
==== Front
Int J Cardiol Heart Vasc
Int J Cardiol Heart Vasc
International Journal of Cardiology. Heart & Vasculature
2352-9067
Elsevier

S2352-9067(24)00067-8
10.1016/j.ijcha.2024.101401
101401
Review
Association of direct oral anticoagulants and warfarin with incidence of dementia in atrial fibrillation patients: A systematic review and meta-analysis
Zhang Chenyang a
Zhang JiaQi b
Zhao Xuan a
Jiang Dongyang a
Liu Xiaoqian a
Liang Ying LY18663707866@163.com
a⁎
a The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Department of General Practice, Shandong Engineering Laboratory for Health Management, China
b Haidu College, Qingdao Agricultural University, China
⁎ Corresponding author. LY18663707866@163.com
04 9 2024
10 2024
04 9 2024
54 1014016 2 2024
18 3 2024
28 3 2024
© 2024 Published by Elsevier B.V.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Objects

To evaluate the association of direct oral anticoagulants (DOACs) and warfarin with dementia incidence in atrial fibrillation (AF) patients.

Methods

Relevant studies were retrieved in databases including Embase, PubMed, Cochrane, Web of Knowledge, and ClinicalTrials.gov. Meta-analysis was then conducted using Stata 12.0 software.

Results

A total of 9 studies involving 447,644 AF patients were included. The results indicated that AF patients treated with DOACs had a lower incidence of dementia compared to those treated with warfarin (RR: 0.692, 95 % CI: 0.603–0.793, P = 0.000), This trend was observed in both age groups, <75 years old (RR: 0.770, 95 % CI: 0.639–0.929, P = 0.006) and ≥75 years old (RR: 0.858, 95 % CI: 0.756–0.973, P = 0.017), particularly in cases of Alzheimer's disease (RR: 0.798, 95 % CI: 0.684–0.932, P = 0.004) rather than vascular dementia (RR: 0.841, 95 % CI: 0.61–0.143, P = 0.269). Furthermore, patients taking rivaroxaban (RR: 0.680, 95 % CI: 0.624–0.741, P = 0.000) and apixaban (RR: 0.598, 95 % CI: 0.528–0.676, P = 0.000) instead of dabigatran (RR: 0.941, 95 % CI: 0.862–1.027, p = 0.17) exhibited a lower incidence of dementia than those took warfarin. Notably, AF patients taking rivaroxaban (RR: 0.75, 95 % CI: 0.67–0.84, P = 0.000) and apixaban (RR: 0.758, 95 % CI: 0.647–0.889, P = 0.001) had a lower incidence of dementia than those taking dabigatran, although the difference between trivaroxaban and apixaban was not statistically significant (RR:1.161, 95 % CI: 0.934–1.443, P = 0.018).

Conclusions

AF patients treated with DOACs, particularly rivaroxaban and apixaban, showed a lower incidence of dementia compared to those treated with warfarin, with a notable disparity observed when compared to dabigatran.

Keywords

Atrial fibrillation
Dementia
Direct oral anticoagulants
Warfarin
Meta-analysis
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pmc1 Introduction

Atrial fibrillation (AF) stands as the most prevalent arrhythmia, presenting a significant clinical risk for numerous adverse health outcomes, such as ischemic stroke, thromboembolism, heart failure, myocardial infarction, and mortality [1]. Emerging evidence also suggests that AF serves as an independent risk factor for cognitive decline and dementia [2]. Dementia, a neurological disorder characterized by progressive deterioration in memory and cognitive function, encompasses conditions like Alzheimer's disease and vascular dementia [3]. The association between AF and dementia has triggered extensive research into potential underlying mechanisms. Primarily, cerebral infarction is believed to be the central pathway linking these conditions, although other contributing mechanisms include AF-induced cerebral hypoperfusion, microhemorrhage, inflammation, oxidative damage, autoimmune responses, as well as genetic predisposition [4].

