Impact of catheter ablation versus medical therapy on cognitive function in atrial fibrillation: a systematic review

Purpose Atrial fibrillation is associated with an increased risk of cognitive impairment. It is unclear whether the restoration of sinus rhythm with catheter ablation may modify this risk. We conducted a systematic review of studies comparing cognitive outcomes following catheter ablation with medical therapy (rate and/or rhythm control) in atrial fibrillation. Methods Searches were performed on the following databases from their inception to 17 October 2021: PubMed, OVID Medline, Embase and Cochrane Library. The inclusion criteria comprised studies comparing catheter ablation against medical therapy (rate and/or rhythm control in conjunction with anticoagulation where appropriate) which included cognitive assessment and/or a diagnosis of dementia as an outcome. Results A total of 599 records were screened. Ten studies including 15,886 patients treated with catheter ablation and 42,684 patients treated with medical therapy were included. Studies which compared the impact of catheter ablation versus medical therapy on quantitative assessments of cognitive function yielded conflicting results. In studies, examining new onset dementia during follow-up, catheter ablation was associated with a lower risk of subsequent dementia diagnosis compared to medical therapy (hazard ratio: 0.60 (95% confidence interval 0.42–0.88, p < 0.05)). Conclusion The accumulating evidence linking atrial fibrillation with cognitive impairment warrants the design of atrial fibrillation treatment strategies aimed at minimising cognitive decline. However, the impact of catheter ablation and atrial fibrillation medical therapy on cognitive decline is currently uncertain. Future studies investigating atrial fibrillation treatment strategies should include cognitive outcomes as important clinical endpoints. Supplementary Information The online version contains supplementary material available at 10.1007/s10840-022-01196-y.


Introduction
The prevalence of atrial fibrillation increases with age and atrial fibrillation results in an increased risk of morbidity and mortality from stroke and congestive cardiac failure amongst other chronic diseases [1]. Improvements in life expectancy have contributed to an increased prevalence of dementia [2].
Although there is accumulating evidence of a causal link between atrial fibrillation and cognitive impairment [3], the mechanism of interaction is unknown.
Atrial fibrillation treatment is heterogenous comprising the use of rhythm control, rate control and anticoagulation therapy. The impact of these treatment strategies on cognition is unclear. Rhythm control with catheter ablation may be more successful at restoring and maintaining sinus rhythm than anti-arrhythmic drugs [4]. However, catheter ablation is also associated with an increased risk of cerebral emboli, particularly in the immediate postablation period [5]. Studies which have examined cognition before and after atrial fibrillation ablation have provided conflicting results [6][7][8][9]. We hypothesised that the risk of cognitive decline may differ in atrial fibrillation patients treated with catheter ablation compared with medical therapy.
The aim of this study was therefore to provide a systematic assessment of the effect of catheter ablation versus medical therapy on cognitive function. We present a systematic review of the available literature assessing cognitive function following catheter ablation compared to medical therapy (comprising rhythm and/or rate control in conjunction with anticoagulation where appropriate) for all patients with atrial fibrillation.

Methods
This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines [10].

Data sources and searches
The PubMed, Ovid MEDLINE, Embase and Cochrane Library databases were searched from their inception to 17 October 2021. Reference lists of included articles were examined for additional studies. The search terms utilised were as follows: "atrial fibrillation" or "a fib" or "afib" or "AF" AND "cognition" or "cognitive impairment" or "cognitive" or "$dementia" or "$alzheimer" or "lewy" or "memory" or "vascular dementia" or "frontotemporal lobar" AND "catheter ablation" or "rfa" or "radiofrequency ablation" or "ablation" or "ca" or "cryoablation" or "cryoballoon" or "pulmonary vein."

Study selection and outcomes
Studies were included according to the following criteria: (1) studies which assessed cognitive function; (2) studies which included a diagnosis of dementia and/or its subtypes as an outcome; (3) studies which included both a group of atrial fibrillation patients treated with catheter ablation and patients treated with medical therapy (rate and/or rhythm control in conjunction with anticoagulation where appropriate). The following exclusion criteria were applied: (1) studies which did not include a group of patients treated with catheter ablation; (2) studies which did not include a group of patients treated with medical therapy; (3) case reports, editorials, reviews, conference proceedings and guidelines were excluded.
References were obtained and uploaded to Rayyan software [11]. Duplicate articles were removed. Two independent reviewers (NB and RY) screened the titles and abstracts of the studies. Articles considered relevant were advanced to full text review. Disagreements were resolved by consensus decision amongst the two authors. It was planned for a third reviewer (SEW) to arbitrate if disagreements could not be resolved; however, this was not required.
Outcomes assessed included diagnosis of dementia and its subtypes. These were ascertained according to International Classification of Disease coding data. Changes in cognitive function were assessed. We categorised these changes as (1) changes ≤ 3 months after therapy and (2) changes > 3 months after therapy.

