
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12537-6
10.1016/j.heliyon.2024.e36506
e36506
Research Article
The anticoagulation one year after ablation of atrial fibrillation in patients with atrial fibrillation (ALONE-AF) trial: Study protocol
Kim Daehoon a
Shim Jaemin b
Choi Eue-Keun c
Oh Il-Young d
Kim Jun e
Lee Young Soo f
Park Junbeom g
Ko Jum-Suk h
Park Kyoung-Min i
Sung Jung-Hoon j
Park Hyung Wook k
Park Hyung-Seob l
Kim Jong-Youn m
Yu Hee Tae a
Kim Tae-Hoon a
Joung Boyoung cby6908@yuhs.ac
a⁎
a Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
b Department of Cardiology, Korea University Hospital, Seoul, Republic of Korea
c Department of Cardiology, Seoul National University Hospital, Seoul, Republic of Korea
d Department of Cardiology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
e Heart Institute, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
f Division of Cardiology, Daegu Catholic University Hospital, Daegu, Republic of Korea
g Department of Cardiology, Ewha Womans University Hospital, Seoul, Republic of Korea
h Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Iksan, Republic of Korea
i Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
j Division of Cardiology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
k Division of Cardiovascular Medicine, Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea
l Division of Cardiology, Keimyung University Hospital, Daegu, Republic of Korea
m Division of Cardiology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea
⁎ Corresponding author. 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. cby6908@yuhs.ac
16 8 2024
30 8 2024
16 8 2024
10 16 e3650611 3 2024
29 7 2024
16 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Background

The ideal long-term antithrombotic strategy for patients after successful catheter-based atrial fibrillation (AF) ablation is still uncertain. Presently, practices vary, and the advantages of oral anticoagulation (OAC) for the post-ablation population are not clearly established. To date, no randomized trials have addressed this therapeutic question. This study aimed to evaluate whether no OAC therapy is superior to apixaban in reducing the risk of stroke, systemic embolism, or major bleeding among patients without apparent recurrent atrial arrhythmias for at least 1 year after their AF ablation procedure.

Methods

The ALONE-AF trial is a prospective, multicenter, open-label, randomized study with blinded outcome assessment. Patients with AF who have at least one non-gender stroke risk factor (as determined by the CHA2DS2-VASc score) and no documented recurrences of atrial arrhythmia for at least 12 months post-ablation will be randomly assigned to apixaban 5 mg b.i.d. or no OAC therapy. The primary endpoint is a composite outcome of stroke, systemic embolism, and major bleeding. Key secondary outcomes include clinically relevant non-major bleeding, all-cause mortality, myocardial infarction, transient ischemic attack, quality of life, and frailty analysis. Participants will be followed for a period of 2 years. The estimated total sample size is 840 subjects, with 420 subjects in each arm.

Conclusion

The ALONE-AF trial aims to provide robust evidence for the optimal anticoagulation strategy for patients with stroke risk factors following successful AF ablation.

Keywords

Atrial fibrillation
Catheter ablation
Anticoagulation
Study protocol
==== Body
pmcClinical Trial Registration: NCT04432220 (https://www.clinicaltrials.gov)

1 Background

Atrial fibrillation (AF) stands as the most prevalent form of sustained cardiac arrhythmia, imposing substantial economic and public health burdens [[1], [2], [3], [4]]. Compared to pharmacological therapy, AF catheter ablation (AFCA) has demonstrated efficacy in reducing acute episodes and prolonging periods of sinus rhythm, thereby enhancing patients' quality of life [1,2,5,6]. However, uncertainty persists regarding the impact of AFCA on the incidence of thromboembolic events [7,8]. While contemporary guidelines generally advocate for continuing oral anticoagulants (OACs) following successful AFCA, the long-term effects of OAC continuation on thrombotic and bleeding complications remain inadequately evaluated in randomized trials [1,2,6]. Earlier observational studies, primarily focusing on warfarin-treated patients, have hinted at a potential reduction in thromboembolic risk with ongoing OAC therapy post-AFCA, albeit with an associated heightened risk of serious bleeding. Observational evidence hints that discontinuing OACs after AFCA may result in a low annual thromboembolic complication rate [[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]]; however, caution is warranted due to study limitations. Further research is needed to guide optimal long-term antithrombotic management post-AF ablation.

