MATERIALS AND METHODS
Data Source
We downloaded FAERS data from January 2004 to December 2019 in the FAERS
Quarterly Data Extract Files website [28]. FAERS data was processed
anonymously, so no ethical review was required.
The FAERS datasets consisted of seven data tables as follow: “DEMO”
table for patient demographic and administrative information, “DRUG”
table for the drug information, “REAC” table for adverse events
information, “OUTC” table for patient outcomes information, “RPSR”
table for report sources information, “THER” table for drug therapy
start and end dates information and “INDI” table for the indications
for drug use. We managed FAERS data in local by Microsoft SQL server
2017 software.
We first removed duplicated cases from the original data as the FDA
recommended. We removed the same records from “DEMO” table and left
one, then deleted the earliest FDA_DT when the CASEIDs were the same
and removed the lower PRIMARYID when the CASEID and FDA_DT were the
same. In the current study, we only included cases reported by health
professionals, including physicians, pharmacists and other health
professionals.
PPI Regimens
Identification
In “DRUG” table, drugs could be documented in various forms, such as
generic names, brand names, synonymous names or their abbreviations. We
used the MedEx software (MedEx UIMA 1.3.7, Vanderbilt university, US) to
standardize different names of the same drug into the “generic name”
[29, 30].
We tried to identify seven single component PPI regimens with the WHO
Anatomical Therapeutic Chemical (ATC) code of A02BC from local FAERS
database. The seven PPI regimens (ATC code) included omeprazole
(A02BC01), pantoprazole (A02BC02), lansoprazole (A02BC03), rabeprazole
(A02BC04), esomeprazole (A02BC05), dexlansoprazole (A02BC06) and
dexrabeprazole (A02BC07). We restricted the drug role as Primary
Suspected (PS) drug.
Dementia Events
Identification
According to Medical Dictionary for Regularly Activities (MedDRA) and
Standardised MedDRA Queries (SMQs) version 23.1. We identified dementia
cases in “REAC” table using SMQ (code: 20000097) broad searching,
including 99 Preferred Terms (PTs). For cases reported more than one PTs
of the same SMQ, we removed duplicate records and kept one. The PTs
details could be found in Supplementary Table S1.
Data Mining
We gathered the characteristics of dementia cases with PPIs treatment,
including cases attributed to different PPIs, age and sex, reporter and
report country, annual case reported, as well as indications.
We employed reporting odds ratio (ROR) and proportional reporting ratio
(PRR) to detect signals of dementia event relevant to PPIs. The
calculation method of ROR, PRR and their 95% confidence interval (95%
CI) were shown in Supplementary Table S2. A significant signal was
defined as both ROR and PRR signal detected. The ROR signal criteria was
cases ≥ 3 and the lower limit of 95% CI exceed one[31]. The PRR
signal criteria was cases ≥ 3, PRR ≥ 2 and χ2 ≥ 4
[32].
We further calculated signals between PPIs use and dementia event in
GERD cases who might receive long-term PPIs treatment.
Statistical Analysis
We estimated the time interval from PPIs use to adverse events reported
in all PPIs (PS) cases reported by health professionals in FAERS. We
unified the time format as yyyy-mm-dd. The time interval was calculated
using event date (EVENT_DT) minus drug start date (START_DT). To make
the calculation more accurately, we excluded cases not in the period of
2004 to 2019, cases without year, month or day data in either EVENT_DT
or START_DT field, and cases with earlier event date than drug start
date. We compared dementia event
between short- and long- duration using Pearson’s chi-squared test.P value less than 0.05 indicated significant difference.
The statistical analyses were conducted by SPSS version 20.0 (IBM
corporation, Armonk, New York, USA) and GraphPad prism version 8.0.2
(GraphPad Software, San Diego, California, USA).