Updated insights on dementia‐related risk of sacubitril/valsartan: A real‐world pharmacovigilance analysis

Abstract Aim Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also involved itself in the degradation of amyloid‐β, there is an ongoing concern about the effect of sacubitril/valsartan on cognition, especially in case of long‐term administration. Methods The FDA Adverse Event Reporting System (FAERS) was mined between 2015Q3 and 2022Q4 to analyze the association between sacubitril/valsartan and adverse events (AEs) involving dementia. Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with “broad” and “narrow” preferred terms (PTs) relevant to dementia was applied to systematically search demented AE reports. The Empirical Bayes Geometric Mean (EBGM) from Multi‐Item Gamma Poisson Shrinker (MGPS) and proportional reporting ratio with Chi‐square (PRR, χ2) were used to calculate the disproportionality. Results We filtered the query for indication and identified 80,316 reports with heart failure indication in FAERS during the analytical period. Among all the reports, sacubitril/valsartan was listed as primary suspected or secondary suspected drug in 29,269 cases. No significantly elevated reporting rates of narrow dementia were evident with sacubitril/valsartan. The EBGM05 for narrow dementia‐related AEs associated with sacubitril/valsartan was 0.88 and the PRR (χ2) was 1.22 (2.40). Similarly, broad demented complications were not over‐reported in the heart failure patients administrated with sacubitril/valsartan (EBGM05 1.11; PRR 1.31, χ2 109.36). Conclusion The number of dementia‐related cases reported to FAERS generate no safety signal attributable to sacubitril/valsartan in patients with heart failure for now. Further follow‐ups are still warranted to address this question.


| INTRODUC TI ON
Sacubitril/valsartan, the first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), was proven successful in treating patients with heart failure. 1,2 It was approved by the United States Food and Drug Administration (FDA) in 2015 with an indication of heart failure. 3 Sacubitril could inhibit neprilysin and lead to decreased breakdown of vasoactive peptides with favorable actions for patients with heart failure. 4,5 However, neprilysin has other substrates in other systems including amyloidβ peptides. 6,7 Inhibiting neprilysin could therefore lead to accumulation of certain amyloidβ, a major pathological feature of Alzheimer's disease (AD), and might increase the risk of dementia-related symptoms. 8,9 So far, results of related researches were still insufficient to show compelling evidence for long-term cognitive safety of sacubitril/valsartan. 10 We have, therefore, conducted a pharmacovigilance analysis for sacubitril/valsartan and adverse events (AEs) involving cognitive impairment using the realworld FDA Adverse Event Reporting System (FAERS) database to update the long-term cognitive safety profile of sacubitril/valsartan.

| Study design and data source
A retrospective, observational, pharmacovigilance study was performed on the de-identified publicly available FAERS data. FAERS is a spontaneous database administered by the FDA and gathers information on AE reports that originate from different sources, including health-care providers, patients, drug manufacturers, and others. 11 Symptoms of AEs are coded using the Medical Dictionary for Regulatory Activities (MedDRA), an internationally standardized, clinically validated terminology. 12 FAERS can be used to analyze unexpected patterns of AEs which are unlikely to be detected in clinical trials due to the limited number of participants. 11,13,14

| Data queries
All reports reported to the FAERS database between July 1, 2015 and December 31, 2022 were downloaded and accessed. We managed the raw FAERS data in local by Microsoft Access software (version 2021). Deduplication was applied prior to conducting any analysis. Only reports with indication of heart failure were included in this study. Each report was classified based on the following binomial factors: (1) "with" or "without" exposure to the administration of sacubitril/valsartan, which was classified as "primary suspected" or "secondary suspected" drug. (2) "With" or "without" the development of an AE category of interest, which was defined by using Standardized MedDRA Queries (SMQs) with "narrow" or "broad" preferred terms (PTs) related to dementia-like AEs in the MedDRA 25.0. The precise terms used are detailed in Appendix 1.

| Data analysis
A population-based pharmacovigilance study using a case/noncase approach was applied to analyze the risk of dementia for sacubitril/valsartan. This approach is a common system used in pharmacovigilance studies to identify drugs safety signals. 11,12,14,15 Mathematically, the idea of the case/non-case system is to compare the frequency of an AE of interest in patients exposed to a specific drug (cases) with the reports of the same AE in patients who were not exposed to this drug (non-cases). 16,17 This so-called case/noncase system can be considered a case-control study, and results can be measured by Multi-Item Gamma Poisson Shrinker (MGPS) algorithm and the proportional reporting ratio (PRR) with its Chi-square (χ 2 ). Figure 1 shows the flow diagram for identifying cases and noncases from the FAERS database.
In our study, disproportionality was analyzed by calculating the

| Statistical analysis
Kolmogorov-Smirnov test was performed to evaluate the normality.
Data are presented as mean ± standard deviation for normally dis-

| Data overview
Over the study period, a total of 12,245,295 AEs were available on FAERS database. Of these, 1,119,964 reports were excluded based on the exclusion criteria. We then filtered the query for indication with heart failure and identified 80,316 reports in FAERS during the analytical period, Overall, 29,269 AEs were found to be related to sacubitril/valsartan. Two hundred and forty reports related to narrow demented AEs and 5808 reports with broad demented AEs were documented. Among them, the sacubitril/valsartan was identified as the suspected drug causing narrow dementia in 99 reports and broad demented AEs in 2486 cases.