The AnticoaguLation ONE year after Ablation of Atrial Fibrillation in Patients with Atrial Fibrillation (ALONE-AF trial; NCT04432220) is a multicenter, randomized controlled study focused on determining the best stroke prevention approach for patients at risk following AF ablation, as indicated by their CHA2DS2-VASc score [20]. For patients who have not experienced atrial arrhythmia recurrences for at least 12 months after AF ablation, the study hypothesizes that discontinuing OAC therapy will lower the risk of adverse outcomes, such as stroke, systemic embolism, and major bleeding, compared to using direct oral anticoagulants (DOACs).

2 Methods

2.1 Study design

The ALONE-AF trial represents a multicenter, open-label, prospective, randomized superiority trial designed to enroll participants at risk for stroke who have not had any recurrences of atrial arrhythmia for at least 12 months following AF ablation. The study's overall flowchart is depicted in Fig. 1. The study protocol received approval from the institutional review board of each participating center, and patient enrollment commenced in July 2020.Fig. 1 Flow chart of the ALONE-AF trial.

Fig. 1

Funding

The trial is funded by Samjin Pharmaceutical Co Ltd and a grant from the Patient-Centered Clinical Research Coordinating Center (PACEN), funded by the 10.13039/100009647 Ministry of Health & Welfare, Republic of Korea (Grant No. HC19C0130).

2.2 Study participants and enrollment criteria

All patients with non-valvular AF undergoing their first AFCA procedure will be screened for eligibility. To be eligible for enrollment, patients must meet the following three criteria: 1) age between 19 and 80 years; 2) a CHA2DS2-VASc score of at least 1 for men or 2 for women; and 3) no atrial arrhythmia recurrence for at least 12 months post-AF ablation, defined as the absence of ≥30 s of atrial fibrillation (AF), atrial flutter (AFL), or atrial tachycardia (AT) in at least two 24–72 h Holter and electrocardiogram (ECG) recordings conducted beyond 3 months after the ablation and before enrollment (requiring at least one 24–72 h Holter monitor and ECG recording within the 2 months prior to enrollment). Patients will be enrolled regardless of the lesion set or energy source used for AF ablation. Key exclusion criteria include: 1) significant renal or liver disease; 2) requirement for anticoagulation for reasons other than AF (such as moderate-to-severe mitral valve stenosis, the presence of a mechanical heart valve, or a history of deep vein thrombosis); and 3) significant structural heart disease. Detailed information on the inclusion and exclusion criteria is presented in Table 1. Written informed consent will be obtained from each subject prior to enrollment.Table 1 Inclusion and exclusion criteria.

Table 1Inclusion criteria	
1. Age between 19 and 80 years	
2. CHA2DS2-VASc score ≥1 (male) or ≥ 2 (female)	
3. No recurrence of atrial arrhythmia at least 12 months after their first-time catheter ablation of atrial fibrillation, defined as an absence of ≥30 s of atrial fibrillation, atrial flutter, or atrial tachycardia in at least two 24–72 h Holter and electrocardiogram recordings conducted beyond 3 months after the ablation and before enrollment (with at least one 24–72 h Holter and electrocardiogram recording mandatory within the 2 months preceding enrollment)	
Exclusion criteria	
1. Significant liver (aspartate transaminase and/or alanine transaminase >3 times the upper limit of normal) or renal disease (serum creatinine ≥3.5 mg/dl or creatinine clearance <30 ml/min)	
2. Requiring anticoagulation due to surgery with a mechanical prosthetic valve, moderate-to-severe mitral stenosis, or deep vein thrombosis	
3. Significant structural heart disease (moderate-to-severe mitral regurgitation, severe valvular regurgitation or stenosis, dilated cardiomyopathy, or hypertrophic cardiomyopathy)	
4. Active malignancy	
5. Pregnancy or breast-feeding	
6. Life expectancy <1 year	
7. Refuse or enable to understand the written informed consent	

