Longer diagnosis‐to‐ablation time is associated with recurrence of atrial fibrillation after catheter ablation—Systematic review and meta‐analysis

Abstract Background Diagnosis‐to‐ablation time (DTAT) has been postulated to be one of the predictors of atrial fibrillation (AF) recurrence, and it is a “modifiable” risk factor unlike that of many electrocardiographic or echocardiographic parameters. This development may change our consideration for ablation. In this systematic review and meta‐analysis, we aim to analyze the latest evidence on the importance of DTAT and whether they predict the AF recurrence after catheter ablation. Methods We performed a comprehensive search on topics that assess diagnosis‐to‐ablation time (DTAT) and AF recurrence from inception up until August 2019 through PubMed, EuropePMC, Cochrane Central Database, and http://ClinicalTrials.gov. Results There was a total of 3548 patients from six studies. Longer DTAT was associated with increased risk for AF recurrence in all studies included. Meta‐analysis of these studies showed that DTAT had a hazard ratio (HR) of 1.19 [1.02, 1.39], P = .03; I 2: 92% for AF recurrence. Upon sensitivity analysis by removing a study, HR became 1.24 [1.16, 1.32], P < .001; I 2: 29%. Meta‐analysis on DTAT time >3 years had HR 1.73 [1.54, 1.93], P < .001; I 2: 45% for the recurrence of AF. Upon subgroup analysis of data that compared >6 years to <1 year, the HR was 1.93 [1.62, 2.29], P < .001; I 2: 0%. Conclusion Longer DTAT time is associated with an increased risk of AF recurrence. Hence, determining management at the earliest possible moment to avoid delay is of utmost importance.


| INTRODUC TI ON
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide. 1 Despite advances in catheter ablation technology, the recurrence for AF is high, ranging from 46.2% to 60.0% in a single-procedure ablation in a 2013 meta-analysis. 2 The number of recurrences is expected to decrease with new methods of ablation. 3 Nevertheless, effort to predict the recurrence of AF is an exciting development. [4][5][6][7] It enables physicians to stratify the risk of AF recurrence and weight the risk and benefit on the patients before performing catheter ablation.
Recently, longer diagnosis-to-ablation time (DTAT) has been postulated to be one of the predictors of AF recurrence. 8 Diagnosisto-time ablation is a "modifiable" risk factor unlike to that of many electrocardiographic or echocardiographic parameters; this risk factor can be minimized. This development is exciting because it may change our consideration for ablation. In this systematic review and meta-analysis, we will analyze the latest evidence on the importance of DTAT and whether they predict the AF recurrence after catheter ablation. To the best of our knowledge, this is the first meta-analysis on the DTAT and its impacts on AF recurrence after catheter ablation.

| Search strategy
We performed a comprehensive and systematic literature search on topics that assesses DTAT and AF recurrence with keywords ["diagnosis to ablation time", "atrial fibrillation", and "recurrence"] and its synonym from inception up until August 2019 through PubMed, EuropePMC, Cochrane Central Database, Clini calTr ials.gov and handsampling from potential articles cited by other studies. The records were then systematically evaluated using inclusion and exclusion criteria. We also perform hand-sampling from references of the included studies. Two researchers (R.P and V.C) independently performed an initial search, discrepancies were resolved by discussion. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of the literature search strategy of studies is presented in Figure 1.

| Selection criteria
The inclusion criteria for this study are all studies that assess the DTAT and AF recurrence. We include all related clinical researches/ original articles and exclude case reports, and review articles.

| Data extraction
Data extraction and quality assessment were done by two independent authors (R.P. and V.C.) using standardized extraction form which includes authors, year of publication, study design, sample size, pa-

| Statistical analysis
To perform the meta-analysis, we used RevMan version 5.3 software (Cochrane Collaboration). We used the hazard ratio (HR) and a 95% confidence interval. We used mean difference and its standard deviation as a pooled measure for the continuous data.
Inconsistency index (I 2 ) test, which ranges from 0% to 100%, was used to assess heterogeneity across studies. A value above 50% or P < .05 indicates statistically significant heterogeneity. We used the Inverse Variance method for HR with a fixed-effect model for meta-analysis, and a random-effect model was used in case of heterogeneity. All P values were two-tailed with a statistical significance set at .05 or below.

| RE SULTS
We found a total of 2462 results. We screened 2243 records after removing duplicates. Eight were relevant titles/abstract. After assessing eight full-text for eligibility, we excluded two because of (a) no outcome of DTAT on the recurrence of AF and (b) outcome cannot be used for meta-analysis due to different reporting. We included six studies in the qualitative synthesis and six studies in meta-analysis ( Figure 1; Table 1). [8][9][10][11][12][13] Five studies were prospective cohorts, and one study was a retrospective cohort. There was a total of 3548 patients from six studies.     Atrial fibrillation causes electrical and structural remodeling in the atrium, which further provides substrate, promote occurrence, and maintenance of AF and worsen the condition in a vicious cycle manner. 15 AF has a progressive nature and the complexity increases over time; hence, a longer DTAT means a lengthier period in which the atrium is in the aforementioned vicious cycle. 16 Theoretically, longer DTAT will have a more severe atrial remodeling compared to shorter DTAT and has a higher chance of AF recurrence after conversion to sinus rhythm.

| Clinical implication
The clinical implication of this finding might be extensive, although further studies should be conducted before integrating this finding to routine clinical practice. There are many electrocardiographic and echocardiographic predictors; however, not much can be done to reduce the risk for AF recurrence in these patients. Diagnosis-to-time ablation is a modifiable risk factor that is dependent on the physician and the patient's agreement. Early ablation is associated with a better AF freedom, however, to translate this to clinical practice, we suggest trials to perform ablation in within 1-3 years of AF diagnosis vs rhythm/rate control and also measures outcome such as major adverse cardiovascular events, mortality, safety, and quality of life.
Such trials will enable us to determine extensively whether more aggressive treatment is needed and may have the potential to change the landscape of AF treatment in the future.

| Study limitation
Limitation of this systematic review includes publication bias in which DTAT might not be reported by studies if it is not significant. The data regarding other outcomes based on DTAT were reported with a different format across the studies, that it was not possible to perform a meta-analysis on the outcome. Due to the limited number of studies and unavailability of data, the authors were unable to perform subgroup analysis or meta-regression to determine whether DTAT will affect paroxysmal and persistent AF differently.

| CON CLUS ION
Longer DTAT time is associated with an increased risk of AF recurrence. Hence, determining management at the earliest possible moment to avoid delay is of utmost importance. Currently, there are studies that indicate rate and rhythm control had similar effectiveness; however, there are no trials that perform ablation in within 1-3 years of AF diagnosis vs rhythm/rate control.
We suggest that further trials perform ablation on patients within 1-3 years of AF diagnosis, taking rate and/or rhythm as the control group.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interests for this article.