Optimal Timing for Atrial Fibrillation Patients to Undergo Catheter Ablation: Insights from Long-Term Outcome Studies

doi:10.21203/rs.3.rs-3898926/v1

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Optimal Timing for Atrial Fibrillation Patients to Undergo Catheter Ablation: Insights from Long-Term Outcome Studies

https://doi.org/10.21203/rs.3.rs-3898926/v1

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Background Despite catheter ablation being an established treatment for atrial fibrillation (AF), optimal timing for this procedure to improve long-term outcomes remains uncertain.

Objective To investigate the impact of diagnosis-to-ablation time (DAT) on AF recurrence and major adverse cardiovascular and cerebrovascular events (MACCE) following catheter ablation.

Methods This study retrospectively analyzed prospective observational data from a single center, including 2,097 participants undergoing AF ablation between January 2016 and December 2020. Baseline characteristics, clinical outcomes, and the incidence of MACCE were evaluated. Patients were stratified by DAT: ≤ 1 year, > 1 to ≤ 3 years, and > 3 years. Cox proportional hazards and logistic regression analyses were used to identify predictors of AF recurrence and MACCE

Results During the 46.89 ± 16.46 months follow-up, AF recurred in 512 patients (24.6%). Early intervention (DAT ≤ 1 year or ≤ 3 years) corresponded with higher AF-free survival, particularly in patients with persistent AF (HR reference to DAT ≤ 1 year: 1.548 [95%CI: 1.139–2.102]). Patients with DAT > 3 years had higher risks of AF recurrence within two years, but long-term recurrence rates stabilized across DAT groups. Left atrial diameter ≥ 40 mm and female gender were identified as independent predictors of AF recurrence. The overall impact of DAT on MACCE occurrence was not significant, with age and vascular disease being independent predictors.

Conclusions Early catheter ablation is preferable for maintaining sinus rhythm, particularly in persistent AF. However, DAT did not influence the incidence of MACCE. These findings endorse the paradigm shift towards early ablation but also emphasize the importance of personalized treatment strategies based on individual patient profiles.

Health sciences/Cardiology/Interventional cardiology

Health sciences/Diseases/Cardiovascular diseases/Arrhythmias/Atrial fibrillation

Atrial fibrillation

catheter ablation

diagnosis-to-ablation time

major adverse cardiac and cerebrovascular events

early intervention

Catheter ablation has been demonstrated to be an effective strategy for reducing recurrence of atrial fibrillation (AF) and for improving quality of life in patients with symptomatic AF when compared to antiarrhythmic drug therapy^1–3. For a long time, the choice between rhythm management and rate management in the treatment of AF has been a challenging dilemma⁴. Although catheter ablation is significantly superior to drug therapy in improving symptoms, it does not truly improve outcomes such as death, disability, or sudden death². Therefore, for a long time, catheter ablation was not the first-line treatment for AF^{3, 4}. In recent years, an increasing number of studies have shown that rhythm management can not only improve symptoms but also significantly reduce the prognosis of major cardiovascular events in patients with and without structural heart disease^5–8. This improvement is related to the advancements in anti-arrhythmic drugs and catheter ablation techniques, and the timing of treatment is also a very critical factor⁹. Early intervention through ablation aims to restore normal sinus rhythm, improve symptoms and quality of life, and potentially even modify the disease progression when implemented before significant structural changes in the atria have occurred¹⁰. A paradigm shift is, therefore, currently occurring with the evolving concept of early catheter ablation. Rather than being reserved as a second-line treatment for AF (following failure of drug-based therapy), there is a growing body of evidence supporting the notion of catheter ablation as a first-line therapys^{1, 11}. So, there arises a question, at what time is intervention a better opportunity, and what exactly are the factors that influence prognosis of AF ablation? Thus far, most research has adopted a one-year span, i.e. diagnosis-to-ablation time (DAT) ≤ 1 year, as the benchmark for assessing the prognostic outcomes of catheter ablation. The findings from these studies indicate that patients with DAT ≤ 1 year can lessen the likelihood of recurrence following the procedure. Additionally, it has been established as an independent predictive factor for postoperative recurrence^12–14. Research classifying patients by quartile DAT times suggests that those with a DAT under one year reap the most benefits^15–18. Tetsuma Kawaji and colleagues observed that a DAT under three years correlated with reduced rates of recurrence and lower cardiovascular rehospitalization rates¹⁹. Similarly, Chew and others, in their systematic review, proposed that a DAT of one year or less—or alternatively, three years or less—was conducive to lower rates of AF recurrence. The findings of Kalman et al. indicate that postponing AF ablation for twelve months for the sake of antiarrhythmic drug management does not diminish ablation efficacy, when compared with earlier ablation carried out within one month of recruitment²⁰. The lack of a clear consensus on the ideal timing for catheter ablation highlights the need for further investigation into how various duration lengths of DAT might influence patient prognosis. This study, therefore, has been designed to assess the effect of DAT on the recurrence of AF and major adverse cardiovascular and cerebrovascular events (MACCE) following catheter ablation. Utilizing long-term follow-up data from our center, we aim to explore the optimal timing for AF catheter ablation and identifying potential factors that may influence its outcomes.