2.3 Randomization and study procedures

Eligible patients will be randomized to receive OAC therapy or no OAC therapy in a 1:1 ratio. Randomization will be conducted using a web-response permuted-block method at each participating center. Participants allocated to the OAC therapy group will receive apixaban at a dose of 5 mg twice daily. The apixaban dose will be reduced to 2.5 mg twice daily for patients who meet at least two of the following conditions: 1) age 80 years or older, 2) body weight 60 kg or less, and 3) serum creatinine level above 1.5 mg/dL [21]. In cases where a subject experiences intolerable adverse effects with apixaban, an alternative DOAC may be prescribed. Subjects assigned to the no OAC therapy group will not receive any oral anticoagulant. However, antiplatelet therapy may be administered if clinically indicated (e.g., for percutaneous coronary intervention or acute coronary syndrome) in both groups. All patients underwent ECG at each visit and 24- to 72-h Holter monitoring at least every six months after enrollment. Additionally, Holter monitoring or event recordings were conducted whenever patients reported symptoms of palpitations suggestive of arrhythmia recurrence. If a patient experiences a documented recurrence of atrial arrhythmia or undergoes repeat AFCA during the study period, they will be censored at that point and prescribed anticoagulation based on the patient's stroke risk or periprocedural needs. Subjects will be followed up for a maximal duration of 24 months.

2.4 Study outcomes

The primary outcome, assessed at the 2-year mark following randomization, is a composite endpoint comprising stroke, systemic embolism, and major bleeding (see Table 2). Stroke is defined as a sudden, focal neurologic deficit resulting from a presumed cerebrovascular cause that persists for more than 24 h and is not attributable to a readily identifiable cause, such as a tumor or seizure [22]. Systemic embolism is defined as abrupt vascular insufficiency accompanied by clinical or radiological evidence of arterial occlusion, occurring in the absence of other likely mechanisms (e.g., trauma, atherosclerosis, or instrumentation). Major bleeding events will be defined according to established criteria [22]. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) criteria [23].Table 2 Study outcomes.

Table 2Primary outcome	
A composite of stroke, systemic embolism, and major bleeding (defined by the ISTH criteria)	
Secondary outcome	
Stroke	
Systemic embolism	
ISTH major bleeding	
ISTH clinically relevant non-major bleeding	
All-cause death	
Myocardial infarction	
Pulmonary thromboembolism	
Hospitalization	
AFQET	
K-MoCA	
Frailty (Questionnaire and grip strength)	
AFQET, Atrial Fibrillation Effect on QualiTy-of-Life; ISTH, International Society on Thrombosis and Hemostasis; K-MoCA, Korean version of Montreal Cognitive Assessment.

Secondary outcomes of the study will include the individual components of the primary outcome, namely stroke, systemic embolism, and major bleeding events. Additionally, we will evaluate the incidence of clinically relevant nonmajor bleeding, as defined by the ISTH criteria [24]. Additional secondary outcomes encompass all-cause mortality, myocardial infarction (MI), pulmonary thromboembolism (PTE), transient ischemic attack (TIA), and hospitalization due to any cause. The definitions of MI and PTE are presented in Supplement. TIA will be defined as the presence of a new focal neurologic deficit presumed to be vascular in origin, with signs or symptoms lasting less than 24 h, without evidence of infarction as assessed by brain imaging [25]. The Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) [26], frailty assessments (including questionnaires and grip strength measurement), and the Korean-Montreal Cognitive Assessment will be evaluated at baseline, as well as at the 1-year and 2-year follow-up time points. Adjudication of study outcomes will be performed by an independent clinical event adjudication committee, which will remain blinded to the primary results of the study.

2.5 Sample size estimation

Based on the assumptions provided, including an annual primary outcome rate of 4.6 % in the OAC therapy group (comprising a 1.0 % annual stroke/systemic embolism rate after AFCA and a 3.6 % annual major bleeding rate observed in a pivotal randomized trial of DOAC) [[27], [28], [29]], the total expected primary outcome rate over 2 years was estimated as 9.2 %. This study aims to show that no OAC therapy will achieve a 5.0 % absolute risk reduction over 2 years (equivalent to a 54 % relative risk reduction driven by the reduction of major bleeding) compared with OAC therapy [29,30]. Considering an anticipated 7 % dropout, and aiming for 80 % power and a 5 % two-sided alpha error, a total of 840 patients will be required, with 420 patients allocated to each arm of the trial.

