Psychiatric disorders associated with PCSK9 inhibitors: A real‐world, pharmacovigilance study

Abstract Background The relationship between Protein Convertase Subtilisin Kexin Type 9 inhibitor (PCSK9i) and psychiatric adverse events (AEs) remains unclear due to the limitations of clinical trials. In this study, PCSK9i‐related psychiatric AEs were realistically observed and systematically summarized in the real world by data mining the FDA AE Reporting System (FAERS). Method Total AEs between the third quarter of 2015 and the first quarter of 2023 were obtained from FAERS. Psychiatric AEs were identified using disproportionality analysis and clinical prioritization of signals using a rating scale, followed by univariate logistic regression to explore factors influencing psychiatric AEs. Results Psychiatric AEs accounted for 6.7% of the total number of PCSK9i reports. Eighteen psychiatric AEs were defined as PCSK9i‐related psychiatric adverse events (ppAEs) (lower 95% CI of both ROR >1 and IC025 > 0). The median age of ppAE reports was 68 years, and female patients accounted for 22.67% of reports, including 41.40% of reports with a serious outcome. Eleven (61.11%) and seven (38.89%) ppAEs were classified as weak and moderate clinical priority, respectively. The median time to onset of ppAEs was 149 and 196 days after treatment with evolocumab and alirocumab, respectively. Patients weighing ≥80 kg were 1.59 times more likely to experience ppAEs. Conclusion The results of this study facilitate the prioritization of psychiatric AE signals by healthcare professionals with the goal of mitigating the risk of PCSK9i‐related psychiatric AEs. However, as an exploratory study, our findings need to be confirmed in large‐scale prospective studies.

LDL-bound cholesterol in plasma, and inhibiting the metabolism of LDL cholesterol (LDL-C). 1 Evolocumab (IgG2 isotype) and alirocumab (IgG1 isotype) are two types of PCSK9i drugs that are injectable monoclonal antibodies. 2 They reduce LDL-C levels by 50%-60% by binding to PCSK9 in the circulation, preventing it from binding to LDLR and reducing LDLR degradation. 3though PCSK9i has been widely used in lipid-lowering therapies and clinical trial evidence suggests that it appears to be well tolerated, the number of pharmacovigilance studies on PCSK9i is increasing.Neuropsychiatric disorders, one of the adverse event (AE) categories of PCSK9i, have a low incidence and vary in severity of symptoms.In 2012, the FDA warned that cholesterol-lowering medications may cause serious and reversible cognitive side effects such as memory loss, amnesia, and confusional state. 4,5ven the very low LDL-C level induced by PCSK9i and the importance of cholesterol for brain function, [6][7][8] the FDA directed PCSK9i developers in early 2014 to focus on monitoring for neurological AEs. 9 Surprisingly, past studies are not in agreement as to whether PCSK9i impairs neurologic function.Several clinical trials and post-marketing studies have reported neurologic AEs with PCSK9i.Early Phase 2 safety studies reported a tendency for PCSK9i to trigger cognitive impairment. 7The OSLER (Open-Label Study of Long-Term Evaluation against LDL-C) study found that 0.9% of patients treated with evolocumab experienced cognitive AEs, including delirium, attention deficit, dementia, perceptual deficits, and psychiatric disorders, compared with 0.3% of patients in the standard of care group. 10Data from the ODYSSEY LONG TERM trial showed that 1.2% of patients in the alirocumab group developed memory impairment compared to 0.5% in the placebo group. 11In an analysis of Eudravigilance, Mauro et al. found that 22.7% of reports with PCSK9i described psychiatric AEs. 12 However, a meta-analysis based on 39 clinical trials showed that the use of two PCSK9i drugs was not associated with an increased risk of cognitive AEs. 13 Giugliano et al. followed 1204 patients (mean age 65 years) treated with evolocumab for 1.6 years and found no association with cognitive AEs. 14 Because of the inconsistent results of previous studies and the paucity of real-world evidence on age and sex differences, there is a strong need for more reports on the long-term effects of PCSK9i, especially long-term safety data from post-marketing surveillance, which can help to develop appropriate, targeted, and safe therapeutic strategies for patients treated with PCSK9i.The U.S.
FDA AE Reporting System (FAERS) is a publicly available database of safety reports submitted by physicians, nurses, patients, and pharmaceutical companies that contains real-world reports of AEs from a wide variety of populations that may have been overlooked in carefully designed clinical trials. 15In recent years, FAERS has played an important role in identifying new, rare, and serious AEs and has become a very valuable resource to support post-marketing surveillance and pharmacovigilance studies. 16,17The aim of this study was to provide an in-depth and comprehensive understanding of PCSK9i-related psychiatric AEs using standardized information in FAERS and to describe the clinical characteristics of psychiatric AEs in terms of disproportionality analysis, stratified analysis, clinical priority of signals, time of occurrence, serious outcomes, and contributing factors to provide a useful reference for clinical practice.