Data extraction and quality assessment
The following data from eligible studies were extracted (Table 1): PubMed ID, first author, year, country, follow up duration, study design, outcome measures, cognitive impairment ascertainment method, total number of study participants, number of patients who received catheter ablation, ablation procedure details, number of patients treated with medical therapy and details about the type of medical therapy used. Hazard ratios from propensity matched groups were used where available.
Quality assessment was performed using the Newcastle Ottawa Scale for cohort studies and a modified version for case-control studies. Three broad domains were evaluated including the selection of study groups, the comparability of these groups and the ascertainment of the exposure or assessment of outcome. An adequate follow up period was defined as 1 year for long-term cognitive function, and key control factors included stroke followed by age, gender and smoking history.

Statistical analysis
Statistical analyses were performed using Review Manager version 5.4.1. The individual studies included in the metaanalysis used Cox proportional hazard regression models to determine hazard ratios. Where meta-analysis was performed, heterogeneity was assessed, and an I 2 value ≥ 50% was considered significant. In this instance, a random-effects model was used to provide a more conservative estimate and because it is less influenced by the weighting of each study [12]. The inverse variance method based on a random-effects model was used to quantitatively summarise the outcome results and derive a pooled hazard ratio for dementia incidence in patients treated with catheter ablation versus medical therapy. A plan was made to assess for publication bias using visual inspection of funnel plot asymmetry if a minimum of 10 studies were included in the meta-analysis [13].

Screening
The search strategy yielded 599 studies after duplicate removal. Full-text screening was performed on 135 studies

Included studies
In the 10 included studies, 15,886 patients were treated with catheter ablation, and 42,684 patients were treated with medical therapy for atrial fibrillation. Detailed characteristics of the studies are provided in Table 1. Baseline characteristics of the study participants are detailed in supplementary  Table S1.

Cognitive function assessment
Numerous neuropsychological tests were utilised to assess cognitive function. These included mini mental state examination, Montreal cognitive assessment, Hasegwa dementia rating scale, national adult reading test, the visual analogue scale, the telephone interview for cognitive status-modified test and a well-established battery of 9 neuropsychological tests based on the Canadian Study of Health and Aging [23] ( Table 1). Reliable change indices, as described by Chelune et al. [24] and Rasmussen et al. [25], were used to track

Identification of studies via databases and registers
Identification Included Screening changes in individuals' test scores and assess for post ablation cognitive decline where reported.

New-onset dementia
Of the 10 studies included, 4 reported hazard ratios for dementia incidence [14][15][16][17] according to International Classification of Disease coding data. Due to the small number of included studies, we did not test for publication bias. The duration of follow-up varied amongst the studies (Table 1). These studies demonstrated an association between patients treated with catheter ablation therapy and a lower incidence of dementia. The 95% confidence intervals were available for 3 of these studies (Fig. 2). A pooled meta-analysis of these studies demonstrated a hazard ratio of 0.60 (95% confidence interval 0.42-0.88, p < 0.05 with an I 2 value of 50%). Hyogo et al. found that new onset dementia occurred in 8 of 2113 (0.4%) atrial fibrillation patients [18]. In the 614 patients who had been treated with catheter ablation, 3 (0.5%) had developed dementia over the 1 year follow up period. A hazard ratio was not obtained (potentially due to the low event rate). For the studies reporting numbers of patients who developed dementia, these data are summarised in supplementary Table S2.

Dementia subtypes
Two studies reported incidence of dementia subtypes: Alzheimer's disease and vascular dementia [15,17]. Both

Discussion
The major findings from this study were (1) there is a significant lack of randomised control trial evidence to assess the impact of catheter ablation versus medical therapy on cognitive outcomes in atrial fibrillation; (2) the impact of catheter ablation on the rate of cognitive decline in patients with and without pre-existing cognitive impairment is currently unknown; (3) the data currently available may suggest that patients treated with catheter ablation may have a lower risk of developing dementia; (4) the data regarding cognitive function in the immediate post ablation period are inconsistent necessitating further study to ascertain the short to medium term effects of catheter ablation on cognitive function.