The analysis included data from 2,097 patients who underwent initial catheter ablation, segmented as follows: 923 patients with DAT≤ 1 year, 516 patients with 1 year<DAT≤ 3 years, and 658 patients with DAT > 3years (Fig. 1). Of this cohort, 126 patients required reoperation during the follow-up period. Mean DAT was 35.9 ± 38.9 months. Table 1 indicates that the mean age of the participants was 59.98 ± 10.57 years, and a predominant 62.7% were male. When compared to patients with DAT ≤ 1 year, those with 1 year<DAT≤ 3 years, or DAT > 3years, exhibited higher average ages. Additionally, a lower proportion of males and fewer cases of persistent AF were observed in these groups (p < 0.05). The CHA₂DS₂-VASc and HAS-BLED scores were also significantly higher (p < 0.05). The incidence of hypertension and vascular disease was notably higher in patients with DAT > years (p < 0.05). The left atrium diameter (LAD) and the medication prescription during observational period did not differ significantly. The follow-up duration was similar across all groups.

Primary outcomes

During the monitoring period of 46.89 ± 16.46 months, AF recurrence was observed in 512 patients, accounting for 24.6% of the cohort; of these recurrences, 87.8% were cases of paroxysmal AF which was not significantly different among groups. As Fig. 2A presented, the percent of AF-free survival did not significantly differ between patients with DAT ≤ 1 year and with 1 year<DAT≤ 3 years, and was lower in patients with DAT > 3years. The Kaplan-Meier curves showed a convergence starting at 3 years post-operation, with an intersection occurring approximately 5 years after the operation (p = 0.1998). For patients with DAT ≤ 3 years and > 3 years, the percent of AF-free survival did not significantly differ (Supplementary Figure S1, p = 0.0727). Considering the differences in gender and AF type composition among different groups, we conducted an analysis on various subgroups. The results were consistent across male and female patients, as well as in those with paroxysmal AF (p = 0.1906, 0.2677, 0.8963 respectively). In patients with persistent AF, the percentage of those maintaining AF-free survival was notably reduced in patients with DAT > 3years (p = 0.0152, Fig. 2B). Compared to individuals with DAT ≤ 1 year, the HR was 1.548 (95%CI: 1.139–2.102), indicating a higher risk of AF recurrence (p = 0.005). Because all patients in this study were followed up for at least two years, we further compared the two-year recurrence rate of AF in patients with different DAT. Kaplan-Meier showed significantly lower AF-free survival probability in the DAT > 3 years group (p = 0.0353, Fig. 2C). The HR, compared with DAT ≤ 1 year group, was 0.921 (95%CI: 0.723–1.172) in 1 year<DAT≤ 3 years group and 1.234 (95%CI: 1.003–0.520) in DAT > 3 years group (p = 0.504 and 0.047, respectively).

The incidence of MACCE was 1.50 per 100 patient-year in this cohort, with no statistical differences among groups. HR, when using DAT < 1 year group as a reference to, were 0.884 (95%CI: 0.570–1.370, p = 0.581) for 1 year<DAT≤ 3 years group, and 0.838 (95%CI: 0.550–1.277, p = 0.411) for DAT > 3 years group). The majority of MACCE were attributable to new thromboembolic events, which occurred at comparable rates across the groups (Table 1). For patients with CHA₂DS₂-VASc score ≥2, the incidence of MACCE was 2.00 per 100 patient-year, again with not statistically different among groups (HR reference to DAT < 1 year group: 0.763 (95%CI: 0.445–1.308, p = 0.326) for 1 year<DAT≤ 3 years group; 0.882 (95%CI: 0.537–1.451, p = 0.622) for DAT > 3 years group).

