Efficacy and Safety of Ablation for Symptomatic Atrial Fibrillation in Elderly Patients: A Meta-Analysis

Background: Age affects the efficacy of pharmacological treatment for atrial fibrillation (AF). Catheter ablation, including radiofrequency (RF) or cryoballoon ablation, is an effective strategy for symptomatic AF. This meta-analysis aimed to analyze the efficacy and safety of AF ablation in elderly patients with AF compared to non-elderly patients with AF. Methods: We searched several databases for articles published between January 1, 2008 and March 31, 2020. Eighteen observational studies with 21,039 patients were analyzed. Data including recurrence of AF or atrial tachyarrhythmia (ATA), complications, procedural time, and fluoroscopic time were compared between the elderly and non-elderly groups. Results: The elderly patients had significantly higher incidences of recurrent AF or ATA after AF ablation compared to the non-elderly patients (<60 years old) (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.11–1.33). The elderly patients had significantly higher incidences of complications of AF ablation compared to the non-elderly patients (OR, 1.37; 95% CI, 1.14–1.64). However, elderly AF patients with age ≥75 years old had similar incidence of recurrent AF or ATA and complication after AF ablation compared to non-elderly patients with AF. Conclusions: The elderly patients had significantly higher incidences of recurrent AF or ATA and complications after ablation for non-paroxysmal AF compared to non-elderly patients with AF (<60 years old), except in patients ≥75 years old.


INTRODUCTION
As the elderly population grows and the quality of the healthcare system improves, the burden of treating elderly patients with atrial fibrillation (AF) increases gradually (1,2). However, higher ischemic risks and less effectiveness of antiarrhythmic medications are expected in elderly patients with AF (3,4). Therefore, there is still a big challenge for physicians to treat elderly patients with AF. In addition, the elderly patients with AF tend to have a large left atrium with electrical and structural remodeling and fibrosis, which also reduce the efficacy of pharmacological treatment (5,6). Catheter ablation has recently emerged as an important therapeutic strategy to achieve and maintain a normal sinus rhythm in symptomatic patients with AF (7,8). Moreover, catheter ablation for AF has been reported to reduce mortality and HF readmission in patients with heart failure (HF) (9). The prevalence of HF was higher in the elderly population than in the younger population (10). However, the efficacy and safety of catheter ablation in elderly patients with AF have not been clearly explored. Previous studies comparing the outcomes of AF ablation between elderly and non-elderly populations had different criteria for elderly or different age distribution and had inconsistent results. This study aimed to explore the efficacy and safety of AF ablation in elderly patients with AF compared to non-elderly patients with AF.

Search Strategies, Trial Selection, Quality Assessment, Review Process, and Data Extraction
Systematic literature searches for published articles between January 1, 2008 and December 31, 2020, in PubMed, Embase, Cochrane Library, ProQuest, ScienceDirect, ClinicalKey, Web of Science, and ClinicalTrials.gov were separately performed by two cardiologists. The keywords "elderly, " "atrial fibrillation ablation, " "radiofrequency ablation, " "cryoballoon ablation, " and "efficacy" were used. We did not set language restrictions to increase the number of eligible articles, and disagreements were resolved by a third reviewer. Only randomized controlled trials and clinical studies that compared the clinical outcomes between elderly and non-elderly groups of different age distributions after non-valvular AF ablation were included in the present FIGURE 1 | Flowchart of the selection strategy and inclusion and exclusion criteria for this meta-analysis. AF, atrial fibrillation. meta-analysis. The inclusion criteria were human studies with a parallel design. The exclusion criteria included conference abstracts, case reports or series, animal studies, and review articles. Figure 1 illustrates the literature search and screening protocol. Our search identified 258 articles after removing duplicates. Among them, 18 observational and cohort studies with 21,039 participants met our inclusion criteria and were included in this study.

Assessment of Risk of Bias in the Included Studies
The risk of bias in the included studies was appraised by two independent reviewers (WC Lee and PJ Wu) according to the Risk Of Bias In Non-Randomized Studies Of Interventions (ROBINS-I) tool, with disagreements resolved by consensus or by arbitration with a third author (HY Fang). The ROBINS-I requires the assessment of the following domains: bias due to confounding, bias in selection of participants into the study, bias in measurement of exposure, bias in Departures from exposure, bias due to missing data, bias in measurement of the outcome, and bias in selection of the reported result.

Statistical Analysis
All analyses were performed using the Comprehensive Meta-Analysis software, version 3 (Biostat Inc., Englewood, NJ, USA) and Cochrane RevMan software (version 5.4.1). The frequency of each evaluated outcome was extracted from each study and was presented as the cumulative rate. The standardization of each evaluated result originated from each study was presented as standardized mean differences (SMDs). A random-effects model was used to pool individual odds ratios (ORs). The chi-square test was used to evaluate heterogeneity across trials (p ≤ 0.1, considered significant). I 2 statistics (>50% was considered significant heterogeneity) was used to examine each outcome. Funnel plots and Egger's test were used to access potential publication bias (p ≤ 0.1 was considered significant). Statistical significance was set at p < 0.05.

