Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study

Abstract

Aims

Accumulating evidence shows that atrial fibrillation (AF) is associated with an increased risk of dementia. Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving the quality of life. We investigated the association of catheter ablation for AF with the occurrence of dementia.

Methods and results

Using the Korean National Health Insurance Service database, among 194 928 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, we studied 9119 patients undergoing ablation and 17 978 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score-matching was used to correct for differences between the groups. During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed lower incidence and risk of overall dementia (8.1 and 5.6 per 1000 person-years, respectively; hazard ratio 0.73, 95% confidence interval 0.58–0.93). The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (hazard ratio 0.76, 95% confidence interval 0.61–0.95) and more pronounced in cases of ablation success whereas no significant differences observed in cases of ablation failure. Ablation was associated with lower risks of dementia subtypes including Alzheimer’s disease and vascular dementia.

Conclusion

In this nationwide cohort of AF patients treated with catheter ablation or medical therapy, ablation was associated with decreased dementia risk. This relationship was evident after censoring for stroke and adjusting for clinical confounders.

Open in new tabDownload slide

See page 4494 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa843)

Introduction

Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia and is therefore a substantial economic and public health burden.^1–4 The age distribution of AF among populations of developed countries is predicted to shift in coming years, with an expected increase in prevalence among the elderly.³ There are ∼40 million people living with dementia worldwide, and this number is expected to increase with a rising aged population.⁵ Although the pathophysiological mechanisms of dementia are largely unknown, evidence is accumulating that AF may contribute to the development of cognitive dysfunction and dementia.^{6  ,  7} The Rotterdam Study demonstrated that cognitive dysfunction was approximately twice as common in subjects with AF as in those without.⁶ Since then, several longitudinal studies have shown that AF is independently associated with an increased risk of cognitive decline or dementia.^{7  ,  8}

Compared with antiarrhythmic drug (AAD) therapy, catheter ablation for AF reduces the number of acute episodes and prolongs the duration of sinus rhythm, thereby improving the quality of life.^{9  ,  10} The effect of ablation on the incidence of dementia has not been elucidated.⁹ Previous studies have reported that AF ablation was associated with declining cognitive function and acute brain lesions.^11–13 Conversely, a recent study demonstrated that cognitive function improved following ablation,¹⁴ and the risk of dementia was reduced significantly in patients who had undergone ablation.¹⁵ Given the conflicting information, we compared the development of dementia due to all-causes (including Alzheimer’s and vascular dementia) in patients with AF treated with ablation or medical therapy.

Methods

This study is a retrospective analysis based on the national health claims database established by the National Health Insurance Service (NHIS) of Korea. Further details are presented in Supplementary material online, Methods. This study was approved by the Institutional Review Board of Yonsei University Health System (4-2016-0179). Informed consent was waived because personal identifying information was removed after cohort creation according to strict confidentiality guidelines.

Study population

From the Korean NHIS database covering a population 51.5 million inhabitants, 834 735 adult patients (≥18 years) were newly diagnosed with AF from 1 January 2005 to 31 December 2015. AF was defined according to the International Classification of Disease 10th Revision codes (ICD-10), I48. The diagnosis of AF has been previously validated in the NHIS database with a positive predictive value of 94.1%.^{2  ,  3  ,  8} Among these patients, the study population included those, who were treated with ablation or medical therapy (received AADs or rate control drugs for at least 30 days; details in Supplementary material online, Table S1). After exclusions, 9119 patients with ablation and 17 978 patients with medical therapy remained for the analysis (Figure 1).

Covariates and outcomes

Details about covariates are presented in Supplementary material online, Methods and Table S1. The primary outcome was the initial occurrence of overall dementia. Secondary outcomes included development of dementia subtypes, including Alzheimer’s disease and vascular dementia. The Korean government covers medical expenditure for dementia patients. Diagnosis of dementia was defined using the following ICD-10 codes of dementia (F00 or G30 for Alzheimer’s disease, F01 for vascular dementia, F02 for dementia with other diseases classified elsewhere, and F03 or G31 for unspecified dementia) and dementia drugs (rivastigmine, galantamine, memantine, or donepezil). The positive predictive value was 94.7% in a validation study of the definition.⁸ Incident ischaemic stroke was defined from any discharge diagnoses (ICD-10: I63, I64) with concomitant brain imaging studies.