Factors contributing to the recurrence of AF and the incidence of MACCE

Table 2 shows that univariable Cox regression analysis highlighted various factors associated with AF recurrence, such as female, diabetes, a high CHA₂DS₂-VASc score, LAD ≥ 40 mm, and obesity (p < 0.10). The DAT did not reach the significant level in the univariable cox analysis (p > 0.10). Multivariable Cox regression analysis demonstrated female, diabetes, and LAD ≥ 40 mm as the independent predictors of AF recurrence. In patients with persistent AF, as expected, DAT > 3 years and LAD ≥ 40 mm were the independent predictors of AF recurrence (Table 3). We also explored the risk factor of AF recurrence at 2 years post operation. After adjustment of age and AF type, female, DAT > 3 years, diabetes, and LAD ≥ 40 mm were the independent predictors of AF recurrence (p = 0.009, 0.029, 0.000, and 0.023 respectively, Fig. 3 and Supplementary Table S1). Furthermore, with cox regression analysis, the independent predictors were concluded in patients with DAT < 3 years (female and LAD ≥ 40 mm, Supplementary Table S2) and with DAT ≥ 3 years (diabetes and LAD ≥ 40 mm, Supplementary Table S3).

The factors contributing to the incidence of MACCE were further analyzed using logistic regression. The analysis revealed that DAT was not a risk factor for the occurrence of MACCE. The variables entered into the multivariable analysis were age, hypertension, diabetes, vascular disease, high CHA₂DS₂-VASc score, HAS-BLED score, LAD ≥ 40 mm, and statin prescription. Ultimately, age and vascular disease were the only factors that reached statistical significance, signifying that they are independent predictors for the incidence of MACCE (Table 4).

This study assessed the effect of DAT on the recurrence of AF and on MACCE following catheter ablation. In our cohort, main findings were: i) early intervention was associated with a higher likelihood of maintaining AF-free status, especially among patients with persistent AF; ii) the DAT < 3 years appears to be an optimal window for performing catheter ablation to maximize the potential for sustained sinus rhythm in AF patients; iii) the overall influence of DAT on the occurrence of MACCE was not significant.

In recent times, the approach of promptly addressing rhythm management in AF has become increasingly recognized and has been integrated into medical guidelines¹. Implementing effective rhythm control strategies can interrupt the self-perpetuating nature of ‘AF begets AF’²¹. This early intervention can decelerate the progression of changes within the heart's electrical pathways, its structure, the vascular endothelium, and metabolic functions—all of which are altered by AF^{21, 22}. By doing so, it is possible to lower the risk of stroke and other heart-related complications associated with AF, especially for selected patients¹. Moreover, this focus on early rhythm management has largely resolved the longstanding controversy of whether to prioritize rhythm control or rate control, thus shifting the paradigm of AF treatment from ‘better symptoms control’ to reducing the incidence of MACCE²³.