Anticoagulants have been shown to prevent stroke events and reduce complications in AF patients. Although studies demonstrate that anticoagulants can lower the incidence of dementia in AF patients, there is a lack of research comparing different direct oral anticoagulants (DOACs) and warfarin [5]. Our study aimed to compare the role of DOACs and warfarin in preventing dementia in AF patients by including relevant studies from multiple databases. This comparative analysis seeks to provide a foundation for clinical practices in preventing dementia in AF patients.

2 Methods

2.1 Search strategy and selection criteria

This paper, registered in the International Systematic Review Prospective Registry (CRD42022372188) and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), aims to provide a comprehensive analysis of relevant studies. The search for these studies was conducted on Embase, PubMed, Cochrane, Web of Knowledge, and ClinicalTrials.gov, with a focus on publications prior to December 01, 2022. The PubMed search term is “dabigatran” or “Pradaxa” or “rivaroxaban” or “Xarelto” or “apixaban”or “Eliquis” or “edoxaban” or “Savaysa” or “anticoagulants” or “Non-vitamin K antagonist oral anticoagulants” or “NOACs” or “direct oral anticoagulants” or “DOACs”or“novel oral anticoagulants” or “new oral anticoagulants” or “factor Xa inhibitors” or “factor II a inhibitors” AND “atrial fibrillation” or “Atrial Fibrillations” AND “dementia” or “cognitive dysfunction” or “Cognitive impairment”or “Cognitive decline” or “cognitive disorders” or “memory disorders”. We also performed a manual search of the reference lists of the key articles.

Our study focused on adult AF patients enrolled in randomized controlled trials (RCTs) or cohort studies. The experimental group received DOACs such as dabigatran, rivaroxaban, apixaban, while the control group was administered warfarin. The specified outcomes of interest encompassed a spectrum of dementia types (e.g., dementia, vascular dementia, Alzheimer's disease, cognitive impairments). Exclusion criteria involved reviews, case reports, animal or cell experiments, conference abstracts, articles lacking full-text accessibility, duplicate publications, and non-English articles.

2.2 Study selection and data extraction

The publications screening process was meticulously conducted by two researchers independently, with a third researcher tasked with evaluating any divergent publications. Data extraction and cross-checking encompassed various elements such as publication years, authors, study types, sample sizes, baseline information of experimental and control patients, intervention measures, outcome indicators, and follow-up information. To determine eligibility, all research titles and abstracts underwent independent evaluation by two authors, Chenyang Zhang and JiaQi Zhang, and subsequent retrieval and evaluation of the entire papers based on inclusion criteria. In instances where discrepancies arose, the third author, Xuan Zhao, was consulted for resolution.

The qualities of cohort studies included were assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS), which comprises 9 items, each scored with 1 point. The scale categorized the studies into low (0–3 points), medium (4–6 points), and excellent quality (7–9 points). Additionally, the Cochrane Bias Risk Assessment tool was employed to evaluate the quality and bias risks of RCTs based on six aspects: selection bias, implementation bias, measurement bias, follow-up bias, publication bias, and other sources of bias.

2.3 Statistical analysis

The Meta-analysis in this study utilized Stata 12.0 software, with qualitative data represented by relative risk ratios (RRs) and 95 % confidence intervals (CIs), and quantitative data represented by mean and 95 % CI. To assess heterogeneity, the Q test and I2 test were employed. If heterogeneity was detected (P < 0.1 or I2 ≥ 50 %), the random effects model was utilized to calculate the combined effect size; otherwise, the fixed-effect model was applied. Sensitivity analysis was employed to evaluate the robustness and reliability of the findings. Furthermore, publication bias was assessed using a funnel plot, and statistical tests by Begg's and Egger's were conducted to examine publication bias.

3 Result

3.1 Search results

In the preliminary screening, a total of 1206 publications were retrieved. Following the application of the inclusion and exclusion criteria, 9 publications were ultimately selected for inclusion, comprising 1 RCT and 8 cohort studies [6], [7], [8], [9], [10], [11], [12], [13], [14]. The process of searching for and screening publications is visualized in Fig. 1. The included studies encompassed a cumulative sample size of 447,644 AF patients who were being treated with anticoagulants. Details on the fundamental characteristics of these studies are presented in Table 1. Quality assessment revealed that all the studies under consideration exhibited high methodological rigor, as evidenced in Table 2 and Table 3.Fig. 1 Publications selection process.

