial appendage flow velocity. The CHA2DS2-VASc score was not different among the 3 groups. Procedure-related ischemic complication occurred in 17 patients (0.54%) with 16 ischemic strokes and 1 TIA event: 5/290 (1.72%), 11/1,539 (0.71%), and 1/1,291 (0.08%) events in non-irrigation, non-slit-based irrigation, and slit-based irrigation catheter groups, respectively (p = 0.001). Slit-based irrigation catheter was superior in direct comparison with non-slit-based irrigation catheter (0.71% vs. 0.08%; p = 0.009). Slit-based irrigation catheters were highly effective in preventing procedure-related ischemic complications.

Introduction

Radiofrequency catheter ablation (RFCA) for symptomatic atrial fibrillation (AF) is an established treatment which is associated with significantly improved quality of life [1]. Recent clinical trials also suggest that RFCA can improve not only quality of life but also hard clinical outcomes including all cause death in patients with both AF and heart failure [2, 3]. Claim data based retrospective data also suggest that RFCA is associated with reduced risk of ischemic stroke [4, 5]. Despite various benefits of RFCA in AF patients, RFCA is associated with several catastrophic complications such as procedure-related stroke or atrio-esophageal fistula [6, 7].

Time interval between occurrence of procedure-related stroke and correct diagnosis due to patient sedation delays appropriate therapy and significant proportion of patients with procedure-related stroke have permanent neurologic consequences. Optimal treatment modalities for procedure-related stroke are also not established since majority of these strokes are due to char formation during radiofrequency energy delivery [8, 9]. Char formation during radiofrequency energy delivery is thought to be related with tissue overheating and acute cellular damage [10]. Irrigation catheters were developed in order to reduce tissue overheating and char formation [11–13]. Among irrigation catheters, open-irrigation catheters showed lower interface temperature, thrombus, and steam pop compared with closed-loop irrigation catheters indicating greater interface cooling capability [14]. Open-irrigation catheters are further classified according to their shape: 6-holes, 12-holes, 56-holes, and slit-based irrigation system. Slit-based irrigation catheters have the largest irrigation space compared to other open-irrigation catheters. However, whether slit-based irrigation catheters are superior to other open-irrigation catheters in terms of stroke prevention remains largely unknown. We aimed to compare the risk of procedure-related ischemic complication among non-irrigation, non-slit-based irrigation, and slit-based irrigation catheters.

Methods

Patients

Consecutive AF patients undergoing RFCA at Korea University Medicine Anam Hospital between June 1998 and April 2019 were analyzed retrospectively. A total of 3,120 patients underwent their first RFCA for AF during the study period. There was no specific exclusion criteria and all patients who underwent their first-time RFCA in our institution were included. This study was approved by the Institutional Review Board of Korea University Medicine Anam Hospital (approval number: 2020AN0165). Written informed consent was waived due to the retrospective nature of the current study. The study protocol adheres to the ethical guidelines of the 2008 Declaration of Helsinki.

Ablation procedure and anticoagulation

The precise protocol for RFCA in our institution is published elsewhere [6]. Pre-procedural anticoagulation was performed with either warfarin or non-vitamin K oral anticoagulant (NOAC). Some patient was not prescribed with anticoagulants. However, we performed transesophageal echocardiography (TEE) in 92.9% of patients to rule out any thrombus or sludge in left atrium (LA) of left atrial appendage (LAA). Emptying, filling, and average flow velocity of the LAA were measured during TEE evaluation. Protocols of our pre-procedural imaging evaluation are published elsewhere [15]. Either computed tomography (CT) or magnetic resonance imaging (MRI) study was performed to assess the anatomy of the pulmonary veins and to create a three-dimensional reconstruction map using either EnSite NavX or CARTO systems. During RFCA, intravenous heparin was administered to maintain activated coagulation time between 300–350 seconds.

After index RFCA, anticoagulation with either warfarin or NOAC was performed for at least two months after the procedure. After two months, anticoagulation therapy was given to patients with CHA2DS2-VASc score ≥ 2. Anticoagulation was discontinued, at the operator’s discretion, if no AF was documented on regular Holter monitoring (every 3 months for the first year and every 6 months thereafter).