The timing of intervention in AF remains a topic of debate due to a lack of consensus. Research, such as that by Bisbal et al., suggests a limited duration of diagnosed AF (DAT ≤ 1 year) as an independently modifiable factor associated with a decrease in AF recurrence during 1-year follow-up. Other risk factors identified include hypertension, heart failure, nonparoxysmal AF, and left atrial (LA) diameter.¹⁴ Similarly, Lunati et al. indicated that early AF cryoablation reduced the risk of recurrence within 6 to 18 months¹³. Bunch et al. conducted two studies in which participants were classified into four groups based on the quartile of DAT: 30–180 days, 181–545 days, 546–1825 days, and more than 1825 days. The findings revealed that patients with longer DAT were typically older and had a higher prevalence of cardiovascular diseases. Furthermore, a one-year follow-up indicated that treatment delays were associated with an elevated risk of AF recurrence in both patients with and without structural heart diseases^{12, 17}. Similarly, in persistent AF patients, Hussein et al. found early catheter ablation (i.e. DAT≤1 year) had a strong association with the 2-year follow-up AF recurrence. LA size was the other independent risk factor for ablation outcomes¹⁵. For long-term follow-up, Greef et al. found that patients with a DAT of 11 months or less were associated with better outcomes, as observed over an average follow-up period of 44.3 months. Additional risk factors identified included the type of AF and the size of the left atrium.¹⁶. Kawaji et al. observed that a DAT of less than 3 years independently favored lower AF recurrence rates over an average 5-year span, without significant differences in outcomes between DAT brackets of ≤ 1 year and 1 to 3 years¹⁹. In the study by Zhou et al., it was found that among younger patients (under 45 years of age), those with a DAT of 1 year or less had a lower risk of cardiovascular events, including AF recurrence, when compared to patients with DAT exceeding 6 years. However, for patients with 1year < DAT ≤3 years and 3 years < DAT ≤6 years, no significant difference in risk was observed. Additionally, being female and having a larger LAD were identified as independent predictors of cardiovascular events¹⁸. In the current study, we found no significant differences in the rates of AF recurrence between patients with a DAT ≤ 1 year and those with 1 year < DAT ≤ 3 years. However, a longer DAT (> 3 years) correlated with a higher risk of AF recurrence over a 2-year follow-up period, but did not influence the long-term recurrence rates. Regarding long-term outcomes, a short DAT was associated with improved results specifically in patients with persistent AF.

The optimal timing for initiating early ablation could be a flexible consideration, influenced by a range of factors such as patient age, existing cardiovascular conditions, and the dimensions of their atrium; while for persistent AF, complex comorbidities, and large left atria, early treatment may yield better results. Studies on the risk factors for different DAT patients also show that left atrial enlargement remains an important independent risk factor. Other studies also indicate that besides DAT, the level of atrial remodeling is still an extremely important indicator affecting postoperative recurrence^{14–16, 18}.

In the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4), early rhythm-control therapy demonstrated a reduced risk of adverse cardiovascular outcomes compared to standard care. Notably, 112 patients (8.0%) at baseline were undergoing ablative treatment, hinting that early ablation may enhance MACCE outcomes⁶. The observational study by Bunch et al. showed no stroke difference in patients with an ejection fraction≤35%, but higher rates of death and heart failure hospitalizations were noted at 1 year with delayed treatment^{12, 17}. Dickow et al., using a large real-world cohorts of United States deidentified administrative claims database and UK Biobank, found early rhythm control within the first year led to a lower risk of the primary composite outcome (all-cause mortality, stroke, or hospitalization for heart failure or myocardial infarction) in individuals with a CHA₂DS₂-VASc score≥4; this association was not observed in those with a score of 2-3²⁴. Kawaji et al., through a long-term follow-up observational study, reported no significant differences in all-cause mortality, heart failure rehospitalization, or ischemic stroke between groups with DAT < 3 years or ≥3 years¹⁹. Our research aligns with these findings, suggesting that DAT is not a predictor for MACCE. Despite early rhythm treatment being able to reduce cardiovascular events⁶, there remains a lack of consensus on whether antiarrhythmic drugs or catheter ablation should be the initial treatment to improve outcomes. There remains a lack of consensus on whether antiarrhythmic drugs or catheter ablation should be the initial treatment to improve outcomes¹¹. Our research has identified age and vascular diseases as independent predictors of MACCE. Previous research has indicated that patients with a longer DAT tend to be older and often have more comorbidities; therefore, the potential positive impact of early catheter ablation on cardiovascular prognosis, whether by improving comorbidities through early intervention or by directly terminating atrial fibrillation, requires further investigation to determine²⁵.

Clinical implications

Although DAT are among the few adjustable factors, the significance of DAT lies in terminating the malignant cycle of ‘AF begets AF’, delaying or even reversing atrial remodeling, which is essential. Therefore, the timing of DAT should be based on the patient's condition, rather than judging by a particular time point. Current research has found that mineralocorticoid receptor antagonists²⁶, sodium-glucose co-transporter-2 inhibitors²⁷, and others can effectively delay the progression of AF and improve the prognosis of atrial fibrillation. The focus should be on how to balance DAT and atrial remodeling, adopting a more comprehensive pharmacological treatment, especially upstream therapy²⁸, to enhance the prognosis of interventional treatments.

