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\begin{document}

\title{A Systematic Review and Meta-analysis to Determine the Effect of Oral
Anticoagulants on Incidence of Dementia in Patients with Atrial
Fibrillation}



\author[1]{Mingjie Lin}%
\author[2]{Wenqiang Han}%
\author[2]{Jingquan Zhong}%
\author[1]{Lin Wu}%
\affil[1]{Peking University First Hospital}%
\affil[2]{Shandong University Cheeloo College of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aims: To assess the effect of oral anticoagulant (OAC) administration on
incidence of dementia in patients with atrial fibrillation (AF) with
Systematic review and meta-analysis in according with the Preferred
Reporting Items for Systematic Review and Meta-analysis Protocols.
Methods: We systematically searched the electronic databases including
Pubmed, Embase, Cochrane library, and ClinicalTrails.gov for relevant
articles. The primary outcome was the incidence of dementia. The
adjusted risk ratio (RR), odds ratio, or hazard ratio were extracted and
pooled by the random-effects models. Subgroup analysis was performed
according to the setting observational window. Risk of bias was assessed
using the Newcastle-Ottawa Scale, while publication bias was assessed by
the Begg's and Egger's tests. Results: Nine studies included in this
review (2 prospective and 7 retrospective observational studies,
including 613,920 patients). The results presented the significant
association between OAC therapy and the reduced risk of dementia
compared with no treatment (RR {[}95\%CI{]} =0.72 {[}0.60, 0.86{]},
I2=97.2\%; P =0.000). In the subgroup analysis, the pooled RR became
statistically non-significant (including four studies, RR {[}95\%CI{]}
=0.75 {[}0.51, 1.10{]}, I2=98.8\%; P =0.000). There is no significant
risk of bias and publication bias. Conclusions: This study indicated the
protective effect of OAC therapy for dementia in patients with AF.
However, the results are limited because of high heterogeneity,
inconsistent direction of effect in subgroup analysis. Further
prospective well-designed study is needed with longer follow-up duration
in younger patients.%
\end{abstract}%



\sloppy


\textbf{A Systematic Review and Meta-analysis to Determine the Effect of
Oral Anticoagulants on Incidence of Dementia in Patients with Atrial
Fibrillation}

\textbf{Running head:} Anticoagulants, dementia, atrial fibrillation

Mingjie Lin, PhD\textsuperscript{1}, Wenqiang Han,
MD\textsuperscript{2}, Jingquan Zhong, PhD, MD\textsuperscript{2,3}, Lin
Wu, BM, MSc, MD\textsuperscript{1,4,5}

\begin{enumerate}
\tightlist
\item
  Department of Cardiology, Peking University First Hospital, Beijing,
  China
\item
  The Key Laboratory of Cardiovascular Remodeling and Function Research,
  Chinese Ministry of Education, Chinese National Health Commission and
  Chinese Academy of Medical Sciences, The State and Shandong Province
  Joint Key Laboratory of Translational Cardiovascular Medicine,
  Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine,
  Shandong University, Jinan, China
\item
  Department of Cardiology, Qilu Hospital (Qingdao), Cheeloo College of
  Medicine, Shandong University, Qingdao, China
\item
  Department of Cardiology, Key Laboratory of Molecular Cardiovascular
  Science, Ministry of Education, Beijing, China
\item
  Key Laboratory of Medical Electrophysiology of Ministry of Education,
  Institute of Cardiovascular Research, Southwest Medical University,
  Luzhou, China
\end{enumerate}

\textbf{Corresponding Author:} Lin Wu, Corresponding author. Department
of Cardiology, Peking University First Hospital, No. 8 Xishiku Road,
Beijing 100034, China; Phone: +86 13716162368;
E-mail:\emph{lin\_wu@163.com}.

\textbf{Acknowledgements:} We sincerely thank Dr. Ali (Abu Sad Mohammed
Arif Ali, Department of Cardiology, Peking University First Hospital,
Beijing, China) for correcting the English. This work was supported by
the National Natural Science Foundation of China (81770325,81930105).
Sponsor is no role in the design, methods, subject recruitment, data
collections, analysis and preparation of paper.

\textbf{Conflict of interest statement:} The authors have no conflicts
to disclose

\textbf{Abstract}

\textbf{Aims:}To assess the effect of oral anticoagulant (OAC)
administration on incidence of dementia in patients with atrial
fibrillation (AF) with Systematic review and meta-analysis in according
with the Preferred Reporting Items for Systematic Review and
Meta-analysis Protocols.

\textbf{Methods:} We systematically searched the electronic databases
including Pubmed, Embase, Cochrane library, and ClinicalTrails.gov for
relevant articles. The primary outcome was the incidence of dementia.
The adjusted risk ratio (RR), odds ratio, or hazard ratio were extracted
and pooled by the random-effects models. Subgroup analysis was performed
according to the setting observational window. Risk of bias was assessed
using the Newcastle-Ottawa Scale, while publication bias was assessed by
the Begg's and Egger's tests.