Table 1 General characteristics of included studies.

Study	Study type	Age (years)	Male (%)	Types of DOACs	Sample size (N)	Follow-up time (years)	Outcome indicators	
DOACs	Warfarin	
Bezabhe WM 2022[6]	RC	71.9 ± 12.60	52.9	NS	5570	2673	3.7 ± 2	③	
Bunch TJ 2022[7]	RCT	73.7 ± 6	53.5	Dabigatran	32
Dabigatran: 32	31	2	③④	
Cadogan SL 2021[8]	RC	76.00	63.4	Dabigatran, Rivaroxaban, Apixaban	18,513	20,687	1.37	③④	
Chen N 2018[9]	RC	67.0	65.0	Dabigatran, Rivaroxaban, Apixaban	139,213
Dabigatran: 46,483 Rivaroxaban: 61,641
Apixaban: 31,089	139,213	0.7 – 2.2	①③⑤	
Hsu JY 2021[10]	RC	NS	59.0	NS	6034	6034	3.27	③	
Jacobs V 2016[11]	RC	72.4 ± 10.9	59.0	Dabigatran, Rivaroxaban, Apixaban	2627
Dabigatran: 583
Rivaroxaban: 1454
Apixaban: 590	2627	0.85	①③	
Kim D 2020[12]	RC	41.3	67.8	Dabigatran, Rivaroxaban, Apixaban	28,683
Dabigatran: 8602
Rivaroxaban: 12,994
Apixaban: 7087	24,553	0.6	①②③⑥	
Mongkhon P 2020[13]	RC	NS	NS	Dabigatran, Rivaroxaban, Apixaban	4657	12,880	5.9	③	
Sogaard M 2019[14]	RC	69.850	53.1	Dabigatran, Rivaroxaban, Apixaban	20,594	13,023	3.4	①②③⑥	
Note. RC: Retrospective cohort; RCT: Randomised controlled trial; DOACs: Direct oral anticoagulants; NS: Not specified; ① alzheimer disease; ② vascular dementia; ③ dementia; ④ cognitive disorder; ⑤ persistent mental disorder; ⑥ other dementia.

Table 2 The quality evaluation of cohort studies.

No	Study	Selection	Comparability	Outcome	Total	
1	Bezabhe WM 2022	★★★★	★★	★☆☆	★★★★★★★☆☆	
2	Cadogan SL 2021	★★★★	★★	★★★	★★★★★★★★★	
3	Chen N 2018	★★★☆	★★	★★☆	★★★★★★★☆☆	
4	Hsu JY 2021	★★★★	★★	★★☆	★★★★★★★★☆	
5	Jacobs V 2016	★★★★	★★	★★★	★★★★★★★★★	
6	Kim D 2021	★★★★	★★	★★☆	★★★★★★★★☆	
7	Mongkhon P 2020	★★★★	☆☆	★★★	★★★★★★★☆☆	
8	Sogaard M 2019	★★★★	★★	★★★	★★★★★★★★★	

Table 3 The quality evaluation of RCT.

Study	Random method	Allocation concealment	Blind method	Integrity of the resulting data	Selectively report research findings	Other bias	
Bunch TJ 2022	Low	Unclear	Low	Unclear	Low	Low	

3.2 Primary outcome

Nine studies with a total of 447,644 patients were included in our analysis [6], [7], [8], [9], [10], [11], [12], [13], [14]. Given the presence of statistical heterogeneity among the studies (I2 = 85.4 %, P = 0.000), we opted for the random effects model for our analysis. The meta-analysis results revealed that the incidence of dementia in the group of patients treated with DOACs was significantly lower compared to those receiving warfarin (RR: 0.692; 95 % CI, 0.603–0.793), a finding of statistical significance (Z = 5.28, P = 0.000), as depicted in Fig. 2.Fig. 2 The incidence of dementia in AF patients using DOACs and warfarin.

