Prognostic impact of catheter ablation in patients with asymptomatic atrial fibrillation

Tetsuma Kawaji; Satoshi Shizuta; Munekazu Tanaka; Shushi Nishiwaki; Takanori Aizawa; Shintaro Yamagami; Akihiro Komasa; Takashi Yoshizawa; Masashi Kato; Takafumi Yokomatsu; Shinji Miki; Koh Ono; Takeshi Kimura

doi:10.1371/journal.pone.0279178

Peer Review History

Original SubmissionJune 28, 2022
31 Aug 2022 Decision Letter - Elena G. Tolkacheva, Editor PONE-D-22-17051 Prognostic Impact of Catheter Ablation in Patients with Asymptomatic Atrial Fibrillation PLOS ONE Dear Dr. Shizuta, 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. Please address all comments indicated by the Reviewers. Please submit your revised manuscript by Oct 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Elena G. Tolkacheva, PhD Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found significant text overlap between your submission and previous work in the introduction and results. We would like to make you aware that copying extracts from previous publications, especially outside the methods section, word-for-word is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications. Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work. We will carefully review your manuscript upon resubmission and further consideration of the manuscript is dependent on the text overlap being addressed in full. Please ensure that your revision is thorough as failure to address the concerns to our satisfaction may result in your submission not being considered further. 3. Thank you for stating the following financial disclosure: "NO" At this time, please address the following queries: a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” c) If any authors received a salary from any of your funders, please state which authors and which funders. d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. Thank you for stating the following in your Competing Interests section: "NO" Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 6. Please include a copy of Table 1 and 2 which you refer to in your text on page 14 and 15. 7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments: We would ask you also comment on your closely related to previously published work: https://link.springer.com/article/10.1007/s00380-022-02023-0. Please in detail explain how you feel this work differs from your previously published work and why the two manuscripts represent independent studies. For further information on our submission guidelines on related manuscripts, please see http://journals.plos.org/plosone/s/submission-guidelines#loc-related-manuscripts. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 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: No Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: 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 ****** 4. 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 ****** 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 describes the impact of catheter ablation on clinical outcomes in asymptomatic and symptomatic patients with and without previous AF complications. The manuscript was well written. However, several points need to be re-considered. 1. The major problem with this study was very complicated and confusing. Moreover, the objectives and design of the study did not match. This study aimed to explore the prognostic impact of catheter ablation in asymptomatic AF patients compared with matched AF controls. However, this study included patients with symptomatic AF. The benefits of catheter ablation for symptomatic AF have been well-discussed. If the authors discuss the benefit of the catheter ablation in asymptomatic AF patients, the patients with symptomatic AF should not be included. 2. On page 8, you stated that “the detailed method of the matching was described in the previous report.” However, there was no citation. I don't know whether this matching method is reliable; can't you use a generally accepted method such as propensity score matching? 3. The ablation technique may differ since the study is from a much older period. Please describe the catheter used, mapping method, etc. 4. Further details regarding follow-up methods need to be described. 