\textbf{Results:} Nine studies included in this review (2 prospective
and 7 retrospective observational studies, including 613,920 patients).
The results presented the significant association between OAC therapy
and the reduced risk of dementia compared with no treatment (RR
{[}95\%CI{]} =0.72 {[}0.60, 0.86{]},
I\textsuperscript{2}=97.2\%;\emph{P} =0.000). In the subgroup analysis,
the pooled RR became statistically non-significant (including four
studies, RR {[}95\%CI{]} =0.75 {[}0.51, 1.10{]},
I\textsuperscript{2}=98.8\%; \emph{P} =0.000). There is no significant
risk of bias and publication bias.

\textbf{Conclusions:} This study indicated the protective effect of OAC
therapy for dementia in patients with AF. However, the results are
limited because of high heterogeneity, inconsistent direction of effect
in subgroup analysis. Further prospective well-designed study is needed
with longer follow-up duration in younger patients.

\textbf{Keywords:}atrial fibrillation; anticoagulant; dementia;
cognitive impairment

\textbf{Review criteria}

The inclusion criteria were: i) patients with AF who were [?] 18 years;
ii) investigating the effects of OACs on the incidence of dementia; iii)
reporting the outcomes as HR, RR, or OR, with 95\%CIs; iv) RCTs or
observational studies.

The exclusion criteria were: i) patients with the history of dementia or
moderate to severe cognitive dysfunction; ii) only crude or unadjusted
HR, RR, or OR; iii) cross-sectional studies; iv) following types of
articles: conference abstracts, editorials, letters, expert opinions,
case reports, case series, or reviews.

\textbf{Messages for the clinic}

The results add the further evidences of strict anticoagulation in
patients with atrial fibrillation because of its additional potential
role on decease risk of incidence of dementia.

The results imply the importance of setting observational window for
unveiling the role of anticoagulation on chronic progressive endpoints.

\textbf{Introduction}

Atrial fibrillation (AF) is one of the most prevalent persistent
arrhythmias.\textsuperscript{1} Dementia is defined as deficits in [?]2
cognitive domains that are sufficiently severe to affect activities of
daily living, being classified into Alzheimer's disease, vascular
dementia, Lewy body dementia, frontotemporal dementia, and other
dementias.\textsuperscript{2} They both predominantly affect the
elderly, and poses significant burden to patients, family, and
healthcare systems. Many prospective and retrospective studies have
stressed a strong association between AF and dementia in patients
without stroke (risk ratio (RR){[}95\% confidence interval
(CI){]}=1.34{[}1.13, 1.58{]}), in patients with first-ever or recurrent
stroke (RR{[}95\%CI{]}=2.7{[}1.82, 4.00{]}), and in a general population
including with or without a history of stroke
(RR{[}95\%CI{]}=1.36{[}1.23, 1.51{]}).\textsuperscript{3, 4} Proposed
mechanisms underlying this link involved overt or covert strokes,
cerebral hypoperfusion due to reduced cardiac output present in AF
rhythm, inflammation, and presence of shared risk factors for AF and
dementia.\textsuperscript{5, 6} Among them, the clinical or subclinical
embolic brain ischemia is considered to be the main cause of cognitive
decline associated with AF.\textsuperscript{5} Thus, it is assumed that
anticoagulation may reduce the risk of cognitive decline and dementia in
patients with AF.

A number of observational studies investigated the effect of oral
anticoagulant (OAC) therapy on incidence of dementia, but the
cause-effect relationship is varied. There are two systematic reviews,
including cross-sectional studies, investigating the effect of OAC use
on the incidence of cognitive impairment and
dementia.\textsuperscript{7, 8} One systematic review including 19
studies suggested that, comparing OAC use to no treatment, the pooled
odds ratio (OR) had no statistical significance in reducing dementia
occurrence (3 studies, OR{[}95\%CI{]} =0.89{[}0.47,
1.69{]});\textsuperscript{7} while another systematic review including 8
studies suggested that the pooled hazard ratio (HR) had statistical
significance in dementia occurrence (5 studies, HR{[}95\%CI{]}
=0.71{[}0.69, 0.74{]}).\textsuperscript{8} The conflicting results
likely resulted from the different number of including studies and
including cross-sectional studies which could limit confidence in a
cause-effect relationship. In order to overcome the main limitation of
previous systematic reviews, Mongkhon et al.\textsuperscript{9}conducted
a new systematic review which excluded the cross-sectional studies. The
pooled adjusted risk ratio (RR) suggested a protective role of OACs on
reducing dementia occurrence (5 studies, RR{[}95\%CI{]} =0.79{[}0.67,
0.93{]}). While in sensitivity analyses using leave-one-out method, the
result had no statistical significance after omitting studies conducted
by Friberg et al.\textsuperscript{10} and Madhavan et
al.\textsuperscript{11} The unstable pooled RR was associated with the
design of studies and the limitation of small numbers of studies; two
included studies \textsuperscript{12, 13} had inclusion of patients with
moderate to severe cognitive impairment and dementia which may have
small benefit from medication interventions;\textsuperscript{14} and
only one study had the observational window, i.e. a blank period after
the start of observation during which the patients diagnosed of dementia
would be excluded to decrease the prescription preference for physicians
between OAC use and non-OAC use. Thus, the association between OAC
therapy and the incidence of dementia remained controversial . Although
there is still a lack of a well-designed randomized controlled trial
(RCT) being published, more than 5 studies\textsuperscript{15-19}
published since the retrieving data of the latest meta-analysis, and
majority of them set the observational window.\textsuperscript{15-17}
Therefore, this systematic review and meta-analysis aims to evaluate the
effect of the use of OACs on incidence of dementia in patients with AF
based on up-to-date evidences; and to evaluate the influence of setting
observational window on the pooled RR in subgroup analysis.