| General characteristics
The demographic characteristics of the sacubitril/valsartanassociated demented reports are presented in Table 1. Male reports were more frequent in all cases. In reports in which age was docu-

| Disproportionality analysis
The results of disproportionality analysis are summarized in To further access the individual characteristics, separate subanalyses based on age and sex were conducted too ( Figure 2).
No risk for narrow or broad dementia-related AEs was noted in both females and males based on the results of EBGM05. Among reports in which age was documented, the EBGM05s for dementia (narrow and broad) were less than 2 in all specified age subgroups.

| DISCUSS ION
There is an ongoing concern about the risk of cognition impairment for the sacubitril/valsartan, an angiotensin-neprilysin inhibitor, especially under long-term administration. 5,10 Theoretical mechanisms of sacubitril/valsartan-induced dementia have been proposed.
Amyloidβ plaque deposition is one of the most noticeable characteristics of AD. Neprilysin is a significant neuropeptidase and amyloiddegrading enzyme. 18 Inhibition of neprilysin by sacubitril might lead to accumulation of amyloidβ in the central nervous system which is the pathognomonic feature of Alzheimer's type dementia. 6,7,18 Some reports indicated that sacubitril can also inhibit the degradation of bradykinin. 19 Numerous studies showed that bradykinin is also involved in the progress of AD and elevated bradykinin in plasma levels has been found in AD patients. 20 There were numerous preclinical studies evaluating the theoretical risk of amyloidβ accumulation following neprilysin inhibition. In two studies conducted by Langenickel et al. 7 and Schoenfeld et al. 21 the maximum concentrations of the active metabolite of sacubitril, sacubitrilat, measured F I G U R E 1 Flowchart of identifying cases and non-cases from FAERS database.
in human cerebrospinal fluids (CSFs) and plasma were 58.8 and 19,600 ng/mL respectively, while in monkeys, maximum concentrations were 19.8 ng/mL in CSF and 34,400 ng/mL in plasma. Despite the concentrations of sacubitrilat in CSF are significantly lower than in plasma, some researchers still indicated that these values might adequate for effective inhibition of neprilysin in the brain since the IC50 of sacubitrilat for neprilysin inhibition is quite low. 10 To be more specific, Schoenfeld et al. 21 also conducted histopathological examinations to prove the effect of sacubitrilat on accumulation of amyloid plaques in different areas of the brain with a conclusion that no significant pathological alterations were noticed in the brain tissue.  24 Long-term analysis assessing cognitive risks are required.
Our study investigated the association between sacubitril/valsartan and dementia-related AEs using 7-year pharmacovigilance data from FAERS in real-world setting.
There is a known suggestion that a substantial proportion of heart failure patients have concomitant cognitive problems. 25 Epidemiological studies showed that the incidence of dementia in patients with heart failure is higher compared with the general populations. [26][27][28][29] Therefore, to be more specific, we filtered the query for an expanded heart failure indication in our study. The overall EBGM05s for narrow and broad dementia-related AEs associated with sacubitril/valsartan were 0.88 and 1.11, respectively, demonstrating that no over-reporting of dementia-related AEs was identified in sacubitril/valsartan within heart failure patients. Studies have identified the epidemiology characteristics of dementia which is increasingly prevalent with advancing age and with little sex difference. 30 Subgroup disproportionality analysis based on sex and age in our study detected no risk of dementia for sacubitril-valsartan in both males and females, and the risk did not exist in elderly people aged over 65 years and all other age groups.
Study limitations should be acknowledged. These limitations are mainly inherent to the nature characteristics of self-reporting database. First of all, in most reports there is no demonstration of a causal relationship between the reported AE and drug exposure.
The inability to make causal conformation is a limitation of all pharmacovigilance studies and cohort observational studies. 31

AUTH O R CO NTR I B UTI O N S
Congqin Chen contributed to data analysis, interpretation, and writing. Lingqing Ding contributed to data analysis and revising.
Fang Fu revised the manuscript. Jie Xiao conceived and designed this study.

FU N D I N G I N FO R M ATI O N
This work was partially supported by The Medical and Health Guidance Project of Xiamen (3502Z20214ZD1168).

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. TA B L E 2 Results of overall disproportionality analysis.

F I G U R E 2
Subgroup disproportionality analysis of dementia following sacubitril/valsartan compared to all other drugs within heart failure patients from FAERS by age and sex (heatmap of EBGM05).

F I G U R E 3
Time to onset of sacubitril/ valsartan-related demented AEs.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data supporting the conclusion of this article will be made available from the corresponding authors upon on reasonable request.