Among the limitations of the current study includes its observational nature, which carries an inherent risk of residual confounding factors that were not captured or controlled for. Additionally, the patients in this study had unsystematic medication regimens post-operation, with a lower rate of anticoagulation and a low proportion of usage of drugs that prevent atrial remodeling. Despite there being no significant differences among the different groups, this could lead to biases in outcomes. The study employed telephone follow-ups, ECGs, and 24-hour Holter monitoring, which are not as comprehensive as long-term Holter monitoring. Therefore, the recurrence rates may be slightly lower than they actually are.

Overall, while our findings support earlier intervention to minimize AF recurrence, individual patient characteristics seem to be more definitive in determining outcomes. This highlights the nuanced nature of AF management, necessitating personalized approaches, and suggests that decisions regarding optimal timing for catheter ablation should be patient-centric, taking into account various individual risk factors and comorbidities.

The research study received approval from the Qilu Hospital Review Board, ensuring that each participant provided written informed consent. All research activities were conducted in compliance with applicable guidelines and conformed to the principles outlined in the Declaration of Helsinki. Our research focused on examining data from a prospective observational AF ablation registry study at our center (recorded in the Chinese Clinical Trial Registry, ChiCTR-OCH-14004674)²⁹. The study's primary objective was to evaluate two main outcomes: the rate of AF recurrence, and the incidence of MACCE, which encompass stroke, transient ischemic attacks (TIAs), systemic embolic incidents, acute myocardial infarction, advanced heart failure, and mortality. Additionally, we monitored occurrences of substantial bleeding episodes as well as cases of patient readmission to the hospital. To be eligible for the study, participants were required to have had an AF catheter ablation procedure performed at our facility within the timeframe from January 2016 through December 2020. The study excluded individuals who were (i) under the age of 18, (ii) followed for less than 12 months after their ablation procedure, or (iii) afflicted with mitral valvular heart disease. The medical record was used to collect DAT information. Data encompassing baseline demographics, physical characteristics such as height and weight, medical histories, alcohol consumption patterns, and echocardiographic results were collected and organized. We calculated the CHA₂DS₂-VASc and HAS-BLED scores in accordance with current guidelines³⁰.

Postprocedural management and follow-up strategy

Patients were scheduled for heart rhythm assessments using electrocardiography (ECG) or 24-hour Holter monitoring at intervals of 1, 3, and 6 months following discharge. Subsequent follow-ups were arranged on a semi-annual basis. Patients exhibiting symptoms associated with cardiac conditions were advised to have an ECG performed. The collection of MACCE data was conducted every 6 months either during clinic visits or via telephone follow-ups. AF recurrence was identified as any instance of atrial tachyarrhythmia with a minimum duration of 30 seconds, recorded following a three-month blanking period post-ablation. The determination to maintain oral anticoagulation in patients without signs of atrial AF recurrence beyond this period was reached in conjunction with the consulting electrophysiologist. A CHA₂DS₂-VASc score exceeding 2 prompted the advisement for continued oral anticoagulant treatment. Following a three-month monitoring period, the discontinuation of antiarrhythmic drugs was generally recommended. The majority of prescriptions for long-term medication were issued during the first year post-ablation.

Statistical analysis

The data analysis was conducted with IBM SPSS version 22.0, setting the significance threshold at p < 0.05. Continuous variables were tested for normality using the Kolmogorov-Smirnov test and are reported as mean ± standard deviation (SD). The t-test was utilized to compare these variables. Categorical variables are presented as frequencies and percentages and were analyzed using either the Chi-square test or Fisher's exact test, as appropriate. The incidence rates of MACCE were reported as the number of events occurring per 100 patient-years. The Kaplan-Meier curve depicted the proportion of patients who remained free of AF recurrences over time, stratified by DAT. To evaluate the risk of AF recurrence and MACCE, a Cox proportional hazards regression analysis was performed, yielding estimates of the corresponding hazard ratios (HRs) and 95% confidence intervals (CIs), which were presented as HR (95% CI). Furthermore, logistic regression analysis was performed to pinpoint risk factors for MACCE, with P < 0.10 set as the significance threshold for inclusion in the model. We took into account potential confounding factors such as age, gender, type of AF, duration of AF since it was first diagnosed, CHA₂DS₂-VASc score along with its individual components, alcohol consumption, LAD of 40 mm or greater, and obesity (body mass index of 28.0 or higher).