\textbf{Methods}

The present study was performed in accordance with the referred outline
in the Cochrane Handbook for Systematic Reviews of
Interventions\textsuperscript{20} and the Preferred Reporting Items for
Systematic Review and Meta-analysis Protocols
(PRISMA-P).\textsuperscript{21, 22} The protocol was prospectively
registered in the Prospero International Prospective Register of
Systematic Reviews (CRD42020189469).

\textbf{Data sources and search strategy}

The electronic databases of Pubmed, Embase, Cochrane library, and
ClinicalTrails.gov were searched to identify all eligible studies from
inception to May 5th, 2020; the search strategy of terms mainly included
three parts: atrial fibrillation; anticoagulants or antithrombins or
factor Xa inhibitors or dabigatran or DOAC or NOAC or warfarin or
vitamin K antagonist*; dementia or Alzheimer disease or cognition
disorders or cognitive dysfunction; and their entry terms in MeSH were
also used. Reference lists of all included articles and previous
meta-analysis articles were manually scanned to supplement the
potentially eligible studies. There were no language restrictions. Two
authors (Mingjie Lin and Wenqiang Han) independently searched databases
and the disagreements were checked by themselves. Full search strategies
for all databases are presented in Supplementary Table 1.

\textbf{Study selection and outcome measurement}

Two reviewers (Mingjie Lin and Wenqiang Han) independently screened the
titles and abstracts according to the designed criteria; and full
articles were obtained for all titles potentially meeting inclusion and
exclusion criteria. Endnote Version x9.1 (Clarivate Analytics (US) LLC)
was used to manage identified studies and recode the decisions.
Reviewers were blinded to each other's decisions. Disagreements between
individual judgements were resolved by discussion between themselves and
another senior reviewer (Jingquan Zhong). The inclusion criteria were:
i) patients with AF who were [?] 18 years; ii) investigating the effects
of OACs on the incidence of dementia; iii) reporting the outcomes as HR,
RR, or OR, with 95\%CIs; iv) RCTs or observational studies. The
exclusion criteria were: i) patients with the history of dementia or
moderate to severe cognitive dysfunction; ii) only crude or unadjusted
HR, RR, or OR; iii) cross-sectional studies; iv) following types of
articles: conference abstracts, editorials, letters, expert opinions,
case reports, case series, or reviews. OACs included vitamin K
antagonists (VKAs) and non-vitamin K OACs (NOACs); the control, i.e.
Non-OACs included antiplatelet agents or no antithrombotic therapy;
dementia included Alzheimer's/Lewy-body/senile/vascular dementia; for
overlapping participants, the studies with the longest follow-up and the
most detailed information were chosen. The PICOS criteria are presented
in Supplementary Table S2.

The primary outcome was the incidence of dementia during the follow-up
in AF patients with and without OAC use. The dementia was diagnosed
based on patient narrative, collateral information from families,
clinical examination, the standardized cognitive
tests,\textsuperscript{2} and diagnostic criteria for dementia including
Diagnostic and Statistical Manual of Mental Disorders (DSM)-III, DSM-IV,
DSM-V, diagnosis based on international classification of diseases codes
(ICD), or United Kingdom (UK) Read codes.\textsuperscript{9, 23} The
additional outcomes were the incidence of dementia in AF patients with:
VKAs vs. non-OACs, VKAs vs. NOACs, NOACs vs. non-OACs, and in AF
patients with and without OACs use whose
CHA\textsubscript{2}DS\textsubscript{2}-VASc score was [?] 2.

\textbf{Data extraction, strength of evidence assessment, and bias
assessment}

Two reviewers (Mingjie Lin and Wenqiang Han) independently extracted the
designed variables and data, including first author, year, country,
study design, number of patients, age, sex, follow-up time, AF
detection, dementia or cognitive deficit definition,
CHADS\textsubscript{2} or CHA\textsubscript{2}DS\textsubscript{2}-VASc
Score,history of stroke, observational window, maximum adjusted
covariates, defined OAC use, drugs of OACs, percentage of OACs use,
comparison group, adjusted OR/RR/HR with 95\% CIs. The correspondent
authors were contacted by e-mail when overall adjusted OR/RR/HR were
missing. The study was excluded if the authors did not reply. Another
reviewer (Jingquan Zhong) checked the extracted data. Disagreements
regarding any extracted data were resolved by discussion among the three
reviewers.