Statistical methods

Propensity score-matching was used to account for the differences in baseline characteristics between patients who underwent ablation and those who were treated with medical therapy alone. A propensity score, the probability of undergoing ablation, was estimated using logistic regression based on socio-demographics, clinical risk scores, medical history, drug treatments for AF, concurrent medication use, and AF duration (variables in Table 1). For both the ablated and the medical therapy patients, the time at risk was counted from index date of the first medical therapy. Effect of ablation was analysed as a time-varying exposure. The Fine and Gray method was used to consider death as a competing risk when comparing the incidences of overall dementia, Alzheimer’s disease, and vascular dementia.¹⁶ The proportional hazards assumption was tested on the basis of Schoenfeld residuals.¹⁷ We conducted a stratified analysis based on whether the drug-treated patients were treated with AADs or rate control drugs only, matching the patients with ablated patients taking the same category of drugs. Balance of covariates was presented in Supplementary material online, Tables S2 and S3. Also, the ablated patients were categorized into ablation success or failure groups, in whom we investigated relationships between ablation success/failure and rates of dementia. The definitions of ablation failure were validated for identifying AF recurrence (Supplementary material online, Figure S1). Detailed methods are presented in Supplementary material online, Methods. A two-sided P-values of <0.05 were considered significant. Statistical analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA) and R version 3.3.2 (The R Foundation, www.R-project.org).

Sensitivity analyses

First, we performed subgroup analyses for the primary outcome stratified by sex, age, residential area, health care utilization, heart failure, hypertension, diabetes, ischaemic stroke, CHA₂DS₂-VASc score, and anticoagulation. Second, propensity score-weighting was used to account for the differences in baseline characteristics between patients who underwent ablation and those who were treated with medical therapy alone. Stabilized weights were derived to obtain estimates representing population average treatment effects with optimal balance between the treatment populations. And we applied weight trimming by trimming those below the 1st percentile and above the 99th percentile of the stabilized weights to reduce the impact of extremely small and large weights. Third, we additionally matched health care utilization during follow-up and residential area between the two groups, taking into account that ablated patients may undergo more comprehensive follow-up and that an AF patient living in a metropolitan city might be more likely to be referred to an arrhythmia specialist and to undergo catheter ablation. Fourth, we performed ‘falsification analysis’ to determine whether ablation was associated with lower rates of 35 falsification endpoints that should not be lower with ablation and would indicate that the presence of hidden confounding. Detailed definitions of the endpoints are presented in Supplementary material online, Table S4. Finally, we used the method of Lin et al. to assess whether the observed differences in the risk of the primary outcome could be fully explained by an unmeasured confounder.¹⁸

Results

Compared with medical therapy patients, ablated patients were more often male, younger, and with an income in the high tertile (Table 1). Ablated patients had less concomitant diseases. After propensity score-matching, all baseline characteristics were well-balanced between the two groups (Table 1). In multivariable analysis, the factors independently associated with the likelihood of undergoing catheter ablation were younger age, higher income, and comorbidities including heart failure, hypertension, and diabetes (Supplementary material online, Table S5).

Risk of dementia

During a median (25th, 75th percentiles) follow-up of 52 (29, 86) months, 164 and 308 cases had dementia in the propensity score-matched ablated and medical therapy group with incidence rates of 5.6 and 8.1 per 1000 person-years, respectively, and an absolute rate difference of −2.5 [95% confidence interval (CI) −3.8 to −1.2] per 1000 person-years (Table 2). The cumulative incidence of dementia was lower in the ablated group than in the medical therapy group (Figure 2A). The number needed to treat for preventing one case of dementia during overall follow-up was 34, with culumative incidences of 6.1% and 9.1% in the ablated and medical therapy groups, respectively. After full adjustment of clinical variables and competing risk of mortality, compared with medical therapy, the risk of primary outcome was reduced by 27% in patients with ablations [hazard ratio (HR) 0.73, 95% CI 0.58–0.93, P < 0.001] (Table 2). The risk of dementia was lower in the ablated group compared with AAD (HR 0.74, 95% CI 0.57–0.94) and rate control only treated groups (HR 0.57, 95% CI 0.40–0.83) (Table 2). Other factors associated with increased dementia risk included: older age (per 10 increase: HR 2.70, 95% CI 2.28–3.20), history of ischaemic stroke (HR 1.55, 95% CI 1.70–2.24), higher Charlson comorbidity indices (per 1 increase: HR 1.10, 95% CI 1.04–1.16), and higher Hospital Frailty Risk scores (per 1 increase: HR 1.05, 95% CI 1.03–1.07).