AF - Atrial Fibrillation

DAT - diagnosis-to-ablation time

MACCE - Major Adverse Cardiovascular and Cerebrovascular Events

TIA- Transient ischemic attacks

LAD - Left Atrium Diameter

ECG - Electrocardiography

HR - Hazard Ratio

CI - Confidence Interval

CHA₂DS₂-VASc - Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (Doubled), Vascular Disease, Age 65–74, Sex Category (Female)

HAS-BLED - Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR (International Normalized Ratio), Elderly (>65), Drugs/Alcohol Concomitantly

Acknowledgments: Not applicable

Funding: This work was supported by Natural Science Foundation of China (81970282, 81930105, 82270331), and by Qingdao Key Clinical Specialty Elite Discipline (QDZDZK-2022008). The funding sources had no roles in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author contributions: ML conceptualized and executed the study, gathered and interpreted the data, and prepared the initial draft of the manuscript. BR, KZ, TC, and JW were involved in study design, conducted the research, and contributed to writing portions of the manuscript. WH, LY, and CC were responsible for data acquisition and follow-up, as well as data analysis. JZ and LW contributed to the study design, data analysis, and critically revised the manuscript. All authors have reviewed and given their final approval of the version to be published..

Data Availability Statements: The data underlying this article will be shared on reasonable request to the corresponding author.

Conflict of Interest: The authors declare they have no conflict of interest

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Table 1. Baseline and follow-up information

	All patients (n = 2097)	DAT≤1 (n = 923)	1 < DAT≤3 (n = 516)	DAT > 3(n = 658)
Age, mean (SD) (years)	59.98(10.57)	58.40(11.12)	61.16(10.35)*	61.28(9.63)*
60–64	412(19.6%)	166(18.0%)	116(22.6%)	130(19.8%)
65–74	578(27.6%)	220(23.8%)	159(30.8%)	199(30.2%)
≥75	165(7.9%)	64(6.9%)	47(9.1%)	54(8.2%)
Male	1315(62.7%)	608(65.9%)	311(60.3%)*	396(60.2%)*
Persistent AF	807(38.5%)	429(46.5%)	164(31.8%)*	214(32.5%)*
DAT, mean (SD) (months)	35.88(38.94)	5.37(4.53)	27.97(6.51)*	84.88(31.84)*
Congestive heart failure	42(2.0%)	24(2.6%)	7(1.4%)	11(1.7%)
Hypertension	1030(49.1%)	431(46.7%)	257(49.8%)	342(52.0%)*
Diabetes mellitus	342(16.3%)	143(15.5%)	86(16.7%)	113(17.2%)
Prior stroke/TIA/systemic embolism	207(9.9%)	85(9.2%)	54(10.5%)	68(10.3%)
Vascular disease	452(21.6%)	168(18.2%)	105(20.3%)	179(27.2%)*
CHA₂DS₂-VASc score, mean (SD)	1.9(1.57)	1.74(1.58)	1.99(1.54)*	2.05(1.55)*
Triglyceride glucose index	8.56(0.56)	8.58(0.56)	8.55(0.55)	8.55(0.55)
HAS-BLED score, mean (SD)	0.52(0.66)	0.46(0.65)	0.57(0.67)*	0.57(0.67)*
Renal disease	2(0.1%)	2(0.2%)	0(0%)	0(0%)
Liver disease	12(0.6%)	9(1.0%)	1(0.2%)	2(0.3%)
Anemia	10(0.5%)	7(0.8%)	2(0.4%)	1(0.2%)
Alcohol consumption	481(22.9%)	222(24.1%)	112(21.7%)	147(22.3%)
Body mass index, kg/m², mean (SD)	26.17(3.51)	26.25(3.58)	26.07(3.55)	26.12(3.39)
LAD 40 -50mm	913(43.5%)	416(45.1%)	215(41.7%)	282(42.9%)
>50mm	144(6.9%)	71(7.7%)	35(6.8%)	38(5.8%)
Observational period prescription
Non-vitamin k oral anticoagulants	1885(89.9%)	828(89.7%)	466(90.3%)	591(89.8%)
Warfarin	199(9.5%)	80(8.7%)	52(10.1%)	67(10.2%)
Antiplatelet drugs	328(15.6%)	147(15.9%)	92(17.8%)	89(13.5%)
ACEI/ARB	514(24.5%)	225(24.4%)	120(23.3%)	169(25.7%)
Statins	594(28.3%)	247(26.8%)	162(31.4%)	185(28.1%)
Follow-up duration, mean(SD) (months)	46.89(16.46)	46.06(16.37)	48.17(17.04)	47.07(16.08)
AF recurrence	516(24.6%)	216(23.4%)	123(23.8%)	177(26.9%)
Persistent AF recurrence	63(3.0%)	20(2.2%)	10(1.9%)	33(5.0%)
Cardiovascular rehospitalization	309(14.7%)	129(14.0%)	83(16.1%)	97(14.7%)
Major cardiovascular and cerebrovascular events	123(5.9%)	57(6.2%)	31(6.0%)	35(5.3%)
New stroke/TIA/systemic embolism	68(3.2%)	33(3.6%)	19(3.7%)	16(2.4%)
Acute myocardial infarction	16(0.8%)	7(0.8%)	5(1.0%)	4(0.6%)
Advanced heart failure	13(0.6%)	5(0.5%)	3(0.6%)	5(0.8%)
Major bleeding	2(0.1%)	1(0.1%)	0(0%)	1(0.1%)
Deaths	38(1.8%)	16(1.7%)	7(1.4%)	15(2.3%)
Long-term prescription
Oral anticoagulants	389(18.6%)	182(19.7%)	85(16.5%)	122(18.5%)
Antiarrhythmic drugs	210(10.0%)	85(9.2%)	47(9.1%)	78(11.9%)
Antiplatelet drugs	680(32.4%)	321(33.8%)	163(31.6%)	205(31.2%)
ACEI/ARB	729(34.8%)	330(35.8%)	168(32.6%)	231(35.1%)
Statins	852(40.6%)	370(40.1%)	227(44.0%)	255(38.8%)
Abbreviations: DAT, diagnosis-to-ablation time; AF, atrial fibrillation; CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 years, sex category (female); HAS-BLED, hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs or alcohol concomitantly; LAD, left atrial diameter; ACEI, angiotensin converting enzyme inhibitors; ARB, Angiotensin receptor blockers.
* P < 0.05, compared withDAT≤1year

