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.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.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], I2=39.4%).32 The
results ask for further RCTs for direct comparison of NOACs and VKAs on
the risk of dementia. In the latest clinical
guideline,1 the high risk of stroke, i.e.
CHA2DS2-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 CHA2DS2-VASc score ≥ 2.
It is known that advanced age, shared risk factors, clinical and silent
cerebral infarcts may link AF and dementia.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.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.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,33 but all included studies didn’t report
the data of AF types, let alone AF burden.