3.3 Subgroup analyses

3.3.1 Dabigatran vs. Warfarin

Four studies [7], [9], [11], [12], with a total of 108,889 patients included, showed no statistical heterogeneity (I2 = 47.3 %, P = 0.128)among them. Therefore, a fixed effects model was chosen for the analysis. The incidence of dementia in the dabigatran group was observed to be lower compared to the warfarin group (RR: 0.941; 95 % CI, 0.862–1.027). However, this difference was not statistically significant (Z = 1.37, P = 0.17), as indicated in Table 4.Table 4 The incidence of dementia in AF patients using different anticoagulants.

Groups	Subgroups	Number of Studies	Sample	RR(95 % CI)	Model	I2	Z	P	
Three kinds of DOACs verus Warfarin	Dabigatran vs. Warfarin	4	108,889	0.941 (0.862–1.027)	Fixed	47.3 %	1.37	0.17	
Rivaroxaban vs. Warfarin	3	142,557	0.680 (0.624–0.741)	Fixed	0.0 %	8.81	0.000	
Apixaban vs. Warfarin	3	75,199	0.598 (0.528–0.676)	Fixed	0.0 %	9.2	0.000	
Comparison between the three DOACs	Rivaroxaban vs. Dabigatran	3	80,103	0.75 (0.67–0.84)	Fixed	4.5 %	5.0	0.000	
Apixaban vs. Dabigatran	3	40,626	0.758 (0.647–0.889)	Fixed	0.0 %	3.41	0.001	
Rivaroxaban vs. Apixaban	3	84,411	1.161 (0.934–1.443)	Random	52.5 %
	1.34	0.18	

3.3.2 Rivaroxaban vs. Warfarin

Three studies [9], [11], [12], with a total of 142,557 patients included, showed no statistical heterogeneity (I2 = 0.0 %, P = 0.894) among them. Therefore, a fixed effects model was chosen for the analysis. The incidence of dementia in the rivaroxaban group was observed to be lower compared to the warfarin group (RR: 0.680; 95 % CI, 0.624–0.741), a finding of statistical significance (Z = 8.81, P = 0.000), as indicated in Table 4.

3.3.3 Apixaban vs. Warfarin

Three studies [9], [11], [12], with a total of 75,199 patients included, showed no statistical heterogeneity (I2 = 0 %, P = 0.521) among them. Therefore, a fixed effects model was chosen for the analysis. The incidence of dementia in the apixaban group was observed to be lower compared to the warfarin group (RR: 0.598; 95 % CI, 0.528–0.676), a finding of statistical significance (Z = 8.2, P = 0.000), as indicated in Table 4.

3.3.4 Rivaroxaban vs. Dabigatran

Three studies [9], [11], [12], with a total of 80,103 patients included, showed no statistical heterogeneity (I2 = 4.5 %, P = 0.351) among them. Therefore, a fixed effects model was chosen for the analysis. The incidence of dementia in the rivaroxaban group was observed to be lower compared to the dabigatran group (RR: 0.75; 95 % CI, 0.67–0.84), a finding of statistical significance (Z = 5.0, P = 0.000), as indicated in Table 4.

3.3.5 Apixaban vs. Dabigatran

Three studies [9], [11], [12], with a total of 40,626 patients included, showed no statistical heterogeneity (I2 = 0.0 %, P = 0.677) among them. Therefore, a fixed effects model was chosen for the analysis. The incidence of dementia in the apixaban group was observed to be lower compared to the dabigatran group (RR: 0.758; 95 % CI, 0.647–0.889), a finding of statistical significance (Z = 3.41, P = 0.001), as indicated in Table 4.

3.3.6 Rivaroxaban vs. Apixaban

Three studies [9], [11], [12], with a total of 84,411 patients included, showed statistical heterogeneity (I2 = 52.5 %, P = 0.122) among them. Therefore, a randomed effects model was chosen for the analysis.