Risk of dementia in catheter ablation versus medical therapy
The studies which examined the incidence of dementia all found catheter ablation may be associated with a lower risk of developing dementia during follow-up compared with medical therapy [14][15][16][17]. The studies varied in their follow up durations with Hsieh et al., demonstrating that this pattern persisted in patients with a follow up period of 9.0 years. These findings were consistent across populations studied in 3 different countries. It is important to interpret these findings with caution. Whilst attempts to correct for underlying baseline differences were made through propensity matching, it is possible that unmeasured differences amongst the groups may have contributed to the findings. Patients referred for catheter ablation may have been less likely to develop dementia for reasons other than the treatment modality itself. We therefore cannot exclude the possibility of a selection bias favouring catheter ablation.
The answer to the question of whether catheter ablation can prevent the onset of dementia in atrial fibrillation will come in the form of a randomised controlled trial.

The link between catheter ablation and cognitive decline
The mechanistic link between catheter ablation and cognitive decline remains to be elucidated. The resolution of cerebral hypoperfusion with sinus rhythm restoration through catheter ablation may prevent cognitive decline [27]. Interestingly, Jin et al. found that patients with sustained atrial fibrillation after catheter ablation had lower improvements in cognitive function at 1 year compared with patients who maintained sinus rhythm [20] suggesting that sinus rhythm maintenance may attenuate cognitive decline. A study by Piccini et al. performed in patients treated with catheter ablation for atrial fibrillation found that patients with recurrent atrial tachycardia and/or atrial fibrillation after ablation had similar improvements in Montreal cognitive assessment scores after 3 months compared with those who did not [28]. This study was performed in patients recruited from the AXAFA-AFNET 5 trial, a study comparing continuous apixaban therapy to vitamin K antagonist therapy during ablation [8]. Unfortunately, these studies do not precisely quantify atrial fibrillation burden throughout their follow up periods. Studies which attempt to correlate cognitive function with duration in sinus rhythm will need to be performed over longer time periods. This could potentially be done with implantable and/or wearable technologies to quantify atrial fibrillation burden. If sinus rhythm-induced improvement in cerebral perfusion was indeed the mechanism by which catheter ablation halted neurocognitive decline, then one could speculate that any rhythm control therapy would result in improvements in cognitive function. However, studies which have compared rhythm control therapy to rate control have provided conflicting results [29][30][31]. One plausible explanation for this discrepancy may be the variable efficacy of anti-arrhythmic medications to restore and maintain sinus rhythm. The effects of anti-arrhythmic medications and chemical cardioversion on cerebral perfusion patterns are currently unclear presenting an area for further study.
Verification of the precise interaction between atrial fibrillation rhythm control strategies and cognitive decline may enable tailored treatment towards subtypes of dementia. Our study showed that catheter ablation might be associated with a lower risk of Alzheimer's disease.
Chronic cerebral hypoperfusion is thought to exacerbate amyloid-beta neuropathology, through the upregulation of amyloid-beta producing enzymes and lowering of amyloid-beta clearing proteins [32]. Catheter ablation-induced resolution of hypoperfusion could explain this association. Intriguingly, the risk of vascular dementia was not lessened to the same extent. This may result from the association between catheter ablation and subclinical cerebral emboli [5].
The association of catheter ablation with asymptomatic cerebral infarcts has led to speculation that the procedure may increase the risk of cognitive impairment. The clinical significance of post ablation infarcts is unclear at present [33]. Asymptomatic cerebral infarcts have been related to an increased risk of dementia in the general population [34]. Whether this is true for the cerebral emboli which result from catheter ablation is unclear. Further studies are warranted to examine the impact of post ablation asymptomatic cerebral infarcts on cognitive function in the longer term.

Changes in cognitive function > 3 months after ablation
Three studies performed repeated cognitive function assessments at intervals over specified time periods [19,20,26]

Cognitive function ≤ 3 months after ablation
The association between catheter ablation and subclinical cerebral emboli [5] has led to speculation that catheter ablation may worsen cognitive function. A notable finding from our study was that Jin et al. found that catheter ablation was associated with cognitive assessment score improvement after 3 months [20] whereas Medi et al. found a worsening of cognitive function at this time period [21]. The studies differed in the type of ablation catheter utilised, their method of anaesthesia and anticoagulation strategies. Differences in method of anaesthesia may also contribute to the difference in post ablation cognitive decline incidence at 2 days in the studies by Zhang et al. and Medi et al. [21,22]. A lower proportion of patients in the study by Zhang et al. had their ablation under general anaesthesia compared with Medi et al. It is becomingly increasingly recognised that the procedural protocols and ablation tools used have an influence on the prevalence of silent cerebral infarcts [5]. Study heterogeneity is therefore likely to have contributed significantly to the differences in these results.