5. Please describe the ablation results and the medications used in the conservative group. 6. Previous AF complications included the hospitalization exacerbation of HF. These patients are supposed to be symptomatically stabilized by AAD and medications for AF. Can these patients be included in the asymptomatic group? Reviewer #2: The retrospective study is interesting and reveals that both patients with symptomatic and asymptomatic AF benefit from Af catheter ablation compared to conservative treatment. A limited benefit of ablation therapy is seen in the subset of asymptomatic Af patients who did not have any previous Af-related complications. In addition to retrospective matched analysis, some limitations need to be mentioned and discussed : Although, the benefit of AF ablation does not reach statistical significance in the subgroup of asymptomatic Af patients without prior complication, the log-rank p-value is 0.08. A larger prospective study needs to address this issue. Please provide the clinical baseline for all subgroups: As stated by the authors, the group of patients with asymptomatic AF without previous complications had more often persistent AF and were more frequently of younger age. This may imply that on a longer FU time would be necessary to detect the rare predefined major events in this younger patient group (death, hospitalisation for HF, stroke, haemorrhage). Moreover, as this group is younger, the vent rate is expected to be lower. Therefore, a higher number of patients is needed to detect statistical differences in major event rates, which are are in this young group. All four patient groups with prior AF-complications are rather small-sized patient groups ranging from 34 to 55 patients (table 2). ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. 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: No Reviewer #2: Yes: Amir JADIDI ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0279178.r001
Revision 1
20 Oct 2022 Author Response Response to Reviewers We deeply appreciate the editors and reviewers for their critically important comments and suggestions on our paper. We have revised our manuscript according to all those comments and suggestions. All essential changes in the revised manuscript were highlighted in red font. Our replies to the reviewers’ comments and suggestions are written below. Reviewer #1: The manuscript describes the impact of catheter ablation on clinical outcomes in asymptomatic and symptomatic patients with and without previous AF complications. The manuscript was well written. However, several points need to be re-considered. 1. The major problem with this study was very complicated and confusing. Moreover, the objectives and design of the study did not match. This study aimed to explore the prognostic impact of catheter ablation in asymptomatic AF patients compared with matched AF controls. However, this study included patients with symptomatic AF. The benefits of catheter ablation for symptomatic AF have been well-discussed. If the authors discuss the benefit of the catheter ablation in asymptomatic AF patients, the patients with symptomatic AF should not be included. Thank you for your important suggestion. As you indicated, the main purpose of the present study was to evaluate the clinical impact of catheter ablation for asymptomatic AF. However, we also think it important to evaluate the impact in the comparison between asymptomatic and symptomatic AF patients. Indeed, in the present study, the benefit of ablation for the primary endpoint was more prominent in symptomatic AF patients than in asymptomatic AF patients. Furthermore, the superiority of ablation over conservative management in asymptomatic AF was significant only in the high-risk subset of patients with previous AF-related complications. As you indicated, we admit that our study is a little complicated, so we have tried our best to improve the presentation style in the revised version of the manuscript to avoid confusion. Your understanding will be deeply appreciated. 