The incidence of dementia in the rivaroxaban group was observed to be lower compared to the apixaban group (RR: 1.161; 95 % CI, 0.934–1.443). However, this difference was not statistically significant (Z = 1.34, P = 0.18), as indicated in Table 4.

3.3.7 Age < 75

Two studies [10], [12] were included with no statistical heterogeneity among the included studies (I2 = 0.0 %, P = 0.740). A fixed effects model was chosen for analysis. Among patients with AF aged < 75 years old, the incidence of dementia in the DOACs group was found to be lower than that in the warfarin group (RR: 0.770; 95 % CI, 0.639–0.929), with statistical significance (Z = 2.72, P = 0.006), as displayed in Table 5.Table 5 The incidence of dementia in AF patients with different age and different types of dementia.

Groups	Subgroups	Number of Studies	RR(95 % CI)	Model	I2	Z	P	
DOACs verus Warfarin	Age							
<75	2	0.770 (0.639–0.929)	Fixed	0.0 %	2.72	0.006	
≥75	2	0.858 (0.756–0.973)	Random	0.52 %	2.38	0.017	
Dementia types							
Alzheimer's disease	2	0.798 (0.684–0.932)	Fixed	0.0 %	2.85	0.004	
Vascular dementia	2	0.841 (0.619–1.143)	Fixed	0.0 %	1.11	0.269	

3.3.8 Age ≥ 75

Two studies [10], [12] were included with statistical heterogeneity among the included studies (I2 = 0.52 %, P = 0.471). A randomed effects model was chosen for analysis. Among patients with AF aged ≥ 75 years old, the incidence of dementia in the DOACs group was found to be lower than that in the warfarin group (RR: 0.858; 95 % CI, 0.756–0.973), with statistical significance (Z = 2.38, P = 0.017), as displayed in Table 5.

3.3.9 Alzheimer's disease

Two studies [12], [14] were included with no statistical heterogeneity among the included studies (I2 = 0.0 %, P = 0.851). A fixed effects model was chosen for analysis. In the Alzheimer's disease group, the incidence of dementia in the DOACs group was lower than that in the warfarin group (RR: 0.798; 95 % CI, 0.684–0.932), with statistical significance (Z = 2.85, P = 0.004), as displayed in Table 5.

3.3.10 Vascular dementia

Two studies [12], [14] were included with no statistical heterogeneity among the included studies (I2 = 0.0 %, P = 0.943). A fixed effects model was chosen for analysis. Although in the vascular dementia group, the incidence of dementia in the DOACs group was lower than that in the warfarin group (RR: 0.841; 95 % CI, 0.61–0.143), the difference did not reach statistical significance (Z = 1.11, P = 0.269), as displayed in Table 5.

4 Sensitivity analyses and publication bias

Sensitivity analyses were conducted by excluding the included studies one by one, and the combined effect sizes did not change significantly, indicating that the results of the meta-analysis were robust and reliable. The funnel plot was used to assess publication bias, and the result showed that the funnel plot was basically symmetrical (Egger's test: P = 0.233 > 0.05; Begg’s test: P = 0.754 > 0.05), suggesting that there was no publication bias in the included studies, as shown in Fig. 3.Fig. 3 Funnel plot of primary outcome.

5 Discussion

In recent years, DOACs have been introduced as effective oral anticoagulants (OACs) that may reduce the risk of stroke in AF patients and its related complications. DOACs are recommended as a superior alternative to warfarin due to their rapid onset of action, limited need for frequent monitoring of international standardized ratio (INR), minimal drug interactions, effective prevention of thromboembolism, and decreased bleeding risk. To explore the impact of OACs on cognitive impairment and dementia, we conducted a thorough analysis by gathering randomized controlled trials (RCTs) and high-quality observational database studies. Our findings indicate that the use of DOACs may exhibit a potential association with a reduced risk of dementia when compared to warfarin.