In the propensity score-matched ablated and medical therapy group, the rates of ischaemic stroke were 1.0 and 2.2 per 100 person-years, respectively. After additionally censoring for incident stroke, the risk of overall dementia was still significantly lower in the ablation group than in the medical therapy (HR 0.76, 95% CI 0.61–0.95, P = 0.015) (Figure 2B and Table 2).

Subgroup analyses showed that the risk of primary outcome was lower in ablated patients regardless of sex, residential area, health care utilization, heart failure or stroke history, estimated stroke risk, and oral anticoagulation during follow-up (Figure 3). Although ablation showed a non-significant trend towards lower dementia risk in those aged at least 75 years, there was no significant interaction according to age (P for interaction = 0.881). The relationship was more pronounced in those undergoing anticoagulation <2 years during follow-up (P for interaction = 0.019).

Risk of Alzheimer’s disease and vascular dementia

Ablation was related to lower incidence and risk of Alzheimer’s disease (4.1 and 5.0 per 1000 person-years, HR 0.77, 95% CI 0.61–0.97, P = 0.030) and vascular dementia (1.2 and 2.2 per 1000 person-years, HR 0.50, 95% CI 0.33–0.74, P < 0.001) compared with the medical therapy (Table 2). The cumulative incidence of Alzheimer’s disease (Figure 4A) and vascular dementia (Figure 4B) was lower in the ablated group than in the medical therapy group.

After censoring for incident stroke, ablation showed a consistent but non-significant trend towards a lower risk of Alzheimer’s disease (Figure 4A, right panel) and was significantly associated with a lower risk of vascular dementia (Figure 4B, right panel).

Ablation success and dementia

Out of 5863 matched patients who underwent catheter ablation of AF, 1202 (20.5%) underwent cardioversion or repeat ablations beyond a 3-month blanking period (Model 1, Figure 5). AAD was started after a drug-free window of 1 month beyond the blanking period in 2292 (39.1%) patients (Model 2). The combination of cardioversion, repeat ablation, and an AAD prescription resulted in an estimate of failure for the index ablation of 45.3% (2661 patients). The estimates of ablation failure over time according to three models are depicted in the Kaplan–Meier plot shown in Supplementary material online, Figure S2. In time-varying competing risk regression, across the three definitions of ablation failure, the association of ablation with lower dementia risk was more prominent in patients with ablation success than in overall ablated patients. In contrast, the protective associations of ablation relative to medical therapy were not observed in those with ablation failure (Figure 5).

Sensitivity analyses

The associations observed in propensity-weighted analyses were more apparent than in the primary results: for the primary outcome of overall dementia, the HR adjusted for clinical variables and competing risk of all-cause death was 0.52 (95% CI 0.44–0.61) for ablation (Supplementary material online, Table S6). After additionally matching for health care utilization during follow-up and residential area (Supplementary material online, Table S7), the associations were consistently observed (Supplementary material online, Table S8). There were no significant relationships between ablation and any of the falsification endpoints (Supplementary material online, Table S9 and Figure S3). An unmeasured confounder could explain the observed differences in the primary outcome only if the confounder was related to a substantially increased risk of the outcome by approximately two-fold or if there was substantial imbalance in its prevalence (Supplementary material online, Figure S4).

Discussion

In this study, our principal finding was that patients with AF undergoing catheter ablation were at a lower risk of dementia compared with drug-treated patients, even after adjusting for variations in background characteristics and competing risk of death. This association was consistently evident after censoring for stroke. Second, the lower risks of dementia associated with AF ablation were consistent across different sex, residential area, health care utilization, heart failure or stroke history, CHA₂DS₂-VASc score, and anticoagulation. Third, the protective associations of ablation with lower dementia risk were more pronounced for patients undergoing successful ablation.

