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.