2. On page 8, you stated that “the detailed method of the matching was described in the previous report.” However, there was no citation. I don’t know whether this matching method is reliable; can’t you use a generally accepted method such as propensity score matching? Thank you for the important comment. Ｗe added descriptions regarding the detailed method for matching between patients receiving catheter ablation and conservative management in the methods section, citing our previous report (Heart Vessels. 2022;37(7):1242-1254). In brief, we first selected a patient in the ablation group and attempted to find a matched control patient based on the prespecified 6 clinical risks; 1) age on the date of first AF documentation; 2) sex; 3) date of first AF documentation; 4) types of AF; 5) EHRA symptom grades (1 to 4); and 6) prior history of HF. Although propensity score matching was not used, we made meticulous efforts to find out the appropriate control group of patients with conservative management. However, because we could not perfectly match the patients, there was an imbalance in the prevalence of low body weight, history of malignancy, and CKD between the ablation and conservative groups even after matching. Therefore, we performed multivariate analysis using the Cox proportional hazard model to adjust those imbalances. We added descriptions regarding this point in the limitations section, as pasted below. <Methods> The current study was a post-hoc subgroup analysis of the previously reported risk-matched study.8 Among 4398 patients with diagnosis of AF in Kyoto University Hospital between January 2005 and March 2015, we performed 1:1 matching to find out an appropriate control patient for a given patient in the ablation group with a prespecified method as follows. First, we selected a patient in the ablation group and attempted to find a matched control patient for the selected patient in the ablation group based on the following clinical information; 1) age on the date of first AF documentation (acceptable range: ± 5 years); 2) sex; 3) date of first AF documentation (acceptable range: ± 365 days); 4) types of AF (paroxysmal or chronic); 5) European Hear Rhythm Association (EHRA) symptom grades (1 to 4); and 6) prior history of HF. When we could not find a matched control patient, the selected patient in the ablation group was excluded from the matched analysis. The control patient who had already been chosen was not matched to another patient in the ablation group to ensure 1:1 matching. Finally, we identified 1074 matched patients (537 patients in the ablation group and 537 patients in the conservative group). The detailed method of the matching was described in the previous report.8 In the present post-hoc subgroup study, we separately assessed the impact of catheter ablation on clinical outcomes in asymptomatic and symptomatic patients with and without previous AF-related complications (ischemic stroke or HF hospitalization).(Line 22 in Page 5 – Line 12 in Page 6) <Limitations> The first, the most critical limitation was the imbalance of baseline characteristics between the ablation group and the conservative group even after matching. The multivariable analyses might have not adequately eliminated the influence of unmeasured confounders in evaluating the impact of catheter ablation on the primary outcome measure. (Line 22-26 in Page 13) 3. The ablation technique may differ since the study is from a much older period. Please describe the catheter used, mapping method, etc. Thank you for the suggestion. As you indicated, the duration of patient enrollment in the present study was long, 11 years. Actually, the ablation catheter used for PVI changed over time during the period. However, the therapeutic strategy of AF ablation in our center was essentially same during the period, i.e., PVI mostly by RFCA with double circular catheters along with routine tricuspid valve isthmus ablation. Cryoballoon PVI was performed only in 4.4% of patients. We added the following descriptions in the methods section and also added S1 Table in the Supplementary materials. <Methods> Pulmonary veins isolation (PVI) was performed mostly by radiofrequency catheter ablation using double circular catheters, placing two 20-pollar circular-shaped catheters (Lasso, Biosense Webster or Orbiter PV, C.R. Bard Electrophysiology, Lowell, MA, USA) in