| Study design
Ongoing post-marketing surveillance of adverse reactions is imminent due to the limitations of clinical trials, such as relatively small sample sizes, limited duration of follow-up, and stringent inclusion, and exclusion criteria.FAERS plays an important role in detecting and identifying new, rare, and serious adverse drug reactions and events.The FAERS database contains real-world reports of AEs from a large number of populations, which may be overlooked in welldesigned clinical trials and have become a very valuable resource to support post-marketing surveillance and early detection of drug safety issues.[20] This was a retrospective study with pharmacovigilance data extracted from the FAERS quarterly data extraction file (download link https:// fis.fda.gov/ exten sions/ FPD-QDE-FAERS/ FPD-QDE-FAERS.html).We collected information on reports of PCSK9i treatment, including case number, AE, sex, age, country of reporting, outcome, duration of treatment, and date of AE.The design of this study is shown in Figure 1.

| Data source
We conducted a retrospective search of PCSK9i related AEs reports between July 1, 2015 and March 31, 2023 in FAERS.Because there may be multiple versions of the same report, we identified and removed duplicates before statistical analysis to ensure the uniqueness of the reports. 21e earliest "FDA_DT" was deleted if "CASEID" was the same; if "CASEID" and "FDA_DT" were the same, the lower "PRIMARYID" was deleted.To clarify drug-AE associations, we selected role_cod as the primary suspect (PS) and retained only reports from individuals aged 18 years and older.Comparisons of categorical variables were performed using Pearson's chi-squared (χ 2 ) or Fisher's exact test, and comparisons of continuous variables, such as age and weight, were performed using the Mann-Whitney U test.Missing gender data were coded as "unknown", and missing age data were estimated from the median of drug recipients in each group.All tests were two-tailed, with p < 0.05 defined as significant.Data processing and statistical analysis were performed using Python and R software (version 4. evolocumab, repatha, and pcsk9).Reports for atorvastatin and ezetimibe were also obtained.
To predict whether the incidence of AEs will increase or decrease over time, we performed a weibull shape parameter (WSP) test. 22,23e weibull distribution is a probability distribution used to describe reliability and lifetime data, and the scale parameter α and shape