2.6 Data collection and management

A baseline evaluation will be carried out to assess the patients' demographics, electrocardiographic data, comorbidities, quality of life, and procedural data related to AFCA. All collected data will be anonymized before being entered into the online database (https://icreat.nih.go.kr). Data collection will occur both at the baseline and after each follow-up evaluation. An independent data monitoring committee will continuously review the study's execution.

2.7 Statistical analyses

Continuous variables will be expressed as means ± standard deviations or medians with interquartile ranges, depending on the distribution. Categorical variables will be displayed as frequencies and percentages. For comparisons, the Student's t-test or Mann-Whitney U test will be employed for continuous variables, while the chi-square test or Fisher's exact test will be utilized for categorical variables, as suitable.

The primary analyses will be performed on the intention-to-treat (ITT) population. For the primary objective, the cumulative event rate during clinical follow-up will be estimated using the Kaplan-Meier method, with a 95 % confidence interval calculated for the difference in event rates. As a sensitivity analysis, the primary endpoint analysis will also be performed on the per-protocol (PP) population. The ITT population will include all randomized patients, compared according to their assigned group regardless of the treatment actually given. The PP population will exclude patients with protocol deviations, including those found to be ineligible, those without informed consent, or those for whom the randomized therapy was not implemented. For secondary endpoints, the incidence or cumulative incidences of each endpoint will be calculated using Kaplan-Meier plots for comparisons. Missing variables will not be imputed for planned analyses, except where specified otherwise. Patients with missing values will be excluded from variable-related analyses but included in analyses not related to the missing variable. Patients lost to follow-up and subsequently lost to assessment of the primary endpoint will be considered censored in the estimation of Kaplan-Meier event rates There is no planned formal interim analysis or guidelines for stopping the study. However, the data and safety monitoring board (DSMB) will review safety data in a blinded manner, with the DSMB statistician providing unblinded summary tables. The DSMB will discuss and determine whether early termination is required due to safety concerns.

Subgroup analyses will be conducted to compare the hazard ratio (HR) of no OAC therapy against OAC therapy, stratified by prespecified subgroups including age (<65 vs. ≥65 years), sex (male vs. female), diabetes (Yes vs. No), hypertension (Yes vs. No), heart failure (Yes vs. No), vascular disease (Yes vs. No), AF type (paroxysmal vs. non-paroxysmal), and time from diagnosis to ablation (<1 year vs. ≥1 year).

3 Discussion

Optimal long-term OAC therapy post-AFCA remains unclear, with varying practices observed worldwide. A survey from Canada indicates that more than 95 % of electrophysiologists would consider stopping OAC therapy if their patients have a CHADS2 score of 1 or lower and no recurrences of atrial arrhythmia [31]. In contrast, an observational study conducted in Japan demonstrates that over half of the patients continued OAC therapy at 1 year post-ablation. The study reveals a higher rate of OAC therapy continuation in patients with a higher CHADS2 score (at least 3) compared to those with a CHADS2 score of 2 or less [19]. Consistently, a survey of European electrophysiologists shows that 16 % would be comfortable discontinuing OAC therapy after AFCA, even though their patients have a high stroke risk as indicated by a CHADS2 score of at least 2 [32].

Noseworthy et al. shows that OAC discontinuation in the long term after ablation is associated with an increased risk of cardioembolism for high-risk patients [33]. Kanaoka et al. demonstrates that the thromboembolic risk in patients undergoing AFCA is lower compared to the general AF population not receiving OACs [19]. Moreover, discontinuing OAC treatment, even in patients with a CHADS2 score of 2, does not lead to an increased incidence of thromboembolism but is associated with a decreased risk of major bleeding. Therefore, the routine continuation of OAC therapy in patients with intermediate stroke risk may not be advisable. Given the acknowledged lack of evidence supporting current guideline recommendations on this topic, there is equipoise, justifying the need for a randomized trial to address this question.

In summary, the ALONE-AF trial seeks to address this gap by investigating whether OAC discontinuation enhances the net clinical benefit among patients who have undergone successful AF ablation. The trial's findings are expected to provide valuable insights into the optimal antithrombotic regimen for post-ablation patients with stroke risk factors.