Two reviewers (Mingjie Lin and Wenqiang Han) independently assessed the
strength of evidence (SOE) and risk of bias. Any disagreements were
resolved through discussion. The SOE was evaluated based on five
domains: study limitations, directness, consistency, precision, and
reporting bias; it was defined as four levels: high, moderate, low,
insufficient.\textsuperscript{24} Risk of bias assessment was evaluated
with the Cochrane risk of bias tool for RCTs\textsuperscript{20} and the
Newcastle-Ottawa Scale (NOS) for observational
studies.\textsuperscript{25} The RCT was classified as low, high, or
unclear risk. The observational study with NOS score [?] 8 was defined as
high quality.

\textbf{Statistical analyses}

The included studies with adjusted OR/RR/HR and 95\% CIs were
meta-analyses. The RRs were used as the general effect estimates of
studies; HRs were considered comparable to RRs;\textsuperscript{9} ORs
were transferred to RRs using the published
method.\textsuperscript{26}The RRs and corresponding 95\% CIs were
calculated using the DerSimonian-Laird random-effects model. Statistical
heterogeneity was tested using Cochran Q test (significance level: 0.1)
and I\textsuperscript{2} Statistics (\textgreater{}50\%: considerable
heterogeneity).\textsuperscript{27} To explore possible sources of
heterogeneity, subgroup analyses were performed based on study designs
(prospective vs. retrospective studies), a history of stroke (patients
with a prior stroke only vs. patients with and without prior stroke),
observational window (with vs. without); sensitivity analysis was
carried out by the leave-one-out method. Publication bias was explored
with a funnel plot, and statistically evaluated by the Begg's and
Egger's tests, and the trim-and-fill method. All analyses were performed
using the STATA 16.0 (StataCorp, College Station, TX, USA), and
a\emph{p} -value of \textless{}0.05 indicated a statistically
significant difference.

\textbf{Results}

\textbf{Study selection and characteristics}

As shown in Figure 1, of the 1788 records identified in the electronic
database, 1435 records were screened based on title and abstract after
removing all duplicate records; 48 full-text articles were assessed for
eligibility, among which 39 full-text articles were excluded because of
overlapping participants,\textsuperscript{28, 29} including participants
with history of dementia or moderate to severe cognitive
dysfunction,\textsuperscript{12, 13} and other reasons . Finally, 9
studies were included in the quantitative synthesis.\textsuperscript{10,
11, 15-19, 30, 31}

As presented in Supplementary Table S3, of the 9 included studies, 6
were conducted in Europe, 2 in North America, 1 in Asia; all studies
were observational; 2 were prospective design, and 7 were retrospective
design; a total of 613,920 patients were included; the follow-up time
were varied from about 2 to 10 years; 1 study included patients with the
history of first-ever ischaemic stroke only, and the others included
mixed patients; 4 studies set the observational window varied from 6
months to 4 years. The quality of included studies was high, reflected
by a NOS score of 9 (Supplementary Table S4).

\textbf{The effect of oral anticoagulant use on incidence of dementia}

For OAC use versus non-OAC use, the results including all 9 studies,
presented a significant association of the OAC use and the reduction of
incidence of dementia (RR {[}95\%CI{]} =0.72 {[}0.60, 0.86{]},
I\textsuperscript{2}=97.2\%; \emph{P} =0.000) (Figure 2A, Table 1); for
studies including patients of
CHA\textsubscript{2}DS\textsubscript{2}-VASc score [?] 2, the results
including 18,076 patients of 2 studies, displayed the similar trend of
the intended outcome(RR {[}95\%CI{]} =0.83 {[}0.72, 0.97{]},
I\textsuperscript{2}=0.0\%;\emph{P} =0.021) (Table 1). For VKA use vs.
non-OAC use, including 514,111 patients of 4 studies, VKA use was
significantly associated with reducing the incidence of dementia (RR
{[}95\%CI{]} =0.78 {[}0.65, 0.93{]},
I\textsuperscript{2}=93.4\%;\emph{P} =0.006) (Figure 2B, Table 1). For
NOAC use vs. non-OAC use, the results including 274,723 patients of 2
studies, had no statistical difference (RR {[}95\%CI{]} =0.61 {[}0.27,
1.42{]}, I\textsuperscript{2}=95.7\%; \emph{P} =0.254) (Table 1). For
VKA use vs. NOAC use, there was no statistically significant difference
of pooled RR synthesized from 2 studies (RR {[}95\%CI{]} =0.91 {[}0.75,
1.12{]}, I\textsuperscript{2}=0.0\%; \emph{P} =0.384) (Table 1).

\textbf{Subgroup analyses}

As listed in Table 2, in subgroup analyses by study design, the results
demonstrated the consistent protective role of OAC use in reducing the
incidence of dementia, with the low heterogeneity for prospective
studies (Supplementary Figure S1); by patients with the history of prior
stroke, the direction of effects were similar; by setting observational
window, the pooled RR did not reach the statistically significant level
for studies with observational window (RR {[}95\%CI{]} =0.75 {[}0.51,
1.10{]}, I\textsuperscript{2}=98.8\%; \emph{P} =0.000) (Supplementary
Figure S2).

\textbf{Sensitivity analyses}

In the sensitivity analyses using a leave-one-out method, the direction
of effects was stable (Supplementary Table S5).