Characteristics of Included Studies
The study selection process is displayed in Figure 1, and 18 studies met the inclusion criteria. In total, 21,039 participants were included. The definition of elderly in each study, participant characteristics, study period, and ablation method are shown in Table 1. The definition of elderly or age distribution differed between enrolled studies including those aged ≥60 (11, 12), ≥65 (13-16), ≥70 (17, 18), ≥75 (19-24), and ≥80 (25-28) years. One study with RF ablation and cryoballoon ablation was excluded in the analysis for ablation method and procedural complications (16).

DISCUSSION
This meta-analysis study showed that elderly patients with AF had a significantly higher incidence of recurrent AF or ATA after AF ablation compared to non-elderly patients with AF (<60 years old), except in patients ≥75 years old. Compared to non-elderly patients with AF, elderly patients with AF had a significantly higher incidence of recurrent AF or ATA after AF ablation for mixed-type (paroxysmal and non-paroxysmal) AF. However, there was no difference in terms of recurrent AF or ATA after AF ablation for paroxysmal AF between elderly and non-elderly patients with AF. The elderly patients with AF had a significantly higher incidence of complication of AF ablation compared to non-elderly patients with AF, except in patients ≥75 years old. There was no difference in the procedure time and fluoroscopic time between elderly and non-elderly patients AF. The elderly group had significantly higher prevalence of diabetes mellitus, hypertension, heart failure, coronary artery disease, and paroxysmal AF compared to the non-elderly group. Except for age, more comorbidities also influenced the incidence of recurrent AF or ATA after AF ablation.
AF is a progressive and an important disease in the elderly population. In addition, age has a great impact in the development of AF and imposes significant limitations in the treatment of AF because of the higher prevalence of conduction abnormalities that limits the use of pharmacological rate or rhythm control strategies (29). AF ablation is effective in achieving and maintaining sinus rhythm, and is associated with lower mortality, improved quality of life, and a lower risk of progression to permanent AF (29,30). Ablation is an effective strategy in treating symptomatic AF in selected elderly patients as a stand-alone therapy or as hybrid therapy with anti-arrhythmic medication, and is associated with decreased healthcare resource utilization in all age groups (19,20). The current guidelines recommended ablation strategy for patients with symptomatic AF associated with heart failure and not specific comment of ablation strategy for the elderly patients (7,8). Traditionally, the definition of elderly was aged 60 or 65 years and over (31). Recently, some researchers redefined elderly as age ≥75 years old (32).
Many papers reported similar efficacy of AF ablation (11, 12, 14-16, [18][19][20][21][22][23][24][25][26][27][28], and similar safety in elderly patients (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Leong-Sit et al. reported a relatively lower complication rate and higher possibilities in freedom from AF off anti-arrhythmic  years was the only predictor of cerebrovascular events after AF ablation in patients ≥65 years old (14). However, all studies were observational studies, and most had limited patient numbers. Of note, in this study, we found that elderly AF patients with age ≥75 years old had similar incidence of recurrent AF or ATA and complication after AF ablation compared to non-elderly patients with AF (<60 years old). However, elderly patients with AF (60-74 years old) had a significantly higher incidence of recurrent AF or ATA and complication after AF ablation compared to non-elderly patients with AF (<60 years old). The mechanisms responsible for discrepancy remain unexplored. Most aged patients had structural and electrical remodeling in left atrium due to longer AF duration and had more comorbidities (5,12,15). After ablation, the degree of reverse electrical and structural remodeling of the left atrium may be influenced by longer AF duration and more comorbidities (33). In addition, a higher prevalence of AF or ATA originating from the nonpulmonary vein triggers in the aged population could contribute to the recurrence of AF or ATA by ablation strategy with pulmonary vein isolation alone. However, more ablation to include non-pulmonary vein triggers may increase the risk of complications.

LIMITATIONS
This study has several limitations. First, all studies were observational cohort studies and not all studies provided detailed information about the AF ablation procedure. Second, the age distribution in each study was not the same. However, a total of 21,039 participants were enrolled from 18 studies. The present study provides important findings on the outcomes of AF ablation in the elderly population with AF. However, large and randomized studies are warranted to validate these findings.

CONCLUSION
The elderly patients with AF had significantly higher incidences of recurrent AF or ATA and complications after ablation for nonparoxysmal AF compared to the non-elderly patients with AF (<60 years old). However, the efficacy and safety of AF ablation in AF patients ≥75 years old were similar to those of non-elderly patients with AF.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
W-CL and P-JW reviewed the articles and wrote the manuscript. H-YF and H-CC prepared figures. P-YL and M-CC did the final revision. All authors reviewed the manuscript.