Several proposed mechanisms link AF with an increased risk of dementia, although the exact causal pathways remain incompletely understood. One major potential mechanism involves the association between AF and stroke in patients, both overt and asymptomatic strokes. AF elevates the risk of ischemic stroke by 4 to 5 times, with stroke significantly escalating the likelihood of developing dementia [15]. A meta-analysis of seven studies showed that the occurrence of AF more than doubled the risk of developing dementia after stroke (odds ratio 2.4) [16]. The potential causes of stroke-related dementia encompass singular substantial site infarction, multiple regional or minor infarctions, or secondary neurodegenerative effects. Apart from symptomatic cerebral infarction, asymptomatic cerebral infarction is also implicated in cognitive decline, with a prevalence 5 times greater than symptomatic infarction at the time of AF diagnosis [17]. While initially symptomatically silent, these infarctions portend future cognitive deteriorations [18], [19]. Microembolization and hypoperfusion linked to AF can induce ischemic demyelination akin to cerebrovascular disease, further contributing to cognitive decline. Several studies have shown that inflammation play a vital role in the pathophysiology that lead to AF, which in turn exacerbates the inflammatory response [20], [21]. Inflammation is believed to heighten hypercoagulability and thrombosis, thereby amplifying the risk of stroke and cerebrovascular dysregulation, which have associations with Alzheimer's disease and vascular dementia [22], [23]. Notably, elevated inflammatory markers have been correlated with cognitive impairments in AF patients. Moreover, the relationship between AF, small brain volume, and cognition is a subject of debate. The Atherosclerosis Risk in Communities (ARIC) neurocognitive study underscores an association between AF and reduced brain volume, particularly in deep gray matter and hippocampal regions, a correlation accentuated in older individuals [24]. The independent link between AF and diminished hippocampal volume remains contentious in current publications.

Based on the above possible mechanisms, anticoagulant therapy for stroke prevention in AF patients may be effective in preventing dementia. A retrospective Australian study involving 18 813 AF patients revealed a significantly lower incidence of dementia in OAC users (HR: 0.59; 95 % CI, 0.44–0.80) [25]. Commonly prescribed anticoagulants for stroke prevention in AF include warfarin and DOACs. The time in therapeutic range (TTR) of warfarin has also been recognized as a key factor in evaluating the risk of dementia. Studies suggest that a higher percentage of excessive anticoagulation exposure during warfarin treatment may elevate the risk of dementia [26]. Moreover, there have been reports linking brain microbleeds, particularly in the lobes of the brain, to cognitive decline. A small prospective study found that AF patients using warfarin, as opposed to DOACs or antiplatelets, experienced an increased occurrence of new microbleeds within one year [27]. With the advent of DOACs, the position of warfarin in non-valvular AF has been gradually shaken. Studies have demonstrated that DOACs exhibit superior efficacy compared to warfarin in reducing the risk of stroke, significant intracranial hemorrhage, and intracranial microhemorrhage, all of which have implications for cognitive function [27], [28]. An Australian study showed that DOACs users had a lower incidence of dementia than warfarin users (HR: 0.46; 95 % CI, 0.28–0.74; P = 0.002) [25]. Conversely, findings from a national cohort study in Denmark revealed no substantial disparity in dementia development between DOACs users and warfarin users, except for a heightened risk among DOACs users aged 80 years and older [29]. However, most current studies are observational, and several relevant prospective studies are ongoing.

Our study comprised 1 RCT and 8 cohort studies, with a total of 447,644 patients, aimed at evaluating the risk of dementia among AF patients treated with DOACs and warfarin. The studies selected exhibited a range of medium to high quality. The utilization of both fixed and random effects models served to bolster the methodological robustness of the investigation, while sensitivity analysis further substantiated the reliability of the outcomes. The study findings revealed a notable disparity in the incidence of dementia between the DOACs and warfarin groups, with the former displaying a significantly lower occurrence. Subsequent subgroup analyses indicated that both rivaroxaban and apixaban demonstrated significantly reduced incidences of dementia compared to warfarin, whereas no statistically significant variance was observed between dabigatran and warfarin groups. Additionally, the incidences of dementia were found to be significantly lower in rivaroxaban and apixaban groups compared to the dabigatran group, with no noteworthy distinction between the rivaroxaban and apixaban cohorts. Notably, the incidence of dementia was consistently lower in the DOACs group compared to the warfarin group, regardless of age (<75 years old or ≥75 years old). While the incidence of Alzheimer's disease was lower in the DOACs group compared to the warfarin group, there was no significant difference in the occurrence of vascular dementia between the two treatment groups.