\textbf{Publication bias and strength of the body of evidence}

The funnel plot presented a relative symmetry (Supplementary Figure S3).
There was no obvious publication bias evaluated by Begg's test
(\emph{P}=0.348) and Egger's test (\emph{P} =0.770), and the pooled RR
was unchanged with the trim-and-fill method (RR {[}95\%CI{]} =0.72
{[}0.60, 0.86{]}, \emph{P} =0.000).

As listed in Supplementary Table S6, with the GRADE system, we graded
SOE for all investigated outcomes as low to moderate, because the
plausible confounding factors may exist for the observational design
although the effect was fully adjusted. The SOE for outcomes between
OAC/VKA/NOAC use and no-OAC use was graded as low due to the
inconsistency and indirectness.

\textbf{Discussion}

The present systematic review and meta-analysis found that OAC use
significantly decreased the risk of developing dementia in patients with
AF by 28\% compared with no treatment. But in the subgroup analyses with
observational window, there is no statistical difference of the risk of
dementia between OAC use and no treatment. The high heterogeneity and
low SOE may impact the confidence of the results.

The main finding of this study, i.e. the effect of OAC use on the
incidence of dementia, is in accordance with the previous two
meta-analyses that demonstrated the protective effect of OACs on the
incidence of dementia, but high heterogeneity and low SOE were the
common limitation.\textsuperscript{8, 9} The present meta-analysis
improved the quality of included studies by excluding the cross
sectional studies and the dementia-included studies, and updated four
studies. The results of the comparison of VKA use and non-OAC use, and
VKA use and NOAC use on the risk of dementia, were consistent with the
recent meta-analysis.\textsuperscript{9} However, in this study, NOAC
use was not associated with the reduced risk of dementia compared with
non-OAC use, which was not in line with the general perception. A recent
meta-analysis, including 6 RCTs and 2 observational studies, found that
NOACs might decrease the risk of cognitive impairment in comparison to
VKAs/acetylsalicylic acid, with marginally significant level of
synthetic effect for random-effects model (HR {[}95\%CI{]} =0.77
{[}0.53, 1.01{]}, I\textsuperscript{2}=39.4\%).\textsuperscript{32} The
results ask for further RCTs for direct comparison of NOACs and VKAs on
the risk of dementia. In the latest clinical
guideline,\textsuperscript{1} the high risk of stroke, i.e.
CHA\textsubscript{2}DS\textsubscript{2}-VASc score [?] 2, is still the
strong indication to prescribe OACs. In the present study, we found the
similar protective effect of OACs on the incidence of dementia in AF
patients with CHA\textsubscript{2}DS\textsubscript{2}-VASc score [?] 2.

It is known that advanced age, shared risk factors, clinical and silent
cerebral infarcts may link AF and dementia.\textsuperscript{2, 5} One of
the leading potential mechanism is the silent cerebral infarcts, which
are very common in patients with AF and are associated with reduced
cognitive functioning. The AF-related silent cerebral infarcts are most
prevalent in the frontal lobes which play an important role in executive
functioning. Therefore, cumulative silent infarcts of the frontal
circuit components may contribute to the development of dementia.
Considering the antithrombotic role of OACs, it is a reasonable belief
that the effective OAC treatment for AF-related infarcts may prevent the
occurrence of dementia. This study may support the validity of this
potential hypothesis. It is worth mentioning, the pooled RR is not
stable in the subgroup analysis with the observational window. In the
non-RCT study, physicians prefer to prescribe OACs to patients with good
cognitive performance, which may cause the increased diagnosis of
dementia within the short time after inclusion. It was seen that
dementia cases occurring in the first year during follow-up were more
prevalent in non-OAC users.\textsuperscript{10} The observational window
may partly prevent the overestimation of the protective effects of OACs.
To this end, the pooled RR with the observational window may be closer
to the real effect of OACs on the risk of dementia. Therefore, although
this meta-analysis indicated a significant association between OAC use
and reduced incidence of dementia, the following limitations of the
included studies need to be noted: i) the observational design for all
included studies was the primary limitation, which may lead to the
different decision of OACs prescription and the different proportion of
complications between OAC use and no treatment patients. Although all
included studies were adjusted for potential baseline covariates, the
maximum adjusted covariates were varied, and some confounding factors
may still remain; ii) it is a long progression from the normal cognitive
performance to the mild cognitive impairment and the more serious
abnormality of dementia.\textsuperscript{2} The long period may result
in the varied effects of studies with different follow-up duration and
different baseline age. In addition, the worse cognitive status prior to
the stage of dementia exactly associated with the no prescription of
OACs, which overestimated the positive effect of OACs on risk of
dementia. The result of the subgroup analysis with the observational
window presented the lower and insignificant pooled RR. Our study
excluded the studies included patients with moderate to severe cognitive
impairment, while much studies didn't report the data of baseline
cognitive status. iii) the adjusted covariates were based on the
baseline data, but several covariates like medication management,
complications, AF types, were time-varying, which result in the
deviation from the true status of patients during follow-up. iv) the AF
burden was significantly associated with the progression of AF-related
complications, and a few study found that persistent/permanent rather
than paroxysmal AF had a high burden to cognitive
impairment,\textsuperscript{33} but all included studies didn't report
the data of AF types, let alone AF burden.