ipsilateral superior and inferior pulmonary veins (S1 Table). An 8-mm tip ablation catheter (Fantasista, Japan Lifeline, Tokyo, Japan and NAVISTAER, Biosense Webster, CA, USA) was used from 2004 to 2009, and a 3.5-mm tip irrigation catheter (NAVISTAER THERMOCOOL, Biosense Webster, CA, USA) was used from 2010 to 2015. Cryoballoon (Arctic Front, Medtronic, Inc., MN, USA) was used for PVI only for paroxysmal AF since its introduction to Japan in 2014. Tricuspid valve isthmus ablation was routinely performed regardless of the presence of typical atrial flutter. Superior vena cava was isolated when it was deemed necessary. Complex fractionated atrial electrogram guided ablation was performed when sinus restoration was not obtained after PVI. Additional left atrial linear ablations were performed for sustained atrial tachycardias during the procedure.(Line 24 in Page 6 - Line 10 in Page 7) <Supplementary material> S1 Table: Details of ablation procedure Ablation group N=537 Pulmonary vein isolation 537 (100%) RFCA 513 (95.6%) Cryoballoon 24 (4.4%) Superior vena cava isolation 144 (26.8%) Complex fractionated atrial electrogram guided ablation 152 (28.3%) Tricuspid valve isthmus linear ablation 509 (94.8%) Mitral valve isthmus linear ablation 14 (2.6%) Non-pulmonary vein foci ablation 7 (1.3%) RFCA=radiofrequency catheter ablation. 4. Further details regarding follow-up methods need to be described. Thank you for your important comment. Patients in the conservative group were followed mostly by the referring physicians at the local clinics without a prespecified follow-up protocol. On the other hand, most patients in the ablation group were followed with the recommended follow-up protocol at our hospital or affiliated hospitals. This difference in the follow-up methods between the groups might have influenced the study results. We added the following descriptions in the methods and limitations sections. <Methods> Ethics Follow-up information was obtained by review of hospital-chart and contact by letters and/or phone-call to the patient, relatives, and/or referring physicians. The follow-up protocol in the ablation groups was described in the next section. On the other hand, there were no prespecified follow-up protocol in the conservative group because the present study was a retrospective analysis. The study protocol was approved by the institutional review board in Kyoto University Hospital. Written informed consent for the catheter ablation procedure and follow-up was obtained from all patients in ablation group and we got consent for the enrollment to the study from all patients in the conservative group at the time of follow-up contact. (Line 13 - 22 in Page 6) <Methods> A 12-lead electrocardiogram was routinely measured at each clinical visit and 24-hour Holter monitoring was recommended at 3-, 6-, 12-month and yearly thereafter. Antiarrhythmic drug was discontinued before ablation procedure, and was restarted only when recurrent atrial tachyarrhythmias were detected. The second ablation was recommended to patients with recurrent atrial tachyarrhythmias after the blanking period of 3 months. Oral anticoagulant (OAC) was continued for at least 3 months after procedure. Thereafter, discontinuation of OAC in patients without arrhythmia recurrence was left to the discretion of the attending physician. (Line 11 - 17 in Page 7) <Limitations> Second, patients in the conservative group were followed mostly by the referring physicians at the local clinics without a prespecified follow-up protocol, whereas most patients in the ablation group were followed with the recommended follow-up protocol at our hospital or affiliated hospitals, which might have influenced the study results. (Line 26 in Page 13- 4 in Page 14) 5. Please describe the ablation results and the medications used in the conservative group. Thank you for the important comment. According to your suggestion, we added the following Tables and Figures showing the details of ablation results and medications, as pasted below. S1 Table: Details of ablation procedure Ablation group N=537 Pulmonary vein isolation 537 (100%) RFCA 513 (95.6%) Cryoballoon 24 (4.4%) Superior vena cava isolation 144 (26.8%) Complex