Definitions

Procedure-related ischemic complication was defined as any ischemic stroke or transient ischemic attack (TIA) which occurred within 30 days post-RFCA. Immediate procedure-related ischemic complication was defined as ischemic stroke or TIA within 3 days post-RFCA.

Ischemic stroke was defined as any neurologic symptom that persisted for more than 24 hours which could not be explained by other medical conditions. Transient ischemic attack was defined as any neurologic symptom that was not attributable to other medical cause, but resolved completely within 24 hours. If acute infarction was observed on brain CT or MRI, the event was classified as ischemic stroke despite complete restoration of neurologic symptoms. Neurologists confirmed the final diagnosis of ischemic stroke and TIA. Neurologic consequence of procedure-related stroke was classified into three stages: (i) None: no neurologic symptoms; (ii) Minimal: permanent neurologic symptoms which does not limit normal daily life; (ii) Significant: permanent neurologic symptoms which have significant limitation on normal daily life or occupation.

Irrigation system

Irrigation system of ablation catheters were classified into three groups: non-irrigation, non-slit-based irrigation, and slit-based irrigation catheters. Non-slit-based irrigation catheters included closed-loop irrigation catheters and hole-based open-irrigation catheters. Slit-based irrigation catheters were consisted of Cool Flex and FlexAbility catheter (Abbott, Chicago, IL, USA). Flow rate of the irrigation fluid was based on the manufacturer’s recommendations.

Statistical analysis

Continuous variables are expressed as mean ± standard deviation. Categorical variables are presented as percentile value. Unpaired t-test was used to compare continuous variables. Categorical variables were compared using either the chi-square test or Fisher’s exact test, as appropriate. Multivariate logistic regression analysis was performed to evaluate the impact of different type of irrigation system on procedure-related ischemic complications. Covariates were included in the multivariate model if significant difference was observed in the baseline characteristics or were a known risk factor for ischemic stroke or TIA. Statistical significance was based on p-value less than 0.05. SPSS version 24.0 (SPSS Inc., Armonk, NY, USA) was used for all statistical analyses.

Results

Patients

During June 1998 to April 2019, a total of 3,120 patients underwent their first RFCA for AF with 290 non-irrigation, 1,539 non-slit-based irrigation, and 1,291 slit-based irrigation ablation catheters. Baseline characteristics of the entire cohort are summarized in Table 1. Mean age was 55.74 ± 10.96 years and 78.9% were male. Previous history of thromboembolic events was observed in 8.4% of the patients and mean CHA2DS2-VASc score was 1.27 ± 1.26.

Table 1. Baseline characteristics of the study population.

Total Procedure-related ischemic complication (-) Procedure-related ischemic complication (+) p value
N = 3,120 n = 3,103 n = 17
Age (year) 55.74 ± 10.96 55.72 ± 10.97 59.29 ± 7.94 0.180
LA diameter (mm) 41.20 ± 6.04 41.18 ± 6.04 44.38 ± 5.44 0.035
Body mass index (kg/m2) 24.98 ± 3.07 24.98 ± 3.07 24.90 ± 2.41 0.912
CHA2DS2-VASc 1.27 ± 1.26 1.27 ± 1.27 1.35 ± 1.12 0.790
LV ejection fraction (%) 54.68 ± 6.14 54.68 ± 6.13 53.46 ± 6.84 0.425
E/e’ 8.79 ± 3.79 8.78 ± 3.80 10.10 ± 2.28 0.273
LAA flow velocity (cm/sec) 48.53 ± 21.43 48.58 ± 21.43 38.80 ± 19.98 0.078
SEC 19.5% 19.4% 40.0% 0.093
Non-paroxysmal AF 40.9% 40.8% 64.7% 0.046
Male sex 78.9% 78.9% 82.4% 0.725
Heart failure 6.5% 6.5% 5.9% > 0.999
Hypertension 38.0% 38.1% 35.3% 0.815
Diabetes 9.6% 9.6% 5.9% > 0.999
Stroke or TIA history 8.4% 8.3% 17.6% 0.165
Vascular disease 7.7% 7.7% 5.9% > 0.999
Substrate modification 45.5% 45.5% 62.5% 0.172
Pre-RFCA anticoagulation 60.4% 60.3% 82.4% 0.064
Post-RFCA anticoagulation 95.0% 95.0% 100.0% > 0.999
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SEC: spontaneous echo-contrast. Other abbreviations are the same as in the text.