Bunch et al. reported that patients ablated for AF have a significantly lower risk of dementia in comparison with age-/gender-matched AF patients without ablation.¹⁵ This study extends prior observations by enrolling a larger number of ablated patients than the previous study and using both propensity score-matching and -weighting approaches. A recent prospective study demonstrated an improvement in cognitive function in well-anticoagulated AF ablated patients.¹⁹ In this study, the lower risks of dementia associated with ablation were consistently observed irrespective of the duration of anticoagulation during follow-up, suggesting the observed association is not attributable to possibly different levels of OAC use between the ablation- and drug-treated groups. On the contrary, ablation therapy for AF has been associated with declining cognitive function at 90 days after the procedure.^{11  ,  12} Furthermore, researchers have detected acute brain lesions without corresponding neurological symptoms in 25% of patients undergoing AF ablation using a high-resolution diffusion-weighted brain magnetic resonance imaging sequence that can identify acute cytotoxic brain oedema.^{12  ,  13  ,  20} However, a direct association of silent cerebral embolism with a decline in neurocognitive function is unproven.²¹ The clinical significance of such asymptomatic cerebral embolic lesions is not known, and many will resolve to the point of being undetectable after weeks or months. These silent cerebral emboli are required to be distinguished from covert embolic strokes consequent to chronic AF.

Our study shows that catheter ablation for AF was associated with the lower risk of both Alzheimer’s disease and vascular dementia. The protective associations of ablation were more pronounced for vascular dementia than for Alzheimer’s disease. Given the relationship between AF and stroke, vascular dementia, encompassing both multi-infarct and small vessel disease dementia, might be considered as an obvious contributory factor for cognitive decline in AF population.⁶ Alzheimer’s disease is the most common type of dementia, and AF has been identified as a risk factor for Alzheimer’s disease.^{7  ,  8} In the majority of cases, the brains of patients with Alzheimer’s disease show vascular microinfarcts, white matter lesions, or vessel wall alterations, suggesting vascular risk factors have been correlated with a higher risk of Alzheimer’s dementia.²² These vascular attributes might help explain the association between AF and the increased risk of Alzheimer’s disease or between ablation and a decreased risk of Alzheimer’s disease.

In this study, the associations between ablation and lower dementia risk were consistently observed, but less pronounced after censoring patients at the time of incident stroke, suggesting that the reduction of overt stroke may account for the observed protective association of ablation. A previous study by Friberg et al. showed AF ablation might be associated with lower incidence of ischaemic stroke, especially in in patients with higher thrombo-embolic risk.²³ The protective association of ablation with dementia was strongly observed for the ablation success group in whom it was likely that sinus rhythm would be maintained. Meanwhile, no significant difference was observed for the ablation failure group, suggesting that successful ablation, not ablation itself, is associated with a lower risk of dementia in patients with AF.

Study limitations

This study has several limitations. Although administrative databases are increasingly used for clinical research, such studies are potentially susceptible to inaccuracies arising from coding errors. To minimize this problem, we applied the definition that we had validated in previous studies using the Korean NHIS database.^{2  ,  3  ,  8  ,  24} Second, our observational study findings cannot be used to establish causal relationships and residual confounding is likely to persist even after propensity score-matching and -weighting. To check out the presence of confounding by indication, the falsification endpoints were assessed. No evidence of a hidden bias working in favour of ablation was found. However, we were unable to determine the exact reasons for undergoing catheter ablation instead of medical treatment, which may introduce potential bias, and the potential remains for unmeasured confounders to have influenced the findings. For example, level of education, baseline cognitive function, and quality of anticoagulation were not assessed and not included in our logistic regression models calculating propensity scores. Since we defined AF diagnoses and ablation cases only with ICD-10 or claim codes, data regarding types of AF (paroxysmal vs. non-paroxysmal) or specific ablation techniques were not available. Finally, the occurrence of mild cognitive impairment was not compared and the dementia outcome was ascertained by clinical diagnosis and associated medication use (a high-specificity assessment method), and thus, milder cases may have remained undetected. However, the association between risk factor and outcome is unlikely to be biased or overestimated by underascertainment of the outcome.

Conclusions

In this nationwide cohort of AF patients treated with catheter ablation or medical therapy, ablation was associated with a lower risk of dementia. This relationship was also evident after censoring for incident stroke, and adjusting for clinical confounders and a competing risk of all-cause mortality.

Supplementary material

Supplementary material is available at European Heart Journal online.

Acknowledgements

The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work.

Funding

Korean Healthcare Technology R&D project funded by the Ministry of Health & Welfare (HI15C1200, HC19C0130) and CMB-Yuhan research grant of Yonsei University College of Medicine (6-2019-0124).

Conflict of interest: G.Y.H.L. has served as a consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo and as a speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees have been received directly/personally. B.J. has served as a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi-Sankyo, and received research funds from Medtronic and Abbott. No fees have been received directly/personally. The remaining authors have nothing to declare.

References

Author notes