fractionated atrial electrogram guided ablation 152 (28.3%) Tricuspid valve isthmus linear ablation 509 (94.8%) Mitral valve isthmus linear ablation 14 (2.6%) Non-pulmonary vein foci ablation 7 (1.3%) RFCA=radiofrequency catheter ablation. Table 1: Baseline characteristics comparing conservative versus ablation groups in asymptomatic and symptomatic AF patients. Note: Only the information regarding medications at baseline are shown here Baseline characteristics Asymptomatic Symptomatic Conservative group N=207 Ablation group N=207 P value Conservative group N=330 Ablation group N=330 P value Medications Oral anticoagulant 169 (81.6%) 207 (100%) <0.001 219 (66.4%) 330 (100%) <0.001 Warfarin 104 (50.2%) 104 (50.2%) 1.00 109 (33.0%) 175 (53.0%) <0.001 DOACs 65 (31.4%) 103 (49.8%) <0.001 112 (33.9%) 155 (47.0%) <0.001 Antiplatelets 50 (24.2%) 43 (20.8%) 0.41 75 (22.7%) 55 (16.7%) 0.049 Antiarrhythmic drugs 31 (15.0%) 45 (21.7%) 0.07 120 (36.4%) 118 (35.8%) 0.87 Beta blockers 82 (39.6%) 63 (30.4%) 0.05 107 (32.4%) 107 (32.4%) 1.00 Verapamil/diltiazem 34 (16.4%) 18 (8.4%) 0.02 67 (20.3%) 38 (11.5%) 0.002 Digitalis 30 (14.5%) 21 (10.1%) 0.18 32 (9.7%) 26 (7.9%) 0.41 ACEI/ARB 91 (44.0%) 100 (48.3%) 0.37 117 (35.5%) 138 (41.8%) 0.09 S1 Figure: Clinical outcomes comparing asymptomatic and symptomatic AF patients in the ablation group A) Event free rate from recurrent atrial tachyarrhythmias with a blanking period of 90 days after procedure B) Discontinuation of OAC S2 Figure: Clinical outcomes in asymptomatic AF patients of the ablation group comparing those with and without the previous AF complications A) Event free rate from recurrent atrial tachyarrhythmias with a blanking period of 90 days after procedure B) Discontinuation of OAC Previous AF complications included the hospitalization exacerbation of HF. These patients are supposed to be symptomatically stabilized by AAD and medications for AF. Can these patients be included in the asymptomatic group? Thank you for your important comment. As you indicated, it may be controversial to categorize patients without any AF-related symptoms at the enrollment of the study as asymptomatic when a history of HF hospitalization was present. However, in the EHRA report (Europace 2007;9:1006–23), AF-related symptoms are recommended to be assessed at the baseline (patient enrollment). Also, importantly, we graded the symptom status at the start of the previous study (Heart Vessels. 2022;37(7):1242-1254), because symptom status was one of the prespecified 6 clinical risk factors for the matching, as written previously at the bottom of Page 2 of this reply document. Your understanding will be deeply appreciated Reviewer #2: The retrospective study is interesting and reveals that both patients with symptomatic and asymptomatic AF benefit from Af catheter ablation compared to conservative treatment. A limited benefit of ablation therapy is seen in the subset of asymptomatic Af patients who did not have any previous Af-related complications. Thank you for your important comment on our paper. Our replies to your comments are written below. In addition to retrospective matched analysis, some limitations need to be mentioned and discussed : Although, the benefit of AF ablation does not reach statistical significance in the subgroup of asymptomatic Af patients without prior complication, the log-rank p-value is 0.08. A larger prospective study needs to address this issue. Thank you for your valuable comments. As you indicated, the benefit of catheter ablation in asymptomatic AF patients without previous AF complications was with marginal insignificance, presumably due to the relatively small number of patients. We added the following sentences in the limitations section. <Limitations> Third, this post-hoc subgroup analysis may have been underpowered especially in patients with the previous AF-related complications. (Line 4 - 5 in Page 14) Please provide the clinical baseline for all subgroups: As stated by the authors, the group of patients with asymptomatic AF without previous complications had more often persistent AF and were more frequently of younger age. This may imply that on a longer FU time would be necessary to detect