\textbf{Strengths and limitations}

The strengths of this systematic review and meta-analysis were: i)
applying a comprehensive search strategy; ii) taking the explicit
criteria for inclusion of interested studies; iii) using strict
statistical methods for analyses; iv) employing the preferred
methodology of systematic review and meta-analysis;\textsuperscript{21,
22} v) performing the test of publication bias with multiple methods.

The limitations of this study were also impossible to ignore, including
that: i) the pooled RR was synthesized from the results of observational
studies which presented plausible confounding factors decreasing the
strength of observed effect. Therefore, the findings should be
interpreted with caution; ii) a high degree of heterogeneity was
presented, which can't be interpreted from a single study because the
sensitivity analyses using a leave-one-out method didn't change the
direction of effect. In this study, the origin of heterogeneity may
mainly result from the study design, i.e. the low heterogeneity in the
prospective studies. However, other factors like races of patients,
follow-up duration, the observational window, may importantly impact the
heterogenous effects of OAC use on risk of dementia.

\textbf{Implications for clinical practice and future investigation}

This study with the latest evidence underlined the important role of
OACs on the prevention of clinical stroke, but also of the silent
cerebral infarcts in patients with AF. While this result was unable to
support the use of OACs solely to prevent dementia.

Given the shortages of previously published studies and the
characteristic of long-term progression of dementia, future
investigation should include: i) well-designed RCTs with longer
follow-up in younger patients for direct comparison of OACs and no
treatment,\textsuperscript{34} or well-designed study taking
comprehensively cognitive test at baseline, adjusting for baseline and
time-varying confounding factors, and applying at least 1-year
observational window; ii) identifying the cause and effect relationship
among AF burden, dementia, and OAC use; iii) evaluating the effect of
the percentage of time at risk with access to OACs, rather than the
baseline prescription on the risk of dementia; iv) reporting the studies
performed in different races.

\textbf{Conclusions}

OAC therapy was associated with reduced incidence of dementia in
patients with AF. However, on account of the high heterogeneity, low
SOE, and no statistical result in observational window subgroup
analysis, the results were limited. Further well-designed studies are
needed to build the reliable link between OAC use and the reduced risk
of developing dementia.

\textbf{References}

{[}1{]} Hindricks G, Potpara T, Dagres N\emph{, et al.} 2020 ESC
Guidelines for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Association of
Cardio-Thoracic Surgery (EACTS). \emph{Eur Heart J} . 2020.

{[}2{]} Dagres N, Chao TF, Fenelon G\emph{, et al.} European Heart
Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart
Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS)
expert consensus on arrhythmias and cognitive function: what is the best
practice? \emph{Heart Rhythm} . 2018;\textbf{15} : e37-e60.

{[}3{]} Islam MM, Poly TN, Walther BA\emph{, et al.} Association Between
Atrial Fibrillation and Dementia: A Meta-Analysis. \emph{Front Aging
Neurosci} . 2019;\textbf{11} : 305.

{[}4{]} Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive
impairment associated with atrial fibrillation: a
meta-analysis.\emph{Ann Intern Med} . 2013;\textbf{158} : 338-346.

{[}5{]} Diener HC, Hart RG, Koudstaal PJ, Lane DA, Lip GYH. Atrial
Fibrillation and Cognitive Function: JACC Review Topic of the
Week.\emph{J Am Coll Cardiol} . 2019;\textbf{73} : 612-619.

{[}6{]} Silva R, Miranda CM, Liu T, Tse G, Roever L. Atrial Fibrillation
and Risk of Dementia: Epidemiology, Mechanisms, and Effect of
Anticoagulation. \emph{Front Neurosci} . 2019;\textbf{13} : 18.

{[}7{]} Moffitt P, Lane DA, Park H, O'Connell J, Quinn TJ.
Thromboprophylaxis in atrial fibrillation and association with cognitive
decline: systematic review. \emph{Age Ageing} . 2016;\textbf{45} :
767-775.

{[}8{]} Cheng W, Liu W, Li B, Li D. Relationship of Anticoagulant
Therapy With Cognitive Impairment Among Patients With Atrial
Fibrillation: A Meta-Analysis and Systematic Review. \emph{J Cardiovasc
Pharmacol} . 2018;\textbf{71} : 380-387.

{[}9{]} Mongkhon P, Naser AY, Fanning L\emph{, et al.} Oral
anticoagulants and risk of dementia: A systematic review and
meta-analysis of observational studies and randomized controlled
trials.\emph{Neurosci Biobehav Rev} . 2019;\textbf{96} : 1-9.

{[}10{]} Friberg L, Rosenqvist M. Less dementia with oral
anticoagulation in atrial fibrillation. \emph{Eur Heart J} .
2018;\textbf{39} : 453-460.

{[}11{]} Madhavan M, Hu TY, Gersh BJ\emph{, et al.} Efficacy of Warfarin
Anticoagulation and Incident Dementia in a Community-Based Cohort of
Atrial Fibrillation. \emph{Mayo Clin Proc} . 2018;\textbf{93} : 145-154.