Procedure-related ischemic complication

Procedure-related ischemic complication occurred in 17 patients: six patients had no permanent neurologic consequences and five patients had permanent neurologic symptoms which significantly limited their normal daily life. Mean CHA2DS2-VASc score was 1.35 ± 1.12 and 14 patients were male. Eleven (64.7%) patients had non-paroxysmal AF and substrate modification in addition to pulmonary vein isolation was performed in 64.7% of patients. Characteristics of these 17 patients with procedure-related stroke are summarized in Table 2. Baseline characteristics of patients with and without procedure-related stroke are compared in Table 1. Patients with procedure-related ischemic complication had larger LA diameter (44.38 ± 5.44 vs. 41.18 ± 6.04 mm; p = 0.035), higher proportion of non-paroxysmal AF (64.7% vs. 40.8%; p = 0.046).

Table 2. Patients who experienced peri-procedural ischemic complication.

RFCA Date Stroke / TIA Time to stroke or TIA (days from RFCA) Neurologic sequela Age Sex Non-Paroxysmal CHA2DS2-VASc Substrate modification Ablation Catheter
1 2000-04-17 Stroke 26 Minimal 61 M 0 0 0 Non-irrigation
2 2003-03-14 Stroke 28 Significant 53 F 0 2 0 Non-irrigation
3 2005-11-14 Stroke 3 Minimal 42 M 1 0 1 Non-irrigation
4 2005-12-08 Stroke 1 Minimal 66 M 1 2 1 Non-irrigation
5 2006-02-20 Stroke 4 None 52 M 1 3 1 Non-irrigation
6 2006-03-15 Stroke 1 Minimal 70 M 0 2 0 Chilli
7 2006-05-29 Stroke 1 Significant 60 M 1 0 1 Chilli
8 2008-12-10 Stroke 9 None 72 F 0 2 0 Celsius
9 2011-02-21 Stroke 0 Significant 67 M 0 1 0 Navistar
10 2012-06-07 Stroke 3 None 50 M 1 2 1 Celsius
11 2013-05-28 Stroke 0 Significant 55 M 1 0 1 Thermocool
12 2013-06-18 Stroke 0 Minimal 57 M 1 0 1 Thermocool
13 2017-04-06 Stroke 0 Minimal 57 M 1 1 1 SmartTouch
14 2017-04-13 Stroke 1 None 60 M 1 1 1 SmartTouch
15 2017-10-18 TIA 0 None 70 F 0 3 0 TactiCath
16 2018-08-16 Stroke 1 None 58 M 1 3 1 Cool Flex
17 2019-02-14 Stroke 0 Significant 58 M 1 1 1 TactiCath
59.29 ± 7.94 82.4% 64.7% 1.35 ± 1.12 64.7%
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Abbreviations are the same as in the text.

Distribution of patients who were treated with antiplatelets, warfarin, NOAC, or no antithrombotic agents before and after RFCA is depicted in Fig 1A and 1B. Type of antithrombotic medication did not affect the incidence of procedure-related ischemic complication (p = 0.261 for pre-RFCA and 0.810 for post-RFCA; Fig 2A and 2B).

Fig 1. Pre- and post-RFCA antithrombotic therapy.

Fig 1

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(A) Type of antithrombotic therapy received before RFCA. (B) Type of antithrombotic therapy received after RFCA. Abbreviations are the same as in the text.

Fig 2. Incidence of peri-procedural ischemic complication according to antithrombotic therapy.