4 Ethics statement

The study protocol received approval from the institutional review board of each participating center, and patient enrollment began in July 2020. The trial is registered on ClinicalTrials.gov on June 12, 2020 (NCT04432220). All participants will provide informed consent to participate in the study.

Funding

This research received support from Samjin Pharmaceutical Co Ltd and a grant from the Patient-Centered Clinical Research Coordinating Center (PACEN), funded by the 10.13039/100009647 Ministry of Health & Welfare, Republic of Korea (Grant No. HC19C0130 ).

Data availability statement

No data is used because this manuscript is a study protocol. Data associated with this trial will be made available from the corresponding author on request, considering privacy-sensitive information.

CRediT authorship contribution statement

Daehoon Kim: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Jaemin Shim: Investigation, Data curation. Eue-Keun Choi: Supervision, Data curation. Il-Young Oh: Supervision, Data curation. Jun Kim: Supervision, Data curation. Young Soo Lee: Supervision, Data curation. Junbeom Park: Supervision, Data curation. Jum-Suk Ko: Supervision, Data curation. Kyoung-Min Park: Supervision, Data curation. Jung-Hoon Sung: Supervision, Methodology. Hyung Wook Park: Supervision, Data curation, Conceptualization. Hyung-Seob Park: Supervision, Data curation. Jong-Youn Kim: Supervision, Project administration. Hee Tae Yu: Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation. Tae-Hoon Kim: Validation, Supervision, Resources, Investigation, Data curation, Conceptualization. Boyoung Joung: Writing – review & editing, Visualization, Validation, Supervision, Resources, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Boyoung Joung reports financial support was provided by Korea Ministry of Health and Welfare. Boyoung Joung reports financial support was provided by Samjin Pharm Co Ltd. Boyoung Joung has served as a speaker for 10.13039/100004326 Bayer , BMS/10.13039/100004319 Pfizer , Medtronic, and 10.13039/501100002973 Daiichi-Sankyo and received research funds from Samjin, 10.13039/100019265 Yuhan , Medtronic, Boston Scientifics and 10.13039/100008977 Abbott Korea . No fees were received personally. The remaining authors have no conflicts of interest to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36506.
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References