| Signal mining
To quantify the association between PCSK9i and psychiatric AEs, we performed disproportionality analyses by calculating the ROR and the lower bound of the information component at a 95% credible interval (IC 025 ).When the 95% CI lower bound of the ROR >1 and the IC 025 > 0, it indicated that PCSK9i induced psychiatric AEs more frequently than other drugs.First, AEs were coded using the preferred term (PT) according to the standardized Medical Dictionary for Regulatory Activities (MedDRA) at five levels: system organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), and lowest level term (LLT). 24Based on the SOC (SOC: 10037175) = "Psychiatric disorders", we obtained PTs for all psychiatric AEs in MedDRA (version 25.0) (n = 865, Table S1), ensuring that the PTs analyzed were from a clinical perspective.ROR and IC 025 were calculated for all PTs according to the formula (Table S2). 25 Next, the full PCSK9i reports were screened to minimize the impact of other AEs, concomitant medications, and indications for medications that may lead to psychiatric disorders.
In FAERS, the outcomes of AEs are categorized as serious or not serious.A report is defined as a serious medical event when it is documented in the OUTC file as a death, life-threatening event, hospitalization, disability, or other serious medical event; the incidence of hospitalizations and serious medical events is calculated from the total number of psychiatric AEs.Inclusion/exclusion criteria for the "Important Medical Events" list.https:// www.ema.europa.eu/ en/ docum ents/ other/ eudra vigil anceinclu sion/ exclu sion-crite ria-impor tant-medic al-event s-list_ en.pdf, accessed November 12, 2019), and biological plausibility (Table S3). 26

F I G U R E 1
The process of data extraction, processing, and analysis from FAERS database.

| Descriptive analysis of psychiatric AEs in PCSK9i patients
First, we investigated the occurrence of psychiatric AEs in patients treated with PCSK9i in FAERS from the third quarter of 2015 to the first quarter of 2023.The detailed data processing is shown in Figure 2.Over the 8-year period, there were 7,957,266 reports in FAERS, and 96,629 reports were associated with the use of PCSK9i (79,063 and 17,566 for evolocumab and alirocumab, respectively).Of all PCSK9i reports, psychiatric AEs were reported in 6489 or 6.71% of the total number of cases (6489/96629, Figure 3A).In addition, the number of PCSK9i reports per two years represented a small fraction of the total number of cases, ranging from 5.38% to 9.11% (Figure 3B).The incidence of psychiatric AEs differed between the two PCSK9i; the number of reports was 4980 and 1509 for evolocumab and alirocumab, respectively, and the rate of reported psychiatric AEs was lower for evolocumab than for alirocumab (6.29% and 8.59%, respectively).patients into two distinct age groups, with the majority of patients treated with PCSK9i being older than 65 years, especially for alirocumab (n = 190, 63.76%).Among individual countries, the United States reported the highest number of psychiatric AEs with 86.56% (2313/2672).A higher proportion of female than male patients was reported in all reports (22.67% vs. 16.03%).Severe outcomes were observed in 41.40% (980/2367) of the cases.All cases were reported after the third quarter of 2015, and the number of reports increased annually from 2016 to 2019, with a slight decrease after 2020 (Table 1).Overall, psychiatric AEs under PCSK9i treatment strategies may represent a non-negligible proportion of their associated AEs.
The results showed that PCSK9i treatment was significantly associated Next, to further explore the correlation between PCSK9i and ppAEs, stratified analyses were performed according to three aspects: age (≤65 and > 65 years), gender (female and male), and weight (≤80 kg and >80 kg).The results, shown in Table 4 and Figure 4D,E, discovered that the lower limit of the 95% CI of the ROR values was greater than 1 in all subgroups, indicating a strong statistical correlation between the two drugs and ppAEs.In female patients, the ROR values for the two drugs were 1.50 and 1.73, respectively, while in males they were 2.69 and 2.14, suggesting that males were more likely to develop ppAEs after PCSK9i treatment.In addition, most cases of ppAEs were more significantly associated with patients older than 65 years and weighing more than 80 kg.
To assess the robustness of the signals, we performed two additional analyses.The first was to compare the signal strength of ppAEs with that of other lipid-lowering drugs.PCSK9i use was

| Time to onset analysis and weibull shape parameter (WSP) test
The time to ppAEs onset is shown in Figure 6B.Notably, 21.45% and 26.84% of patients reported the time to onset of ppAEs after treatment with evolocumab and alirocumab, respectively, with a median time to onset of 149 days (IQR 36-314 days) and 196 days (IQR 80-471 days), respectively.After WSP test, we found that the upper limit of the 95% CI for the shape parameter β was <1, suggesting that ppAEs are characterized by an early failure type.The results suggest a progressive decrease in the risk of ppAEs over time (Table 8).Second, reports of severe and non-severe outcomes were compared to identify risk factors (gender, age, weight) (Table 9).For gender alone, there was a statistically significant difference between severe and non-severe cases treated with both PCSK9i [evolocumab: (χ 2 = 19.22,p < 0.0001), alirocumab: (χ 2 = 7.24, p = 0.007)].

| DISCUSS ION
This pharmacovigilance study is based on real-world data from FAERS and provides a comprehensive and systematic update of the latest evidence on PCSK9i-related psychiatric safety.We identified 18 psychiatric AEs that were highly associated with PCSK9i treatment, highlighted the association between exposure to lipidlowering medications and psychiatric AEs, and explored the clinical characteristics of the occurrence of such AEs.
Psychiatric disorders are a stable but less common class of AEs associated with PCSK9i.PCSK9i was approved for marketing in 2015, and the number of psychiatric AE reports in that year was low, with a total of only 51 reports, 44 reports for evolocumab, and only 7 reports for alirocumab.FAERS-based analyses showed that the proportion of psychiatric AEs was slightly higher in reports from patients treated with alirocumab than in reports from patients treated with evolocumab (6.30% vs. 8.59%).From the 96,629 reports of PCSKi-related psychiatric AEs captured in FAERS, we identified 18 AEs that were strongly associated with PCSK9i, defining them as ppAEs.However, with the exception of "fear of injection", none of the common psychiatric disorders such as "dysphonia", "memory impairment", "cognitive disorder", "sleep apnoea syndrome", and "obstructive sleep apnoea syndrome" that are listed in PCSK9i were mentioned in the drug labeling, suggesting that healthcare professionals need to pay further attention to unexpected AEs in the future.
The results of our analysis showed the highest number of dysphonia (n = 882) with a strong association with PCSK9i use (ROR = 6.84).
Similar to our findings, Peter et al. reported dysphonia and paroxysmal loss of voice the day after the first subcutaneous injection of alirocumab (75 mg) in a 68-year-old female patient. 27However, none of the available literature on the target and mechanism studies of alirocumab explicitly identifies the larynx as a site of toxicity.We also  28,29 and is particularly susceptible to altered upper airway anatomy and defective compensatory neuromuscular activity. 30Diseases associated with neuromuscular injury also predispose to obstructive sleep apnoea syndrome, progressive respiratory muscle weakness and chronic hypercapnic respiratory failure. 31Since the pathogenesis of obstructive sleep apnoea syndrome is closely related to neuromuscular injury, and real-world evidence suggests that the most common adverse effects associated with PCSK9i are muscle toxicity as well as myalgia. 32Therefore, we hypothesized that obstructive sleep apnoea syndrome after PCSK9i use may be a secondary effect of PCSK9i leading to myotoxicity, and that further studies are needed to investigate the effects of PCSK9i on obstructive sleep apnoea syndrome and the mechanisms underlying this potential association need to be further investigated.
We made innovative use of multidimensional analyses such as subgroup analysis, influencing factors, clinical prioritization of signals, and comparisons of serious and non-serious outcomes to provide insight into the primary outcomes.Subgroup analyses showed that the frequency of reported ppAEs was significantly higher in women (n = 763) than in men (n = 525) for both PCSK9i, especially for evolocumab, where women accounted for 55% of the total number of psychiatric AE reports for PCSK9i, which is consistent with another study based on the Eudravigilance database. 7It may be due to estrogenic and pharmacokinetic changes that psychiatric disorders tend to occur in the female population, especially during the postpartum, menstrual, and menopausal periods. 33Elderly patients >65 years of age generally had higher ROR values than middle-aged adults (2.20 vs. 3.60), suggesting that older adults taking PCSK9i may be more susceptible to psychiatric AEs.Another FAERS-based study also reported that numerous AEs for evolocumab and alirocumab occurred more frequently in older adults >65 years of age, 32 possibly due to age-related decreases in both drug metabolism and excretory and digestive abilities, which may lead to increased plasma concentrations of PCSK9i. 34Therefore, caution should be exercised when prescribing PCSK9i to patients >65 years of age.Subgroup analyses were also performed based on body weight (≤80 kg and >80 kg), and we found that both categorized groups showed a significant ROR signal intensity greater than 1.Weiss et al. reported a significant increase in the likelihood of comorbid CNS disorders such as mood, eating, and sleep disorders in obese populations. 35 hypothesized that excess body weight may, to some extent, be an important factor in the induction of ppAEs by PCSK9i.However, when analyzed by univariate logistic regression, the sample sizes in the different groups were small, and conclusions regarding the factors influencing ppAEs need to be further validated by larger studies or clinical trials.
We also used a clinical prioritization assessment to prioritize ppAEs.The results showed that 7 moderate and 11 weak clinical priority signals were identified.The strongest priority signals were "dysphonia", "cognitive disorder", and "amnesia" with a score of 6.
In contrast, a study based on a hospital registry and nine pharmacovigilance databases reported that PCSK9i-induced AEs were typically mild.The present analysis suggests that gender, but not age or weight, may be associated with an increased risk of ppAEs severity. 36Severe cases in the evolocumab group were older (median age 69 years vs. 67 years) and weighed less (median weight 77 kg vs. 86 kg) than non-severe cases, but there was no statistical difference between the two groups.However, after both PCSK9i treatments, women had a significantly higher rate of severe ppAEs than men,