Fig 2

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(A) Incidence of peri-procedural ischemic complication according to type of antithrombotic therapy received before RFCA. (B) Incidence of peri-procedural ischemic complication according to type of antithrombotic therapy received before RFCA. Abbreviations are the same as in the text.

Irrigation system

Baseline characteristics of patients who were ablated with slit-based irrigation (n = 1,291) vs. other catheters (n = 1,829) are summarized in Table 3. Those who were ablated with slit-based irrigation catheter were older (56.65 ± 10.62 vs. 55.10 ± 11.15 years; p < 0.001); had larger LA (41.63 ± 6.18 vs. 40.89 ± 5.93 mm; p = 0.001); lower LAA flow velocity (46.59 ± 21.63 vs. 50.08 ± 21.15 cm/sec; p < 0.001); and lower prevalence of spontaneous echo-contrast (17.0% vs. 21.5%; p = 0.002) and vascular disease (5.0% vs. 9.6%; p < 0.001); and higher prevalence of non-paroxysmal AF (45.5% vs. 37.7%; p < 0.001).

Table 3. Baseline characteristics of the study population according to ablation catheter used.

Slit-based Irrigation Other catheters p value
n = 1,291 n = 1,829
Age (years) 56.65 ± 10.62 55.10 ± 11.15 < 0.001
LA diameter (mm) 41.63 ± 6.18 40.89 ± 5.93 0.001
Body mass index (kg/m2) 25.01 ± 3.10 24.96 ± 3.05 0.608
CHA2DS2-VASc 1.25 ± 1.22 1.29 ± 1.29 0.425
LV ejection fraction (%) 54.52 ± 5.93 54.80 ± 6.28 0.213
E/e’ 8.78 ± 3.27 8.79 ± 4.18 0.931
LAA flow velocity (cm/sec) 46.59 ± 21.63 50.08 ± 21.15 < 0.001
SEC 17.0% 21.5% 0.002
Non-paroxysmal AF 45.5% 37.7% < 0.001
Male sex 78.9% 78.9% > 0.999
Heart failure 5.9% 7.0% 0.216
Hypertension 36.9% 38.8% 0.289
Diabetes 9.0% 10.1% 0.316
Stroke or TIA history 8.7% 8.1% 0.599
Vascular disease 5.0% 9.6% < 0.001
Substrate modification 44.9% 46.0% 0.562
Pre-RFCA anticoagulation 67.3% 55.6% < 0.001
Post-RFCA anticoagulation 97.2% 93.5% < 0.001
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SEC: spontaneous echo-contrast. Other abbreviations are the same as in the text.

One procedure-related ischemic complication occurred in patients who were ablated with slit-based irrigation (0.08%) whereas 16 events occurred in patients ablated with other catheters (0.87%; p = 0.003; Fig 3A). When classified into three groups, non-irrigation catheters had highest incidence of procedure-related ischemic complication (1.72%) followed by non-slit-based irrigation catheters (0.71%) and slit-based irrigation catheters (0.08%) (p = 0.001; Fig 3B). Slit-based irrigation catheter was also superior in direct comparison with non-slit-based irrigation catheter (0.71% vs. 0.08%; p = 0.009). Incidence of immediate procedure-related ischemic complication (occurring within 3 days of post-RFCA) also differed significantly according to catheter type (Fig 3C and 3D). The results were identical when closed-loop irrigation catheters were classified as non-irrigation catheters (S1 Fig). Multivariate model revealed that use of slit-based irrigation catheter was the only significant predictor of procedure-related ischemic complication (Table 4). The influence of chronological variations in the use of different type of ablation catheters were also adjusted and type of ablation catheter remained the only independent variable for procedure-related ischemic complication (S1 and S2 Tables).

Fig 3. Incidence of peri-procedural ischemic complication according to catheter type.

Fig 3

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(A, B) Incidence of peri-procedural ischemic complication according to catheter type. (C, D) Incidence of immediate peri-procedural ischemic complication according to catheter type.

Table 4. Multivariate model for procedure-related ischemic complication.

Model 1 (event n = 15) Model 2 (event n = 17)
OR (95% CI) p value OR (95% CI) p value
Slit-based irrigation catheter 0.073 (0.009–0.562) 0.012 0.070 (0.009–0.536) 0.010
Age (year) 1.019 (0.962–1.079) 0.525 1.041 (0.989–1.097) 0.123
Sex 1.158 (0.306–4.380) 0.829 1.398 (0.389–5.032) 0.608
Heart failure 0.535 (0.064–4.482) 0.564 0.642 (0.083–4.977) 0.672
Hypertension 0.653 (0.208–2.056) 0.467 0.737 (0.258–2.108) 0.570
Diabetes mellitus 0.634 (0.081–4.980) 0.665 0.532 (0.069–4.109) 0.545
Previous ischemic stroke/TIA 1.732 (0.467–6.418) 0.411 1.504 (0.412–5.484) 0.536
Vascular disease 0.562 (0.071–4.466) 0.586 0.472 (0.060–3.685) 0.474
Non-paroxysmal AF 2.011 (0.462–8.747) 0.352 2.388 (0.678–8.409) 0.175
Substrate modification 0.732 (0.190–2.829) 0.651 0.796 (0.245–2.587) 0.704
Left atrial diameter (mm) 1.042 (0.945–1.149) 0.410 Not included Not included
Flow velocity of Left atrial appendage (cm/sec) 0.992 (0.960–1.025) 0.624 Not included Not included
SEC 1.385 (0.425–4.514) 0.589 Not included Not included
Pre-RFCA anticoagulation 5.151 (0.623–42.606) 0.128 2.375 (0.612–9.213) 0.211
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OR: odds ratio. Other abbreviations are the same as in the text.

Discussion

This study revealed that slit-based irrigation catheters can be effective in preventing procedure-related ischemic complication. Non-irrigation catheters showed highest risk for procedure-related ischemic complication and peri-procedural anticoagulation did not influence the risk for procedure-related ischemic complication. This data is the largest study to date analyzing safety issue of different irrigation systems and the first report demonstrating that irrigation systems can affect actual clinical stroke and TIA.

Ischemic complication during RFCA

Together with atrio-esophageal fistula, peri-procedural ischemic complication is most dreaded complication in AF patients undergoing RFCA [16, 17]. Since patients are in deep sedation or under general anesthesia, they cannot complain any neurologic symptoms when their cerebral arteries are occluded by thrombus or char. It takes several hours to complete the procedure and to recover from sedation or general anesthesia. Therefore, immediate revascularization was often not feasible. Furthermore, char formation during radiofrequency energy delivery makes harder thrombus material which makes revascularization therapy even more difficult. Although massive thrombus and char embolization during RFCA is a rare event, it is usually unrecoverable once occurred.

In our registry, five patient had significant neurologic sequelae defined as permanent neurologic symptoms limiting their normal daily life or occupation. Making ischemic stroke during treatment process of AF is an irony and 0.16% (5 among 3,120 patients) risk of having significant neurologic sequelae cannot be ignored.

Irrigation system

Local temperature elevation at the distal tip of ablation catheter during RFCA can result in temperature-dependent coagulum and char formation [10]. Histological review of these deposits revealed that it was consisted of denaturized and aggregated proteins rather than classical thrombus [10]. Therefore, reducing the temperature of distal electrode tip can potentially reduce char and thrombus formation.

In our registry, patients who were ablated with non-irrigation catheters showed highest risk of having procedure-related ischemic complication (1.72%) followed by non-slit-based irrigation (0.71%) and slit-based irrigation catheters (0.08%). Irrigation catheters were developed for two major reasons: formation of deeper lesions and reduction of ischemic complications [11]. Previous studies demonstrated that irrigation catheters were capable of making deeper lesions as compared with non-irrigation catheters [18, 19]. Although irrigation catheters have shown that coagulum formation can be reduced as compared to non-irrigation catheters, whether irrigation catheters can reduce clinical ischemic complications remains largely unknown [11].