1 Joglar J.A. Chung M.K. Armbruster A.L. Benjamin E.J. Chyou J.Y. Cronin E.M. Deswal A. Eckhardt L.L. Goldberger Z.D. Gopinathannair R. Gorenek B. Hess P.L. Hlatky M. Hogan G. Ibeh C. Indik J.H. Kido K. Kusumoto F. Link M.S. Linta K.T. Marcus G.M. McCarthy P.M. Patel N. Patton K.K. Perez M.V. Piccini J.P. Russo A.M. Sanders P. Streur M.M. Thomas K.L. Times S. Tisdale J.E. Valente A.M. Van Wagoner D.R. ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American college of Cardiology/American heart association joint committee on clinical practice guidelines Circulation 149 1 2023 e1 e156 10.1161/cir.0000000000001193 2024 38033089
2 Hindricks G. Potpara T. Dagres N. Arbelo E. Bax J.J. Blomström-Lundqvist C. Boriani G. Castella M. Dan G.A. Dilaveris P.E. Fauchier L. Filippatos G. Kalman J.M. La Meir M. Lane D.A. Lebeau J.P. Lettino M. Lip G.Y.H. Pinto F.J. Thomas G.N. Valgimigli M. Van Gelder I.C. Van Putte B.P. Watkins C.L. ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC Eur. Heart J. 42 5 2020 373 498 10.1093/eurheartj/ehaa612 2021
3 Kim D. Yang P.S. Jang E. Yu H.T. Kim T.H. Uhm J.S. Kim J.Y. Pak H.N. Lee M.H. Joung B. Lip G.Y.H. Increasing trends in hospital care burden of atrial fibrillation in Korea, 2006 through 2015 Heart 104 24 2018 2010 2017 10.1136/heartjnl-2017-312930 29666179
4 Kim D. Yang P.S. Jang E. Yu H.T. Kim T.H. Uhm J.S. Kim J.Y. Pak H.N. Lee M.H. Joung B. Lip G.Y. 10-year nationwide trends of the incidence, prevalence, and adverse outcomes of non-valvular atrial fibrillation nationwide health insurance data covering the entire Korean population Am. Heart J. 202 2018 20 26 10.1016/j.ahj.2018.04.017 29802976
5 Mark D.B. Anstrom K.J. Sheng S. Piccini J.P. Baloch K.N. Monahan K.H. Daniels M.R. Bahnson T.D. Poole J.E. Rosenberg Y. Lee K.L. Packer D.L. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial JAMA 321 13 2019 1275 1285 10.1001/jama.2019.0692 30874716
6 Calkins H. Hindricks G. Cappato R. Kim Y.H. Saad E.B. Aguinaga L. Akar J.G. Badhwar V. Brugada J. Camm J. Chen P.S. Chen S.A. Chung M.K. Nielsen J.C. Curtis A.B. Davies D.W. Day J.D. d'Avila A. de Groot N. Di Biase L. Duytschaever M. Edgerton J.R. Ellenbogen K.A. Ellinor P.T. Ernst S. Fenelon G. Gerstenfeld E.P. Haines D.E. Haissaguerre M. Helm R.H. Hylek E. Jackman W.M. Jalife J. Kalman J.M. Kautzner J. Kottkamp H. Kuck K.H. Kumagai K. Lee R. Lewalter T. Lindsay B.D. Macle L. Mansour M. Marchlinski F.E. Michaud G.F. Nakagawa H. Natale A. Nattel S. Okumura K. Packer D. Pokushalov E. Reynolds M.R. Sanders P. Scanavacca M. Schilling R. Tondo C. Tsao H.M. Verma A. Wilber D.J. Yamane T. HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation Heart Rhythm 14 10 2017 e275 e444 10.1016/j.hrthm.2017.05.012 2017 28506916
7 Packer D.L. Mark D.B. Robb R.A. Monahan K.H. Bahnson T.D. Poole J.E. Noseworthy P.A. Rosenberg Y.D. Jeffries N. Mitchell L.B. Flaker G.C. Pokushalov E. Romanov A. Bunch T.J. Noelker G. Ardashev A. Revishvili A. Wilber D.J. Cappato R. Kuck K.H. Hindricks G. Davies D.W. Kowey P.R. Naccarelli G.V. Reiffel J.A. Piccini J.P. Silverstein A.P. Al-Khalidi H.R. Lee K.L. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial JAMA 321 13 2019 1261 1274 10.1001/jama.2019.0693 30874766
8 Kirchhof P. Camm A.J. Goette A. Brandes A. Eckardt L. Elvan A. Fetsch T. van Gelder I.C. Haase D. Haegeli L.M. Hamann F. Heidbuchel H. Hindricks G. Kautzner J. Kuck K.H. Mont L. Ng G.A. Rekosz J. Schoen N. Schotten U. Suling A. Taggeselle J. Themistoclakis S. Vettorazzi E. Vardas P. Wegscheider K. Willems S. Crijns H. Breithardt G. Investigators E.-A.T. Early rhythm-control therapy in patients with atrial fibrillation N. Engl. J. Med. 383 14 2020 1305 1316 10.1056/NEJMoa2019422 32865375
