Study Characteristics and Quality
The baseline characteristics of the included studies are illustrated inTable 1 . Among the 9 included observational studies, 3 were
from the UK[29], Germany[8], and Japan [30], the other 6
were derived from nationwide or health insurance claims databases in the
United States[15, 23-27]. Of the 3 included post-hoc analyses of
RCTs[9, 10, 28], all were multicenter large-scale randomized
clinical trials. The mean age of patients ranged from 60.1 to 83.0
years, and the sample size was from 1,558 to 188,863. Across studies,
the study populations in the NOACs group were administrated with
dabigatran, apixaban, rivaroxaban, and edoxaban. Supplementary
Table Ⅱ shows the clinical outcomes of the included articles and the
adjustment for confounding factors of the outcomes. Risk of bias
evaluation was performed, shown in Supplementary Table Ⅲ . All
the studies had a NOS of ≥6 points suggesting moderate-to-high quality.
Polypharmacy definition
There was a slight variation in the definition of polypharmacy used
across the studies included in our meta-analysis. We defined
polypharmacy as a discrete definition. When dividing the boundaries of
non-polypharmacy, moderate polypharmacy, and severe polypharmacy, the
threshold used by the study author was used. Specifically, 5 studies
[10, 15, 23-25] included articles defined moderate polypharmacy as
the use of 5-9 drugs, 3 studies [8, 28, 30] included articles
defined moderate polypharmacy use as the use of 5-8 drugs, and 2 studies
[9, 29] included articles defined moderate polypharmacy use as 6-8
drug use, and 1 article[27] defined moderate polydrug use as 4-8
drug use. Correspondingly, 6 articles [8, 9, 27-30] defined severe
polypharmacy as the use of ≥9 drugs, and 6 articles [10, 15, 23-26]
defined severe polypharmacy as the use of ≥10 drugs. It should be noted
that the article by Martinez et al. [26] defines polypharmacy as the
use of 5 or more drugs and explores the grouping of 10 or more drugs in
the secondary analysis. Therefore, we did not classify its data into the
moderate polypharmacy group but used its secondary analysis data as the
severe polypharmacy group. Detailed classification information is shown
in Table 1 .