Previous study reported that irrigated tip catheter did not reduce the incidence of symptomatic peri-procedural ischemic stroke [20]. However, the study enrolled patients from February 2001 to January 2008 where no slit-based irrigation catheters were available and our study demonstrated a lower incidence of procedure-related ischemic complication in slit-based irrigation catheters. Our study also showed lower incidence of procedure-related ischemic complication in non-slit-based irrigation catheters compared non-irrigation catheters (0.71% vs. 1.72%). The discrepancy between the two studies can be due to small sample size or different type of non-irrigation catheter (predominantly 8mm tip in the study by Scherr et al. and 4mm tip in ours).

Anticoagulation

Previous studies reported that continuation of anticoagulation in peri-operative period can reduce ischemic complication after RFCA [21, 22]. However, pre- or post-RFCA anticoagulation did not affect the incidence of peri-procedural ischemic complication in our study. Since embolic material formed by catheter ablation is mainly consisted of denaturized and aggregated proteins rather than classical thrombus, peri-procedural ischemic complication can still occur despite optimal anticoagulation therapy [10]. Indeed, heat induced protein denaturation and aggregation occurred independently from heparin concentration [10]. Nevertheless, optimal anticoagulation therapy should be done in peri-procedural period since denaturized material formed by radiofrequency energy can activate coagulation cascade. Both irrigation and anticoagulation are essential.

Limitations

Our results are based on retrospective analysis and therefore, are not free from intrinsic limitation of such analysis. Differences in baseline characteristics such as prevalence of vascular disease, AF type, LA diameter, and LAA flow velocity were observed between slit-based vs. non-slit based catheter groups although it was adjusted in the multivariate model. Unmeasured confounders might exist in our cohort. Systematic variations in the ascertainment of stroke or TIA over time might exist since our cohort extends more than 20 years. However, all stroke or TIA events were diagnosed by neurologists and this was centrally reviewed during data collection process. Although total patient number was large, the number of peri-procedural ischemic complication was small limiting statistical power. Slit-based irrigation catheters do not have contact-force sensing capability. Therefore, ablation parameters such as ablation index or lesion size index which has shown to improve ablation outcome cannot be utilized when using slit-based irrigation catheters [23, 24]. This can be a critical limitation of slit-based irrigation catheters and contact-force sensing ability should be added in the near future.

Conclusion

Slit-based irrigation catheters may reduce the risk of peri-procedural ischemic complication compared with non-irrigation or non-slit-based irrigation catheters. Our results should be tested in future clinical trials.

Supporting information

S1 Fig. Incidence of peri-procedural ischemic complication according to catheter type.

(PDF)

Click here for additional data file. (201.3KB, pdf)
S1 Table. Chronological difference among use of different catheter types.

(PDF)

Click here for additional data file. (238.7KB, pdf)
S2 Table. Multivariate model for procedure-related ischemic complication.

(PDF)

Click here for additional data file. (256.5KB, pdf)

Abbreviations

AF

atrial fibrillation

CT

computed tomography

MRI

magnetic resonance imaging

NOAC

non-vitamin K oral anticoagulant

LA

left atrium

LAA

left atrial appendage

RFCA

Radiofrequency catheter ablation

TEE

transesophageal echocardiography

TIA

transient ischemic attack

Data Availability

The data set cannot be made publicly available as it contains confidential patient information. The medical law of Republic of Korea strictly inhibits public sharing of individual patient-level data such as age, sex, body weight, or medical histories. Furthermore, Institutional Review Boards of Korea University Medical Center Anam Hospital also prohibits public sharing of individual patient-level data. However, these raw data can be provided to interested researchers upon approval of the Institutional Review Boards. The data can be requested from the Institutional Review Board of Korea University Medical Center Anam Hospital (contact via +82-02-920-6566, or +82-02-920-6086, eirbadmin@kumc.or.kr, or http://irb.kumc.or.kr).