9 Oral H. Chugh A. Ozaydin M. Good E. Fortino J. Sankaran S. Reich S. Igic P. Elmouchi D. Tschopp D. Wimmer A. Dey S. Crawford T. Pelosi F. Jr. Jongnarangsin K. Bogun F. Morady F. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation Circulation 114 8 2006 759 765 10.1161/circulationaha.106.641225 16908760
10 Rossillo A. Bonso A. Themistoclakis S. Riccio G. Madalosso M. Corrado A. De Piccoli B. Raviele A. Role of anticoagulation therapy after pulmonary vein antrum isolation for atrial fibrillation treatment J. Cardiovasc. Med. 9 1 2008 51 55 10.2459/JCM.0b013e32801462d4
11 Bunch T.J. Crandall B.G. Weiss J.P. May H.T. Bair T.L. Osborn J.S. Anderson J.L. Lappe D.L. Muhlestein J.B. Nelson J. Allison S. Foley T. Anderson L. Day J.D. Warfarin is not needed in low-risk patients following atrial fibrillation ablation procedures J. Cardiovasc. Electrophysiol. 20 9 2009 988 993 10.1111/j.1540-8167.2009.01481.x 19473299
12 Themistoclakis S. Corrado A. Marchlinski F.E. Jais P. Zado E. Rossillo A. Di Biase L. Schweikert R.A. Saliba W.I. Horton R. Mohanty P. Patel D. Burkhardt D.J. Wazni O.M. Bonso A. Callans D.J. Haissaguerre M. Raviele A. Natale A. The risk of thromboembolism and need for oral anticoagulation after successful atrial fibrillation ablation J. Am. Coll. Cardiol. 55 8 2010 735 743 10.1016/j.jacc.2009.11.039 20170810
13 Saad E.B. d'Avila A. Costa I.P. Aryana A. Slater C. Costa R.E. Inácio L.A. Jr. Maldonado P. Neto D.M. Camiletti A. Camanho L.E. Polanczyk C.A. Very low risk of thromboembolic events in patients undergoing successful catheter ablation of atrial fibrillation with a CHADS2 score ≤3: a long-term outcome study, Circulation Arrhythmia and electrophysiology 4 5 2011 615 621 10.1161/circep.111.963231 21841192
14 Yagishita A. Takahashi Y. Takahashi A. Fujii A. Kusa S. Fujino T. Nozato T. Kuwahara T. Hirao K. Isobe M. Incidence of late thromboembolic events after catheter ablation of atrial fibrillation Circ. J. 75 10 2011 2343 2349 10.1253/circj.cj-11-0065 21778595
15 Guiot A. Jongnarangsin K. Chugh A. Suwanagool A. Latchamsetty R. Myles J.D. Jiang Q. Crawford T. Good E. Pelosi F. Jr. Bogun F. Morady F. Oral H. Anticoagulant therapy and risk of cerebrovascular events after catheter ablation of atrial fibrillation in the elderly J. Cardiovasc. Electrophysiol. 23 1 2012 36 43 10.1111/j.1540-8167.2011.02141.x 21806701
16 Winkle R.A. Mead R.H. Engel G. Kong M.H. Patrawala R.A. Discontinuing anticoagulation following successful atrial fibrillation ablation in patients with prior strokes J. Intervent. Card Electrophysiol. 38 3 2013 147 153 10.1007/s10840-013-9835-1
17 Gaita F. Sardi D. Battaglia A. Gallo C. Toso E. Michielon A. Caponi D. Garberoglio L. Castagno D. Scaglione M. Incidence of cerebral thromboembolic events during long-term follow-up in patients treated with transcatheter ablation for atrial fibrillation Europace 16 7 2014 980 986 10.1093/europace/eut406 24446510
18 Ha A.C. Hindricks G. Birnie D.H. Verma A. Long-term oral anticoagulation for patients after successful catheter ablation of atrial fibrillation: is it necessary? Curr. Opin. Cardiol. 30 1 2015 1 7 10.1097/hco.0000000000000121 25389647
19 Kanaoka K. Nishida T. Iwanaga Y. Nakai M. Tonegawa-Kuji R. Nishioka Y. Myojin T. Okada K. Noda T. Kusano K. Miyamoto Y. Saito Y. Imamura T. Oral anticoagulation after atrial fibrillation catheter ablation: benefits and risks Eur. Heart J. 2023 10.1093/eurheartj/ehad798
20 Lip G.Y. Nieuwlaat R. Pisters R. Lane D.A. Crijns H.J. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation Chest 137 2 2010 263 272 10.1378/chest.09-1584 19762550
