Introduction
Atrial
fibrillation (AF) is one of the most prevalent persistent
arrhythmias.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.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]).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.5, 6 Among them, the clinical or subclinical
embolic brain ischemia is considered to be the main cause of cognitive
decline associated with AF.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.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]);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]).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.9conducted 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.10 and
Madhavan et al.11 The unstable pooled RR was
associated with the design of studies and the limitation of small
numbers of studies; two included studies 12, 13 had
inclusion of patients with moderate to severe cognitive impairment and
dementia which may have small benefit from medication
interventions;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 studies15-19 published since the retrieving
data of the latest meta-analysis, and majority of them set the
observational window.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.