{[}12{]} Mavaddat N, Roalfe A, Fletcher K\emph{, et al.} Warfarin versus
aspirin for prevention of cognitive decline in atrial fibrillation:
randomized controlled trial (Birmingham Atrial Fibrillation Treatment of
the Aged Study). \emph{Stroke} . 2014;\textbf{45} : 1381-1386.

{[}13{]} Douiri A, McKevitt C, Emmett ES, Rudd AG, Wolfe CD. Long-term
effects of secondary prevention on cognitive function in stroke
patients. \emph{Circulation} . 2013;\textbf{128} : 1341-1348.

{[}14{]} Joe E, Ringman JM. Cognitive symptoms of Alzheimer's disease:
clinical management and prevention. \emph{BMJ} . 2019;\textbf{367} :
l6217.

{[}15{]} Mongkhon P, Fanning L, Lau WCY\emph{, et al.} Oral
anticoagulant and reduced risk of dementia in patients with atrial
fibrillation: A population-based cohort study. \emph{Heart Rhythm} .
2020;\textbf{17} : 706-713.

{[}16{]} Field TS, Weijs B, Curcio A\emph{, et al.} Incident Atrial
Fibrillation, Dementia and the Role of Anticoagulation: A
Population-Based Cohort Study. \emph{Thromb Haemost} . 2019;\textbf{119}
: 981-991.

{[}17{]} Nah MA, Lee KS, Hwang TY. Association Between Atrial
Fibrillation and the Risk of Dementia in the Korean Elderly: A 10-Year
Nationwide Cohort Study. \emph{J Prev Med Public Health} .
2020;\textbf{53} : 56-63.

{[}18{]} Krawczyk M, Fridman S, Cheng Y, Fang J, Saposnik G, Sposato LA.
Atrial fibrillation diagnosed after stroke and dementia risk: cohort
study of first-ever ischaemic stroke patients aged 65 or
older.\emph{Europace} . 2019;\textbf{21} : 1793-1801.

{[}19{]} Ding M, Fratiglioni L, Johnell K\emph{, et al.} Atrial
fibrillation, antithrombotic treatment, and cognitive aging: A
population-based study. \emph{Neurology} . 2018;\textbf{91} :
e1732-e1740.

{[}20{]} Higgins J, Thomas J, Chandler J\emph{, et al.} Cochrane
Handbook for Systematic Reviews of Interventions version 6.0 (updated
July 2019). Cochrane: Cochrane, 2019.

{[}21{]} Shamseer L, Moher D, Clarke M\emph{, et al.} Preferred
reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015: elaboration and explanation. \emph{BMJ} .
2015;\textbf{350} : g7647.

{[}22{]} Moher D, Shamseer L, Clarke M\emph{, et al.} Preferred
reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015 statement. \emph{Syst Rev} . 2015;\textbf{4} : 1.

{[}23{]} Pink J, O'Brien J, Robinson L, Longson D, Guideline C.
Dementia: assessment, management and support: summary of updated NICE
guidance. \emph{BMJ} . 2018;\textbf{361} : k2438.

{[}24{]} Berkman ND, Lohr KN, Ansari MT\emph{, et al.} Grading the
strength of a body of evidence when assessing health care interventions:
an EPC update. \emph{J Clin Epidemiol} . 2015;\textbf{68} : 1312-1324.

{[}25{]} Wells G, Shea B, O'Connell D\emph{, et al.} The
Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised
studies in meta-analyses. Ottawa Hospital Research Institute, 2014.

{[}26{]} Zhang J, Yu KF. What's the relative risk? A method of
correcting the odds ratio in cohort studies of common
outcomes.\emph{JAMA} . 1998;\textbf{280} : 1690-1691.

{[}27{]} Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. \emph{BMJ} . 2003;\textbf{327} :
557-560.

{[}28{]} Friberg L, Andersson T, Rosenqvist M. Less dementia and stroke
in low-risk patients with atrial fibrillation taking oral
anticoagulation. \emph{Eur Heart J} . 2019;\textbf{40} : 2327-2335.

{[}29{]} Kim D, Yang PS, Yu HT\emph{, et al.} Risk of dementia in
stroke-free patients diagnosed with atrial fibrillation: data from a
population-based cohort. \emph{Eur Heart J} . 2019;\textbf{40} :
2313-2323.

{[}30{]} Barber M, Tait RC, Scott J, Rumley A, Lowe GD, Stott DJ.
Dementia in subjects with atrial fibrillation: hemostatic function and
the role of anticoagulation. \emph{J Thromb Haemost} . 2004;\textbf{2} :
1873-1878.

{[}31{]} Marzona I, Baviera M, Vannini T\emph{, et al.} Risk of dementia
and death in patients with atrial fibrillation: A competing risk
analysis of a population-based cohort. \emph{Int J Cardiol} .
2016;\textbf{220} : 440-444.

{[}32{]} Zhang C, Gu ZC, Shen L\emph{, et al.} Non-vitamin K Antagonist
Oral Anticoagulants and Cognitive Impairment in Atrial Fibrillation:
Insights From the Meta-Analysis of Over 90,000 Patients of Randomized
Controlled Trials and Real-World Studies. \emph{Front Aging Neurosci} .
2018;\textbf{10} : 258.