Funding Statement

This work was supported by a grant from Korea University Anam Hospital, Seoul, Republic of Korea (grant No. K1922851). https://medicine.korea.ac.kr/web/www Y. G. Kim received the fune. Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Giuseppe Coppola

20 Jul 2020

PONE-D-20-15554

Slit-based Irrigation Catheters can Reduce Procedure-related Ischemic Stroke in Atrial Fibrillation Patients Undergoing Radiofrequency Catheter Ablation

PLOS ONE

Dear Dr. Shim

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Giuseppe Coppola

Academic Editor

PLOS ONE

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Reviewers' comments:

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1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript is quite interesting, BUT there is a big problem between what it is stated in the text and what one can read in table 3. For instance, in the text it is said that "slit - based" had "higher prevalence of SEC", but in table 3 incidence in slit based is 17% and in other is 21.5% (exatcly the opposite!).

Another important issue is that "other catheters" were less anticoagulated BEFORE ablation (55.6% vs 67.3%) and remained less anticoagulated AFTER ablation (93.5% vs 97.2%) and both values were statistically signiticant. Finally, incidence of vascular diseases was almost twice as high in "other catheters" group. This point should be highlighted in the discussion

Thus, or there is some mistake in the table or this could represent an important bias in judging superiority of the slit-based catheters. Authors must explain this discrepance.

Reviewer #2: Kim et al present the results of a retrospective study of peri-procedural ischemic stroke in 3120 patients undergoing first RF catheter ablation at a single center over 20 years. They conclude that use of slit-based irrigated catheters was associated with a lower incidence of ischemic stroke, and this was independent of other risk factors in multivariate analysis.

Questions and comments:

--How do the authors account for the possibility of changes in operative technique over the 20+ year period of analysis? If non-irrigated catheters were used predominantly in the early years, followed by non-slit-based irrigated catheters, followed by irrigated catheters, there might have been other differences that were not accounted for but correlated with the type of irrigation. For example, was the ACT target identical from 1998 to 2009? Was the timing of the heparin bolus the same, or did operators wait until after transseptal access was achieved in the early years? Was perioperative oral anticoagulation completely constant over this long time period? Were any changes made to sheath aspiration/flush technique, or number/type of diagnostic catheters? How many ablation catheters incorporated contact-force sensing? Was there a difference in warfarin vs NOAC use?

--Why do authors lump together internally irrigated catheters and external non-slit-based irrigation catheters? These are very different designs, in fact more dissimilar than slit-based and non-slit-based irrigation catheters, and it seems unwarranted to include them in a single group for analysis.

--How many of the 17 ischemic complications occurred >24 hours after the ablation procedure?

--What proportion of patients in the non-irrigated, non-slit-based irrigated and slit-based irrigated groups had substrate ablation in addition to PVI? Why was substrate ablation not included as a variable in the multivariate model presented in Table 4?

--The text says the slit-based irrigated group had higher prevalence of SEC, but Table 3 says it was lower. Which is correct? Why was SEC not included as a variable in the multivariate model presented in Table 4?

--Since irrigated catheters are no longer used for AF ablation, and the slit-based irrigated catheters analyzed here (CoolFlex and Flexability) do not incorporate contact-force sensing, the Discussion should include some comment on the trade-off of giving up contact-force sensing for slit-based irrigation, including new lesion metrics (Ablation Index, Lesion Size Index) that rely on these catheters.

Reviewer #3: The authors use a retrospective analysis of a single center large database to provide data that slit-like irrigation is associated with reduced rates of thromboembolic complications following AF ablation compared to other irrigated and non-irrigated catheters. The overall number of patients undergoing ablation is large, although this database spans 20 years of practice with a number of systematic changes over time. Stroke or TIA occurred significantly less with irrigated catheters than non-irrigated catheters. More importantly, slit-like irrigation appeared to be associated with less events compared to non-slit irrigation catheters despite similar number of cases. If true, this is an important observation.

The major limitation is the contemporaneous changes in clinical practice, especially anticoagulation during the 20 years of analysis. As practice evolves, often a whole-system change occurs at a center making one catheter and non-fluoroscopic mapping system dominant for a particular time. This can make an untended impact on outcomes in a retrospective analysis like this. Specifically, the introduction and use of uninterrupted anticoagulation during this period. Specifically, the number of patients undergoing ablation with uninterrupted anticoagulation needs to be very similar between groups of irrigated catheters for any confidence that there is a real difference in the irrigation architecture as a mechanism of the difference in outcome. If this cannot be assured, it becomes very difficult to know if the difference should drive changes in practice.