Table 2. Univariable and multivariable cox regression for atrial fibrillation recurrence (n=2097)

Variable	Univariate		Multivariate
Variable	HR(95%CI)	P-value	HR(95%CI)	P-value
Age	1.002(0.994–1.011)	0.564	0.999(0.989–1.010)	0.883
Female	1.253(1.052–1.492)	0.012	1.319(1.078–1.614)	0.007
Persistent AF	1.114(0.934–1.328)	0.229	1.068(0.888–1.284)	0.484
DAT intervals
DAT≤1 year	Reference	-
1 year < DAT≤3years	1.003(0.804–1.251)	0.980
DAT > 3 years	1.180(0.967–1.439)	0.103
Congestive heart failure	0.897(0.464–1.733)	0.745
Hypertension	1.027(0.864–1.221)	0.761
Diabetes mellitus	1.592(1.293–1.960)	0.000	1.588(1.252–2.012)	0.000
Prior stroke/TIA /systemic embolism	0.984(0.733–1.321)	0.915
Vascular disease	1.094(0.890–1.344)	0.392
CHA₂DS₂-VASc score	1.061(1.005–1.119)	0.031	0.973(0.894–1.058)	0.515
HAS-BLED score	0.918(0.803–1.050)	0.212
Alcohol consumption	0.871(0.704–1.077)	0.201
LAD ≥ 40 mm	1.371(1.154–1.630)	0.000	1.318(1.097–1.584)	0.018
Observational period prescription
ACEI/ARB	1.166(0.954–1.424)	0.133
Statins	1.029(0.830–1.274)	0.796
Long-term prescription
ACEI/ARB	1.097(0.916–1.313)	0.315
Statins	1.090(0.909–1.306)	0.354
Obesity#	1.239(1.029–1.493)	0.024	1.163(0.962–1.404)	0.118
Abbreviations: DAT, diagnosis-to-ablation time; AF, atrial fibrillation; CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 years, sex category (female); HAS-BLED, hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs or alcohol concomitantly; LAD, left atrial diameter.
# BMI ≥ 28.0