the rare predefined major events in this younger patient group (death, hospitalisation for HF, stroke, haemorrhage). Moreover, as this group is younger, the vent rate is expected to be lower. Therefore, a higher number of patients is needed to detect statistical differences in major event rates, which are are in this young group. Thank you for your important comment. As you indicated, patients with previous AF complications had significantly higher cardiovascular risks and lower cardiac function relative to those without, regardless of AF symptoms. The differences in the baseline characteristics among 4 subgroups may have influenced the study results. However, the baseline characteristics of the ablation versus conservative groups were generally well balanced in all the subgroups. According to your suggestion, we added S3 and S4 Tables, as pasted below. We also added descriptions regarding this point in the results and the limitations sections. S3 Table: Baseline characteristics of asymptomatic and symptomatic AF patients with and without previous AF-related complications Asymptomatic No previous AF-related complications N=317 Asymptomatic With　previous AF-related complications N=97 Symptomatic No　previous AF-related complications N=584 Symptomatic With previous AF-related complications N=76 P value Age (years old) 65.8±6.4 67.4±7.7 66.0±8.8 69.2±7.6 <0.001 ≥ 75 years old 27 (8.5%) 14 (14.4%) 94 (16.1%) 21 (27.6%) <0.001 Women 49 (15.5%) 15 (15.5%) 199 (34.1%) 25 (32.9%) <0.001 Weight (kg) 65.7±11.8 62.4±13.3 62.1±12.7 ｗ <0.001 Low body weight 43 (14.3%) 28 (30.1%) 125 (22.8%) 23 (30.7%) <0.001 Non-paroxysmal AF 168 (53.0%) 64 (66.0%) 90 (15.4%) 14 (18.4%) <0.001 AF duration (years) 1.2 (0.4-4.3) 1.5 (0.5-5.3) 1.4 (0.4-3.7) 1.7 (0.5-4.7) 0.34 Hypertension 212 (66.9%) 71 (73.2%) 356 (61.0%) 53 (69.7%) 0.04 Diabetes 61 (19.2%) 22 (22.7%) 99 (17.0%) 16 (21.1%) 0.49 Previous AF-related complications 0 (0.0%) 97 (100%) 0 (0.0%) 76 (100%) <0.001 History of heart failure hospitalization 0 (0.0%) 37 (38.1%) 0 (0.0%) 76 (100%) <0.001 Ischemic stroke 0 (0.0%) 67 (69.1%) 0 (0.0%) 60 (79.0%) <0.001 CHA2DS2-VASc score 1.8±1.2 3.9±1.3 2.0±1.3 4.2±1.4 <0.001 ≥ 2 172 (54.3%) 95 (97.9%) 364 (62.3%) 75 (98.7%) <0.002 History of malignancy 317 (18.6%) 14 (14.4%) 98 (16.8%) 12 (15.8%) 0.77 eGFR (ml/min/1.73m2) 52.2±16.9 48.5±14.0 55.2±17.3 47.4±14.9 <0.001 ≤60 ml/min/1.73m2 230 (74.7%) 79 (83.2%) 364 (65.0%) 55 (75.3%) <0.001 Echocardiographic data Left ventricular ejection fraction (%) 63.1±11.0 59.1±15.9 66.4±10.0 64.3±12.3 <0.001 ≤ 40 % 11 (3.9%) 15 (16.1%) 9 (1.6%) 4 (5.5%) <0.001 Left atrial diameter (mm) 43.0±8.1 44.5±8.8 39.5±7.3 40.0±7.6 <0.001 ≥ 50 mm 45 (16.0%) 23 (25.0%) 53 (9.6%) 7 (9.6%) <0.001 Medications Oral anticoagulat 285 (89.9) 91 (93.8%) 481 (82.4%) 68 (89.5%) <0.001 Warfarin 143 (45.1%) 65 (67.0%) 249 (42.6%) 35 (46.1%) <0.001 Direct oral anticoagulants 142 (44.8%) 26 (26.8%) 234 (40.1%) 33 (43.4%) 0.01 Antiplatelet use 59 (18.6%) 34 (35.1%) 106 (18.2%) 24 (31.6%) <0.001 Anti-arrhythmic drugs 56 (17.7%) 20 (20.6%) 207 (35.5%) 31 (40.8%) <0.001 Beta blockers 111 (35.0%) 34 (35.1%) 183 (31.3%) 31 (40.8%) 0.33 Verapamil/diltiazem 42 (13.3%) 10 (10.3%) 92 (15.8%) 76 (17.1%) 0.39 Digitalis 35 (11.0%) 16 (16.5%) 50 (8.6%) 8 (10.5%) 0.13 ACEI/ARB 142 (44.8%) 49 (50.5%) 222 (38.0%) 33 (43.4%) 0.05 S4 Table: Baseline characteristics comparing conservative and ablation groups in asymptomatic AF patients with and without previous AF-related complications Baseline characteristics Previous AF-related complications No Previous AF-related complications Conservative group N=42 Ablation group N=55 P value Conservative group N=165 Ablation group N=152 P value Age (years old) 67.5±8.4 67.4±7.3 0.96 66.0±6.5 65.6±6.3 0.53 ≥ 75 years old 7 (16.7%) 7 (12.7%) 0.59 14 (8.5%) 13 (8.6%) 0.98 Women 5 (11.9%) 10 (18.2%) 0.39 27 (16.4%) 22 (14.5%) 0.64 Weight (kg) 61.1±11.6 63.2±14.4 0.46 63.6±12.3 67.8±10.9 0.002 Low body weight 13 (34.2%) 15 (27.3%) 0.47 31 (21.0%) 12 (7.9%) 0.001 Non-paroxysmal AF 26 (61.9%) 38 (69.1%) 0.46 90 (54.5%) 78 (51.3%) 0.56 AF duration (years) 1.3 (0.5-4.4) 2.1 (0.5-5.8) 0.20 1.3 (0.4-4.6) 1.0 (0.4-3.8) 0.43 Hypertension 31 (73.8%) 40 (72.7%) 0.91 103 (62.4%) 109 (71.7%) 0.08 Diabetes 11 (26.2%) 11 (20.0%) 0.47 38 (23.0%) 23 (15.1%) 0.07 Previous AF-related complications 42 (100%) 55 (100%) - 0 (0%) 0 (0%) - History of heart failure hospitalization 19 (45.2%) 18 (32.7%) 0.21 0 (0%) 0 (0%) - Ischemic stroke 25 (59.5%) 42 (76.4%) 0.08 0 (0%) 0 (0%) - CHA2DS2-VASc score 3.8±1.3 3.9±1.2 0.65 1.8±1.2 1.7±1.1 0.63 ≥ 2 40 (95.2%) 55 (100%) 0.18 93 (56.4%) 79 (52.0%) 0.43 History of malignancy 7 (16.7%) 7 (12.7%) 0.59 46 (27.9%) 13 (8.6%) <0.001 eGFR (ml/min/1.73m2) 48.7±15.5 48.3±12.9 0.89 51.6±18.9 52.9±14.6 0.50 ≤60 ml/min/1.73m2 31 (77.5%) 48 (87.3%) 0.21 109 (69.9%) 121 (79.6%) 0.049 Echocardiographic data Left ventricular ejection fraction (%) 55.0±16.4 62.0±15.1 0.04 64.6±11.2 61.8±10.7 0.03 ≤ 40 % 8 (21.1%) 7 (12.7%) 0.29 2 (1.5%) 9 (5.9%) 0.046 Left atrial diameter (mm) 45.8±10.3 43.6±7.6 0.24 43.9±9.3 42.3±6.7 0.09 ≥ 50 mm 11 (29.7%) 12 (21.8%) 0.39 26 (20.0%) 19 (12.5%) 0.09 Medications Oral anticoagulat 36 (85.6%) 55 (100%) 0.001 133 (80.6%) 152 (100%) <0.001 Warfarin 25 (59.5%) 40 (72.7%) 0.17 79 (47.9%) 64 (42.1%) 0.30 Direct oral anticoagulants 11 (26.2%) 15 (27.3%) 0.91 54 (32.7%) 88 (57.9%) <0.001 Antiplatelet use 14 (33.3%) 20 (36.4%) 0.76 36 (21.8%) 23 (15.1%) 0.12 Anti-arrhythmic drugs 5 (11.9%) 15 (27.3%) 0.06 26 (15.8%) 30 (19.7%) 0.35 Beta blockers 18 (42.9%) 16 (29.1%) 0.16 64 (38.8%) 47 (30.9%) 0.14 Verapamil/diltiazem 5 (11.9%) 5 (9.1%) 0.65 29 (17.6%) 13 (8.6%) 0.02 Digitalis 5 (11.9%) 11 (20.0%) 0.28 25 (15.2%) 10 (6.6%) 0.01 ACEI/ARB 19 (45.2%) 30 (54.6%) 0.36 72 (43.6%) 70 (46.1%) 0.67 <Methods> Patients with the previous AF-related complications had significantly higher cardiovascular risks and lower cardiac function than those without, regardless of AF symptoms (S3 Table). (Line 3 - 4 in Page 10) <Limitations> he first, the most critical limitation was the imbalance of baseline characteristics between the ablation group and the conservative group even after matching. The multivariable analyses might have not adequately eliminated the influence of unmeasured confounders in evaluating the impact of catheter ablation on the primary outcome measure. (Line 22 – 26 in Page 13) All four patient groups with prior AF-complications are rather small-sized patient groups ranging from 34 to 55 patients (table 2). Thank you for your important comment. As you indicated, the number of patients in the subgroups with previous AF complications were relatively small, as shown in S3 and S4 Tables shown above. We added descriptions regarding this point in the limitations section. Third, this post-hoc subgroup analysis may have been underpowered especially in patients with the previous AF-related complications. (Line 4 - 5 in Page 14) Attachments Attachment Submitted filename: Response t o Reviewers.docx https://doi.org/10.1371/journal.pone.0279178.r002
2 Dec 2022 Decision Letter - Elena G. Tolkacheva, Editor Prognostic Impact of Catheter Ablation in Patients with Asymptomatic Atrial Fibrillation PONE-D-22-17051R1 Dear Dr. Shizuta, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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. Kind regards, Elena G. Tolkacheva, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): 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: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know 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: All reviewer comments are appropriately revised and addressed. I have no more additional questions about this manuscript. Reviewer #2: The authors have adequately adressed my comments, and mention the limitations of this rtrospective analysis. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. 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: No Reviewer #2: Yes: Amir JADIDI ******** https://doi.org/10.1371/journal.pone.0279178.r003
Formally Accepted
6 Dec 2022 Acceptance Letter - Elena G. Tolkacheva, Editor PONE-D-22-17051R1 Prognostic Impact of Catheter Ablation in Patients with Asymptomatic Atrial Fibrillation Dear Dr. Shizuta: 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Elena G. Tolkacheva Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0279178.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .