Does Catheter Ablation Lower the Long-Term Risk of Stroke and Mortality in Patients with Atrial Fibrillation? A Concise Review of the Current State of Knowledge

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and carries a significant risk of morbidity and mortality. Multiple trials have highlighted the benefit of catheter ablation over medical therapy in restoring sinus rhythm and improving quality of life. Whether it reduces long-term risk of stroke and mortality is still unclear. We performed a literature search using the PubMed database to review the current state of knowledge regarding the long-term outcomes of stroke and mortality in ablated patients compared to patients who receive medical therapy. Our review mainly consisted of recent randomized controlled trials and large observational studies. Results from large observational studies show that catheter ablation significantly reduces the risk of stroke in high-risk patients and mortality compared to medical therapy. However, randomized controlled trials have only demonstrated a mortality benefit in patients with comorbid systolic heart failure. In patients with paroxysmal AF, ablation therapy significantly limits the progression to persistent AF and has a higher efficacy in restoring sinus rhythm. Maintenance of sinus rhythm is the most important factor associated with lower long term risk of stroke and mortality. Large randomized controlled trials similar to the Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial are still needed to clarify whether catheter ablation is superior over medical therapy in improving the long-term outcomes of stroke and mortality.


Introduction And Background
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is regarded as a future epidemic among aging populations with an estimated worldwide prevalence of 0.51% and consistently increasing incidence rates [1]. It imposes a five-fold increased risk of stroke and a two-fold increased risk of dementia and mortality [2,3]. From another perspective, atrial fibrillation receives an annual share of 26 billion dollars of the US healthcare expenditure, and the increasing rate of incidence predicts further cost burden in the future [2].
Treatment for atrial fibrillation is either pharmacological or non-pharmacological. As for pharmacological therapy, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was set to settle the long-standing debate of rate control vs. rhythm control and concluded that there was no superiority to either strategy. However, the investigators reported more adverse effects in the rhythm control arm, which could have potentially masked the results that failed to show any benefit (mortality or stroke risk reduction) for maintaining sinus rhythm [4].
Catheter ablation is the non-pharmacological form of therapy that has gained popularity in recent years. Randomized controlled trials have shown that in comparison to anti-arrhythmic drugs, catheter ablation is more successful in reducing arrhythmia recurrence and improving quality of life [5][6][7][8]. However, data comparing the long-term outcomes of stroke and mortality is still insufficient [9]. In this article, we review the current evidence to highlight whether there is any long-term benefit of catheter ablation over anti-arrhythmic drug therapy.

Review
The literature search ( Table 1) was performed on the PubMed database using regular keywords. Studies were then filtered based on the following inclusion and exclusion criteria.  After applying the inclusion criteria, search results (224 in total) were then manually reviewed to apply exclusion criteria, yielding 32 relevant articles that did not include case reports, case series, systematic reviews, and meta-analyses. Of the 32 articles, 16 were observational studies (mostly retrospective cohort), five were review articles, and 11 were randomized controlled trials. In addition, the American Heart Association (AHA)/American College of Cardiology (ACC) 2014 and 2019 guidelines were also reviewed to shed light on current treatment guidelines. Total study subjects of clinical trials were 5,542 compared to 98,445 patients who were enrolled in observational studies. Twenty-seven of the 32 chosen articles have been published within the last six years (84.375%). The review encompasses catheter ablation in AF patients with and without heart failure (HF). Figure 1 summarizes the literature search process. In the analysis of selected articles for the presented literature, we found sufficient evidence of the long-term benefit of catheter ablation in specific sub-populations of AF patients. However, evidence on whether catheter ablation reduces mortality and stroke risk in all patients with atrial fibrillation is still lacking. Articles reviewed specifically point to mortality benefit in patients with AF and HF [10][11][12], along with stroke risk reduction in patients with AF and high CHA₂DS₂-VASc score (≥2) [13][14][15]. Multiple studies have also highlighted that maintaining sinus rhythm was the most important factor in predicting stroke-free survival and lower mortality [15][16][17]. Furthermore, besides the current consensus of preserving catheter ablation for symptomatic patients with drug-refractory atrial fibrillation [18], there is sufficient evidence that catheter ablation for patients with paroxysmal AF is highly effective in curtailing progression to persistent AF [19] and achieves better results of sinus rhythm maintenance [20]. Observational studies showing a mortality benefit with catheter ablation are summarized in Table 2  However, treatment assignment sensitivity analysis showed that there is a benefit for ablation over medical therapy if patients assigned to ablative therapy did receive ablation. Moreover, there was a 27% crossover from the medical therapy group to the ablation group, which highlights the relative inefficacy and hazardous side effect profile of antiarrhythmic medications. In a recent, large 2019 propensity-matched observational study it was also concluded that there was no difference in mortality and cardiovascular deaths between ablated patients and medically treated patients [26]. The study follow-up period, however, was only one year, which may indicate that the mortality benefits of ablation therapy are not seen before ≥ two years of post-ablation follow-up.
AF and heart failure are frequently co-existent conditions. It is often difficult for clinicians to determine the 'chicken-egg' relationship between the two as both conditions share similar risk factors and may lead to each other. Atrial fibrillation compromises left ventricular function due to loss of atrial systole and may cause tachycardia-mediated cardiomyopathy [27], while heart failure may induce atrial remodeling and fibrosis, which promotes AF. Multiple studies (   [31]. Regarding the long-term risk of stroke, in 2017, a large study in Israel investigated the longterm outcomes of ablation therapy in 969 patients against a propensity score-matched cohort of 3772 non-ablated patients (ratio of 1: ≤4). At baseline, most of the study subjects in both groups were at high risk for stroke (mean CHA₂DS₂-VASc score: 3.6 ± 2.0). However, after longterm follow-up, the rates of transient ischemic attack (TIA), stroke, and mortality were significantly lower among the ablation group compared with the non-ablation group [13]. Other previously discussed observational studies have reported similar findings among patients at high risk for stroke [14][15][16] Furthermore, in patients with a previous history of cerebrovascular accident, it was found that the risk of a subsequent stroke in ablated AF patients was similar to that of non-AF patients and significantly lower than that of non-ablated AF patients [32]. Despite the apparent benefit, the role of oral anticoagulants (OACs) in stroke prevention should not be overlooked in ablated patients. In a large recent study of US national registry data, it was found that in about one out of four patients treated with catheter ablation, OACs were discontinued despite having a high risk of stroke (CHA₂DS₂-VASc ≥ 2) [26]. A recent propensity-matched retrospective cohort study in Japan investigated the long-term risk of stroke in ablated patients with non-ablated patients. It was found that there was no difference in the incidence of stroke between ablated and nonablated patients over a follow-up period of 28.0 ± 17.1 months despite significantly lower rates of mortality and cardiovascular deaths in the ablated group. Interestingly, OACs were discontinued in 230 out of 512 ablated patients, among which 25% had a CHA₂DS₂-VASc score >3 [21]. Thus, it remains clear that ablation therapy should not be used for the sake of discontinuing OACs in patients at high risk of stroke, but instead both therapies should be combined for better mitigation of stroke risk.
Some studies suggest a unique advantage for ablation therapy in patients with paroxysmal AF. In these patients, it has been found that catheter ablation limits the progression to persistent AF by a rate of <3% over two to five years compared to a rate of 11-26% over one year observed in medically treated patients [19]. Furthermore, in another study, it was found that patients with paroxysmal AF were more likely to maintain sinus rhythm after ablation therapy compared to those with persistent AF (proportion of time in sinus rhythm: 0.74 ±0.34 vs. 0.52±0.38; p<0.0001) [20]. The mortality rate in this study was significantly higher over 10 years in patients with persistent AF than those with paroxysmal AF and similar to other studies, maintenance of sinus rhythm was associated with a substantially lower risk of cardiac mortality (HR: 0.41; 95% CI:0.20-0.84, p=0.015). Predictors of mortality were age, comorbid diseases (coronary artery disease, hypertension, diabetes mellitus, and obstructive sleep apnea), lower LVEF, and increased left atrium (LA) size.
Discussing long-term outcomes of a procedure may seem futile if we do not consider the different modes of carrying it out and whether one method is more successful. In 2019, a randomized controlled trial on 346 patients with drug-refractory paroxysmal AF compared radiofrequency ablation with 2-minute cryoballoon ablation and 4-minute cryoballoon ablation. All patients were subjected to continuous rhythm monitoring using an implantable loop recorder to test the primary outcome of freedom from arrhythmia recurrence at one year. The efficacy of the three procedures at one year was not statistically different (79.1% in radiofrequency group vs. 78.2% in 4-minute cryoballoon ablation group, and 73.3% in the 2minute cryoballoon ablation; p=0.26).
In general, catheter ablation is considered a relatively safe procedure with a low risk of complications. Results from the California Study of Ablation for Atrial Fibrillation (CAABL-AF) study that included 4169 ablated patients showed a 0.001% risk of mortality and 0.003% risk of stroke within 30 days of the procedure [22]. Another propensity-matched retrospective study compared the outcome of stroke in 12,177 ablated patients to an equal group of cardioversion patients and found out that the initial risk of stroke within 30 days of the procedure was higher in the ablation group (RR: 1.53; P=0.05) [33]. In contrast, a 2014 randomized controlled trial investigated the periprocedural (within 48 hours of ablation) risk of stroke in patients who discontinued warfarin before the procedure (bridged with heparin) versus patients who were maintained on warfarin and found that uninterrupted warfarin reduced the risk of thromboembolic events by 95% [34]. This finding surely carries a lot of weight in reducing periablation stroke risk and shall modify the current standards of practice, especially if complemented by other similar trials.
The main limitation of this study is that we did not include data from systematic reviews and meta-analyses. However, most of the studies reviewed were recent large observational studies or randomized controlled trials to shed light on the latest state of knowledge.

Conclusions
Several observational studies have found that catheter ablation for atrial fibrillation reduces long-term risk of stroke and mortality compared to medical therapy. Randomized controlled trials have mainly demonstrated this benefit in the HF population but not the non-HF population. Reduction in stroke risk was most significant among patients with a high CHA₂DS₂-VASc score (≥2) and those with a previous history of stroke, provided anti-coagulant therapy is not discontinued. The most important factor implicated in the reduction of stroke and mortality is maintenance of sinus rhythm, which is better achieved by ablation therapy compared to anti-arrhythmic medications. Catheter ablation may offer a special advantage in patients with paroxysmal AF since it has been shown to better limit its progression to persistent AF than anti-arrhythmic medication. Furthermore, patients with paroxysmal AF who undergo catheter ablation tend to maintain sinus rhythm for a larger proportion of time than persistent AF patients. Catheter ablation is considered a relatively safe procedure with minimal periprocedural stroke and mortality risk. Periprocedural stroke risk is significantly reduced when warfarin therapy is maintained as opposed to warfarin discontinuation and bridging with heparin before the procedure. Large randomized controlled trials similar to the CABANA trial are still needed to confirm the long-term benefit of catheter ablation over medical therapy, as shown by observational studies as findings of the CABANA trial have been inconclusive and showed no significant superiority.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.