Table 3. Univariable and multivariable cox regression for atrial fibrillation recurrence in persistent AF patients (n=807)

Variable	Univariate		Multivariate
Variable	HR(95%CI)	P-value	HR(95%CI)	P-value
Age	1.005(0.992–1.017)	0.477	0.999(0.984–1.013)	0.842
Female	1.219(0.917–1.621)	0.173	1.302(0.952–1.781)	0.098
DAT intervals
DAT≤1 year	Reference	-
1 year < DAT≤3years	1.106(0.768–1.591)	0.589	1.052(0.702–1.577)	0.806
DAT > 3 years	1.548(1.139–2.102)	0.005	1.496(1.077–2.076)	0.016
Congestive heart failure	0.777(0.345–1.750)	0.542
Hypertension	0.934(0.713–1.225)	0.623
Diabetes mellitus	1.444(1.016–2.052)	0.040	1.332(0.916–1.936)	0.133
Prior stroke/TIA /systemic embolism	0.998(0.647–1.539)	0.992
Vascular disease	1.042(0.731–1.487)	0.819
CHA₂DS₂-VASc score	1.020(0.937–1.111)	0.647
HAS-BLED score	0.885(0.713–1.097)	0.264
Alcohol consumption	0.895(0.653–1.227)	0.491
LAD ≥ 40 mm	1.533(1.126–2.088)	0.007	1.482(1.062–2.069)	0.021
Observational period prescription
ACEI/ARB	1.353(0.999–1.831)	0.051	1.195(0.876–1.632)	0.261
Statins	1.240(0.893–1.722)	0.199
Long-term prescription
ACEI/ARB	1.227(0.932–1.615)	0.146
Statins	1.024(0.769–1.364)	0.870
Obesity#	1.164(0.872–1.552)	0.302
Abbreviations: DAT, diagnosis-to-ablation time; AF, atrial fibrillation; CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 years, sex category (female); HAS-BLED, hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs or alcohol concomitantly; LAD, left atrial diameter.
# BMI ≥ 28.0

Table 4. Univariable and multivariable logistic regression for major cardio- and cerebrovascular events (n=2097)

Variable	Univariate		Multivariate
Variable	HR(95%CI)	P-value	HR(95%CI)	P-value
Age	1.047(1.027–1.067)	0.000	1.043(1.008–1.078)	0.014
Female sex	1.204(0.832–1.744)	0.325	0.751(0.449–1.255)	0.275
Persistent AF	1.267(0.877–1.830)	0.207	1.080(0.653–1.788)	0.764
DAT intervals
DAT≤1 year	Reference	-	Reference	-
1 year < DAT≤3years	0.971(0.618–1.525)	0.899	0.923(0.513–1.661)	0.788
DAT > 3 years	0.854(0.553–1.316)	0.474	0.745(0.419–1.325)	0.316
Congestive heart failure	0.386(0.053–2.833)	0.350
Hypertension	1.445(1.000-2.089)	0.050	0.919(0.521–1.621)	0.770
Diabetes mellitus	1.807(1.178–2.755)	0.007	1.449(0.802–2.617)	0.219
Prior stroke/TIA /systemic embolism	0.798(0.411–1.549)	0.505
Vascular disease	1.550(1.036–2.319)	0.033	2.225(1.135–4.362)	0.020
High CHA₂DS₂-VASc score*	2.145(1.477–3.115)	0.000	1.422(0.855–2.374)	0.380
HAS-BLED score	1.600(1.252–2.045)	0.000	1.183(0.764–1.831)	0.451
Alcohol consumption	0.761(0.478–1.212)	0.250
LAD ≥ 40 mm	1.607(1.111–2.325)	0.012	1.425(0.855–2.374)	0.174
ACEI/ARB	1.217(0.794–1.866)	0.367
Statins	1.937(1.204–3.116)	0.006	1.543(0.933–2.554)	0.091
Obesity#	0.999(0.665–1.501)	0.997
Abbreviations: AF, atrial fibrillation; CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 years, sex category (female); HAS-BLED, hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs or alcohol concomitantly; LAD, left atrial diameter.
* >1 in male or > 2 in female; # BMI ≥ 28.0

No competing interests reported.

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Optimal Timing for Atrial Fibrillation Patients to Undergo Catheter Ablation: Insights from Long-Term Outcome Studies

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