Limitations
The main limitation of our study was the lack of randomised control trial level evidence. This makes it difficult to make firm conclusions based on the data currently available. Questions pertaining to the impact of catheter ablation on cognitive function in patients with pre-existing cognitive impairment, risk of dementia and short-to medium-term cognitive function remain unanswered based on the evidence reviewed in this study. The lack of such data stresses the requirement for further study to investigate the impact of atrial fibrillation treatment modalities on cognitive function. Selection bias may have contributed to the findings of this review. For example, variations in age, sex and cardiovascular comorbidities between groups treated with either medical therapy or catheter ablation in the available literature may have contributed to differences in cognitive outcomes between groups. Most of the studies identified were observational in nature. Whilst 7 of the 10 studies attempted to match for confounders, unaccounted-for confounders could have explained some of the results observed. Additionally, various assessments of cognition were used. Some studies used an International Classification of Disease diagnosis of dementia as an endpoint whereas others used cognitive function assessments. Given the heterogeneity of these cognitive assessment methods, it is possible that the type of assessment used may have influenced the results observed. Most of the outcomes discussed in this review are therefore reported descriptively. This limitation reflects the limitations inherent in the available published data, again highlighting the need for further mechanistic research in this area.
The medical management and types of anticoagulation strategies utilised also differed likely resulting in variability amongst the studies. The same can be said of the ablation procedures used. Many of the studies included in the systematic review failed to provide details about the medical management and/or catheter ablation strategies employed (Table 1). This is likely to have affected the results obtained and importantly precludes meaningful assessment of the influence of procedural characteristics and choice of ablation technology on cognitive outcomes. Furthermore, baseline cranial imaging was not performed in the studies included. We cannot exclude the possibility of pre-existing abnormalities affecting the results of the studies.

Future directions
To mitigate the risk of selection bias, randomised trials are required to compare the effects of atrial fibrillation treatment strategies on cognition. The Cognitive Impairment in Atrial Fibrillation study (DIAL-F, ClinicalTrials.gov Identifier: NCT01816308) will compare catheter ablation against antiarrhythmic drug therapy. Future trials to assess the impact of other modalities such as electrical cardioversion and rate control would also be useful. Catheter ablation itself is also heterogeneous, and it is therefore feasible that different catheter ablation techniques will have differing effects on cognition presenting another important area for future study.
Studies should also be designed to investigate the mechanisms through which atrial fibrillation treatment strategies may affect cognition. The Neurocognition and Greater Maintenance of Sinus Rhythm in Atrial Fibrillation (NOGGIN AF, project number 1R01AG074185-01) trial will compare cognitive function in patients treated with catheter ablation versus medical therapy. This study will compare structural cortical characteristics and cerebral perfusion patterns providing important information about how such treatment strategies could differentially affect cerebral structure and function. Additionally, it would be useful to ascertain whether there is a relationship between atrial fibrillation treatment and levels of biomarkers indicative of cognitive impairment in plasma and cerebrospinal fluid.
Studies should also be designed to identify whether catheter ablation-induced changes in other parameters such as cardiac function and/or symptom burden correlate with changes in cognitive function. This could enable a greater understanding of the mechanistic link between atrial fibrillation and cognitive decline. It would also be useful to examine whether a patient's atrial fibrillation classification influences the risk of cognitive decline with medical or interventional therapy. This information could be used to identify the patient groups most likely to benefit from atrial fibrillation treatment strategies aimed at halting cognitive decline.

Conclusion
The link between atrial fibrillation and dementia is increasingly reported. Treatment strategies should be aimed at minimising the cognitive decline process observed in patients with atrial fibrillation. Given the limitations of the available data, we are unable to make firm conclusions; however, this study suggests that catheter ablation may offer promise to prevent neurocognitive decline in atrial fibrillation. Further studies are therefore warranted to elucidate the mechanistic link between atrial fibrillation and cognitive decline, delineate the true impact of catheter ablation versus medical therapy on cognitive function, and to strive to identify the patient groups most likely to benefit from treatment aimed at halting cognitive decline.