{[}33{]} Manolis TA, Manolis AA, Apostolopoulos EJ, Melita H, Manolis
AS. Atrial Fibrillation and Cognitive Impairment: An Associated Burden
or Burden by Association? \emph{Angiology} . 2020;\textbf{71} : 498-519.

{[}34{]} Rivard L, Khairy P, Talajic M\emph{, et al.} Blinded Randomized
Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive
Impairment in Atrial Fibrillation (BRAIN-AF): Methods and
Design.\emph{Can J Cardiol} . 2019;\textbf{35} : 1069-1077.

Table 1. Summary of findings of the effect of oral anticoagulant therapy
on the risk of dementia\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Outcome & Number of studies & Sample size & Pooled
RR(95\%CI)\tabularnewline
\midrule
\endhead
OACs vs. non-OAC & 9 & 613920 & 0.717(0.596-0.862)\tabularnewline
OACs vs. non-OAC in patients with
CHA\textsubscript{2}DS\textsubscript{2}-VASc Score[?]2 & 2 & 18076 &
0.834(0716-0.973)\tabularnewline
VKA vs. non-OAC & 4 & 514111 & 0.776(0.647-0.930)\tabularnewline
NOACs vs. non-OAC & 2 & 274723 & 0.614(0.266-1.418)\tabularnewline
VKA vs. NOACs & 2 & 220483 & 0.914(0.746-1.120)\tabularnewline
\bottomrule
\end{longtable}

Table 1. Summary of findings of the effect of oral anticoagulant therapy
on the risk of dementia (continued)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Z-value & P-value & Heterogeneity & Heterogeneity & Heterogeneity &
Heterogeneity\tabularnewline
\midrule
\endhead
& & Q statistic & P-value & I2 & \selectlanguage{greek}τ\selectlanguage{english}2\tabularnewline
3.54 & 0.000 & 287.71 & 0.000 & 97.2\% & 0.0649\tabularnewline
2.31 & 0.021 & 0.29 & 0.593 & 0.0\% & 0.000\tabularnewline
2.74 & 0.006 & 45.50 & 0.000 & 93.4\% & 0.0247\tabularnewline
1.14 & 0.254 & 23.05 & 0.000 & 95.7\% & 0.3492\tabularnewline
0.87 & 0.384 & 0.15 & 0.703 & 0.0\% & 0.000\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: RR=relative risk, CI=confident interval, OACs=oral
anticoagulants, VKA=vitamin K antagonist, NOACs=non-VKA oral
anticoagulants, NA=not applicable

Table 2. Subgroup analyses of the effect of oral anticoagulant therapy
on the risk of dementia\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Subgroup Characteristics & Number of studies & Pooled RR(95\%CI) &
Z-value & P-value\tabularnewline
\midrule
\endhead
Study design & & & &\tabularnewline
Prospective studies & 2 & 0.531(0.348-0.812) & 2.93 &
0.003\tabularnewline
Retrospective studies & 7 & 0.746(0.613-0.907) & 2.94 &
0.003\tabularnewline
A history of stroke & & & &\tabularnewline
Patients with and without stroke & 8 & 0.726(0.591-0.893) & 3.04 &
0.000\tabularnewline
Patients with stroke only & 1 & 0.650(0.580-0.720) & 7.81 &
0.002\tabularnewline
Observational window & & & &\tabularnewline
Yes & 4 & 0.745(0.505-1.100) & 1.48 & 0.138\tabularnewline
No & 5 & 0.720(0.612-0.848) & 3.94 & 0.000\tabularnewline
\bottomrule
\end{longtable}

Table 2. Subgroup analyses of the effect of oral anticoagulant therapy
on the risk of dementia (continued)

Heterogeneity\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Q statistic & P-value & I\textsuperscript{2} &
\selectlanguage{greek}τ\selectlanguage{english}\textsuperscript{2}\tabularnewline
0.64 & 0.425 & 0.0\% & 0.000\tabularnewline
285.55 & 0.000 & 97.9\% & 0.0653\tabularnewline
286.27 & 0.000 & 97.6\% & 0.0715\tabularnewline
NA & NA & NA & NA\tabularnewline
244.58 & 0.000 & 98.8\% & 0.1514\tabularnewline
30.18 & 0.000 & 86.7\% & 0.0216\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: RR=relative risk, CI=confident interval, NA=not
applicable

\textbf{Figure legends}

Figure 1. Flow chart of search result

Figure 2. Risk of dementia of patients with atrial fibrillation
receiving oral anticoagulant (OAC) and non-OAC (A); risk of dementia of
patients with atrial fibrillation receiving vitamin K antagonists and
non-OAC (B). RR: risk ration; CI: confidence interval; OAC: oral
anticoagulant; VKA: vitamin K antagonists

Supplementary Figure S1. The subgroup analysis with prospective and
retrospective study. RR: risk ration; CI: confidence interval; OAC: oral
anticoagulant

Supplementary Figure S2. The subgroup analysis with and without
observational window. RR: risk ration; CI: confidence interval; OAC:
oral anticoagulant

Supplementary Figure S3. The funnel plot showing a relative symmetry of
publication bias. rr: risk ration\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\selectlanguage{english}
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