The incidence of dementia in the dabigatran group was higher compared to the rivaroxaban and apixaban groups, while there was no significant difference between the dabigatran group and the warfarin group. This disparity may be attributed to several factors. Firstly, findings from Mark J. Alberts’s study indicated that patients on twice-daily anticoagulants, particularly dabigatran (75.5 %, with 80 % on a 150 mg dose), exhibited lower compliance rates compared to those on once-daily regimens (32.1 % vs. 27.2 %; p < 0.001) [30]. Another study involving 5376 patients receiving dabigatran at US Veterans hospitals reported that 28 % of patients had a proportion-of-days covered (PDC, a measure of compliance) of less than 80 %. Moreover, they observed a 13 % increased risk of stroke or death with every 10 % decrease in dabigatran PDC [31]. In addition, dabigatran may cause some adverse gastrointestinal events, which may be due to the presence of tartaric acid particles in dabigatran formulations, creating an acidic environment. A lower pH level is linked to digestion issues and an elevated risk of gastrointestinal bleeding [32]. Additionally, dabigatran has been implicated in causing esophagitis and esophageal damage, including the development of esophageal ulcers. Toya et al. reported in 2016 that approximately 20 % of patients using dabigatran experienced esophageal mucosal injuries. It is theorized that the tartaric acid core present in dabigatran not only contributes to gastrointestinal bleeding but also, post-digestion, adheres to the esophagus, leading to mucosal damage that may slough off due to peristalsis [33]. Elderly patients are at a heightened risk of dabigatran-induced esophageal contact due to reduced physical activity levels and salivation. Clinicians should be vigilant when patients present with symptoms such as dysphagia, upper abdominal pain, chest pain, retrosternal pain, vomiting, or prolonged dysphagia, as these could indicate the development of esophagitis or esophageal damage secondary to dabigatran use [34].

Our study has some limitations that should be noted. Firstly, although the studies we included matched some dementia risk factors, other dementia-related variables existed. Information such as education level, race and income are potential confounders in the risk of dementia in AF patients. Secondly, most of the included studies were observational studies and the follow-up time was relatively insufficient, so further prospective RCT studies are needed for further confirmation.

6 Conclusion

AF patients who were treated with DOACs exhibited lower incidences of dementia compared to those treated with warfarin, regardless of their age being below 75 years old or 75 years old and above. Furthermore, this reduced risk of dementia was observed to be particularly more pronounced in Alzheimer's disease cases rather than vascular dementia. Specifically, AF patients who took rivaroxaban and apixaban instead of dabigatran had lower incidences of dementia than those took warfarin. AF patients who took rivaroxaban and apixaban had lower incidences of dementia than those took dabigatran, but there was no significant difference between them. To strengthen the association between DOACs and the mitigation of dementia risk, additional RCTs and long-term observational studies grounded in real-world data are essential.

7 Funding statement

None.

CRediT authorship contribution statement

Chenyang Zhang: Conceptualization, Data curation, Formal analysis, Methodology, Software, Writing – original draft, Writing – review & editing. JiaQi Zhang: Data curation, Formal analysis, Writing – review & editing. Xuan Zhao: Data curation, Formal analysis, Writing – review & editing. Dongyang Jiang: Data curation, Writing – review & editing. Xiaoqian Liu: Conceptualization, Data curation, Writing – review & editing. Ying Liang: Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We are grateful to all participates for their contributions for the present study.
==== Refs
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