The number of outcomes are very small. As such, a small difference in confounding practice (like OAC use during the procedure) can have a major impact.

As such, the authors need to make it clear if the catheter types, especially the different irrigated catheters, were used at the same time or overlapping time periods. More importantly, a clear analysis of the number of patients undergoing uninterrupted OAC is required.

It is recognized that the slit irrigation group had worse risk factors that would confound by making the thromboembolic rates higher in this group. It might also make the authors more likely to use uninterrupted OAC for this group.

There are other limitations in this kind of analysis that cannot be clarified including possible systematic differences in the ascertainment of stroke over time in a database.

What specific definition of stroke was used as opposed to TIA and mimickers like migraine? Ordinarily TIA is not used as a hard endpoint, although there is only one TIA among the outcomes.

Coolflex catheters do not have force measuring capabilities. As such, authors have traded off this function for different irrigation. This raises the importance of the veracity of this data as a change to a slit irrigation ablation eliminates an ablation technology important at many centers.

**********

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Reviewer #1: Yes: Giosue Mascioli, MD; FAIAC; FEHRA, FESC

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2020 Oct 1;15(10):e0239339. doi: 10.1371/journal.pone.0239339.r002

Author response to Decision Letter 0

19 Aug 2020

We appreciate your time and effort to review our manuscript.

We have uploaded a separate file containing our response to your comments.

Thank you.

Sincerely,

Jaemin Shim. MD.

Attachment

Submitted filename: Revision Letter.docx

Click here for additional data file. (203.3KB, docx)

Decision Letter 1

Giuseppe Coppola

4 Sep 2020

Slit-based Irrigation Catheters can Reduce Procedure-related Ischemic Stroke in Atrial Fibrillation Patients Undergoing Radiofrequency Catheter Ablation

PONE-D-20-15554R1

Dear Dr.  Shim,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Giuseppe Coppola

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The Authors adequately adressed all the issues elicited by the reviewers. Being a retrospective study, not all bias can be solved, but anyhow the results presented after this new analysis are interesting and convincing. In my opinion the manuscript can now be published as it is.

Reviewer #2: The authors have submitted a substantially improved version of this manuscript that adequately addresses my concerns.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Giosue Mascioli

Reviewer #2: No

Acceptance letter

Giuseppe Coppola

22 Sep 2020

PONE-D-20-15554R1

Slit-based Irrigation Catheters can Reduce Procedure-related Ischemic Stroke in Atrial Fibrillation Patients Undergoing Radiofrequency Catheter Ablation

Dear Dr. Shim:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Giuseppe Coppola

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Incidence of peri-procedural ischemic complication according to catheter type.

    (PDF)

    Click here for additional data file. (201.3KB, pdf)
    S1 Table. Chronological difference among use of different catheter types.

    (PDF)

    Click here for additional data file. (238.7KB, pdf)
    S2 Table. Multivariate model for procedure-related ischemic complication.

    (PDF)

    Click here for additional data file. (256.5KB, pdf)
    Attachment

    Submitted filename: Revision Letter.docx

    Click here for additional data file. (203.3KB, docx)

    Data Availability Statement

    The data set cannot be made publicly available as it contains confidential patient information. The medical law of Republic of Korea strictly inhibits public sharing of individual patient-level data such as age, sex, body weight, or medical histories. Furthermore, Institutional Review Boards of Korea University Medical Center Anam Hospital also prohibits public sharing of individual patient-level data. However, these raw data can be provided to interested researchers upon approval of the Institutional Review Boards. The data can be requested from the Institutional Review Board of Korea University Medical Center Anam Hospital (contact via +82-02-920-6566, or +82-02-920-6086, eirbadmin@kumc.or.kr, or http://irb.kumc.or.kr).

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