21 Granger C.B. Alexander J.H. McMurray J.J. Lopes R.D. Hylek E.M. Hanna M. Al-Khalidi H.R. Ansell J. Atar D. Avezum A. Bahit M.C. Diaz R. Easton J.D. Ezekowitz J.A. Flaker G. Garcia D. Geraldes M. Gersh B.J. Golitsyn S. Goto S. Hermosillo A.G. Hohnloser S.H. Horowitz J. Mohan P. Jansky P. Lewis B.S. Lopez-Sendon J.L. Pais P. Parkhomenko A. Verheugt F.W. Zhu J. Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation N. Engl. J. Med. 365 11 2011 981 992 10.1056/NEJMoa1107039 21870978
22 Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study Am. Heart J. 159 3 2010 340 347.e341 10.1016/j.ahj.2009.11.025 20211293
23 Schulman S. Angerås U. Bergqvist D. Eriksson B. Lassen M.R. Fisher W. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients J. Thromb. Haemostasis 8 1 2010 202 204 10.1111/j.1538-7836.2009.03678.x 19878532
24 Kaatz S. Ahmad D. Spyropoulos A.C. Schulman S. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH J. Thromb. Haemostasis 13 11 2015 2119 2126 10.1111/jth.13140 26764429
25 Easton J.D. Saver J.L. Albers G.W. Alberts M.J. Chaturvedi S. Feldmann E. Hatsukami T.S. Higashida R.T. Johnston S.C. Kidwell C.S. Lutsep H.L. Miller E. Sacco R.L. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American heart association/American stroke association stroke council; council on cardiovascular surgery and anesthesia; council on cardiovascular radiology and intervention; council on cardiovascular nursing; and the interdisciplinary council on peripheral vascular disease. The American academy of neurology affirms the value of this statement as an educational tool for neurologists Stroke 40 6 2009 2276 2293 10.1161/strokeaha.108.192218 19423857
26 Spertus J. Dorian P. Bubien R. Lewis S. Godejohn D. Reynolds M.R. Lakkireddy D.R. Wimmer A.P. Bhandari A. Burk C. Development and validation of the atrial fibrillation effect on QualiTy-of-life (AFEQT) questionnaire in patients with atrial fibrillation Circ Arrhythm Electrophysiol 4 1 2011 15 25 10.1161/CIRCEP.110.958033 21160035
27 Reynolds M.R. Gunnarsson C.L. Hunter T.D. Ladapo J.A. March J.L. Zhang M. Hao S.C. Health outcomes with catheter ablation or antiarrhythmic drug therapy in atrial fibrillation: results of a propensity-matched analysis Circ Cardiovasc Qual Outcomes 5 2 2012 171 181 10.1161/circoutcomes.111.963108 22373904
28 Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N. Engl. J. Med. 365 10 2011 883 891 10.1056/NEJMoa1009638 21830957
29 Karasoy D. Gislason G.H. Hansen J. Johannessen A. Køber L. Hvidtfeldt M. Özcan C. Torp-Pedersen C. Hansen M.L. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long-term follow-up in nationwide cohort of Denmark Eur. Heart J. 36 5 2015 307 314a 10.1093/eurheartj/ehu421 25368205
30 Hart R.G. Pearce L.A. Aguilar M.I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation Ann. Intern. Med. 146 12 2007 857 867 10.7326/0003-4819-146-12-200706190-00007 17577005
31 Mardigyan V. Verma A. Birnie D. Guerra P. Redfearn D. Becker G. Champagne J. Sapp J. Gula L. Parkash R. Macle L. Crystal E. O'Hara G. Khaykin Y. Sturmer M. Veenhuyzen G.D. Greiss I. Sarrazin J.F. Mangat I. Novak P. Skanes A. Roux J.F. Chauhan V. Hadjis T. Morillo C.A. Essebag V. Anticoagulation management pre- and post atrial fibrillation ablation: a survey of canadian centres Can. J. Cardiol. 29 2 2013 219 223 10.1016/j.cjca.2012.04.013 22840300
32 Lip G.Y. Proclemer A. Dagres N. Bongiorni M.G. Lewalter T. Blomström-Lundqvist C. Periprocedural anticoagulation therapy for devices and atrial fibrillation ablation Europace 14 5 2012 741 744 10.1093/europace/eus105 22532381
33 Noseworthy P.A. Yao X. Deshmukh A.J. Van Houten H. Sangaralingham L.R. Siontis K.C. Piccini J.P. Sr. Asirvatham S.J. Friedman P.A. Packer D.L. Gersh B.J. Shah N.D. Patterns of anticoagulation use and cardioembolic risk after catheter ablation for atrial fibrillation J. Am. Heart Assoc. 4 11 2015 10.1161/JAHA.115.002597