TA B L E 6
Univariate logistic regression analysis of the odds ratio of ppAEs (controlling for multiple conditions).
with a statistically significant difference between the two groups, meaning that women were at higher risk of reporting severe ppAEs after PCSK9i treatment.We suggest that the higher incidence of serious outcomes in female patients may be related to the source of AE reporting.Women are more likely to suffer from anxiety, depression, and eating disorders due to the effects of estrogen, etc. 37 FAERS is a self-reporting system, and female patients may be motivated to report more serious AEs.
Clinicians are interested in whether their patients are more or less likely to safely benefit from PCSK9i therapy.Therefore,  also critical steps to mitigate AEs 38,39 ; Second, preventive measures can be taken for patients prior to the administration of the drug.
If patients are anxious about injections, soft music can be played and the drug can be injected in a comfortable environment without overstimulation to alleviate the patient's mental stress; Third, clinicians need to fully consider the need for adjunctive medications.
For example, sleep apnoea syndrome can be improved with sedative drugs. 39In the presence of psychiatric adverse reactions, the dose of PCSK9i may be appropriately reduced, although efficacy may be compromised as well as suspension or discontinuation of therapy due to serious adverse reactions.
While the primary responsibility of this study was to identify potential psychiatric hazards or risks associated with PCSK9i in an effort to minimize the risk of clinical medication events, this study has several limitations.First, the FAERS is a system based on spontaneous reports from healthcare professionals, patients, and insurance personnel with specific selective biases, such as different drug manufacturing lots, racial disparities in reported cases and inconsistencies in reporters' perceptions of specific adverse reactions, and the fact that not all reports of the occurrence of serious adverse reactions are collected.As a result, we were unable to establish causal relationships between ppAEs and their incidence; Second, more detailed information beyond the report of each case was not available.

CO N FLI C T O F I NTE R E S T S TATE M E NT
None of the other authors reported a conflict of interest related to the study.
3.0).All PCSK9i related reports were extracted based on the generic name (drug name and prod_ai columns) and trade name (SEROQUEL in the drugname column) in the DRUG file (alirocumab, praluent, | 3 of 17 DENG et al. parameter β are used to describe the weibull distribution.First, we calculate the median time to onset of AEs as follows: Time-toonset (TTO) = EVENT time (EVENT_DT in DEMO file) -START time (START_DT in THER file).The results of the WSP test reflect three types of hazard models: the wear-out failure type indicates that the hazard of AEs increases over time (β > 1, 95% CI >1); the early failure type indicates that the hazard of AEs decreases over time (β < 1, 95% CI <1), and the random failure type implies that the risk of AEs increases over time (β equal to or close to 1, 95% CI including values of 1).WSP tests were performed with Minitab statistical software (v20.0;Minitab LLC).

| 5 of 17 DENG
The median age of patients treated with both PCSK9i therapies was 68 years (evolocumab: interquartile range [IQR] 61-75, 1564 reports with age data; alirocumab: interquartile range [IQR] 62-74, 298 reports with age data).Using 65 years as the cutoff, we categorized F I G U R E 2 The flowchart includes data acquisition and data analysis.F I G U R E 3 Statistics on the incidence of PCSK9i psychiatric AEs reported in FAERS during 2015-2023.(A) Calendar year data comparing the number of PCSK9i reports with psychiatric AEs to the number of PCSK9i reports without psychiatric AEs in FAERS during 2015-2023.(B) Overall comparison of the number of PCSK9i reports with psychiatric AEs versus PCSK9i reports without psychiatric AEs in FAERS, 2015-2023.et al.

Figure
Figure6Cshows the outcome metrics of patients who received both PCSK9i treatments.Based on the different types of outcomes, we categorized the cases into severe and non-severe outcomes and compared the clinical characteristics between the two groups.The results showed that after evolocumab treatment, the hospitalization rate and severe

Figure 3
shows that the number of PCSK9i AE reports per quarter increased significantly from 2015 to 2018, with the total number of reports in 2017-2018 being almost 7.5 times higher than in the previous 2 years.However, in the 2019-2020 window, the number of PCSK9i AE reports decreased significantly to only 42.22% of the previous number, and then gradually increased again in 2021-2022.We speculate that the decrease in the number of AE reports in 2019-2020 may be due to the global outbreak of COVID-19 in 2020, where healthcare workers, patients, and drug R&D companies became more concerned about the impact of COVID-19 on health and lives, and therefore neglected to report PCSK9i AEs.With the end of COVID-19, the number of reported PCSK9i AEs was 7226 in the first quarter of 2023, based on which it is speculated that the number of PCSK9i reports may gradually stabilize from the first quarter of 2023.
found a significant association between PCSK9i use and obstructive sleep apnoea syndrome and sleep apnoea syndrome, especially obstructive sleep apnoea syndrome (ROR = 31.77,n = 82), which was the most common of the AEs with the PCSK9i with the highest association.Unexpectedly, however, there was no convincing clinical evidence of an association between PCSK9i and obstructive sleep apnoea syndrome.Obstructive sleep apnoea syndrome is characterized by recurrent collapse of the upper airway and neuromuscular dysfunction of the upper airway dilator muscles (especially the genioglossus) during sleep,

F I G U R E 5
AEs co-reported with ppAEs.(A) Percentage of ppAEs cases that did and did not present with co-reported AEs.(B) Statistics on co-reported adverse event PTs (SOC level).Percentage values labeled in the figure represent the proportion of cases with such adverse reactions among all ppAEs cases to the total number of cases with co-reported adverse reactions.(C) Statistics on co-reported adverse event PTs.Percentage values labeled in the graph represent the proportion of ppAEs cases in which such adverse reactions occurred.

F I G U R E 6
Results of univariate logistic regression analyses of factors influencing ppAEs (A), time to onset of ppAEs (B), and overall outcome indicators (C).TA B L E 7 Clinical priority assessing results of disproportionality signals.

For
example, for the COVID-19 infections, we have not yet been able to determine whether COVID-19 had an effect on the occurrence of ppAEs; Third, we were not able to fully distinguish between drug indications and the effect of other AEs on ppAEs.Although we analyzed other AEs associated with ppAEs, we only obtained the proportion of concomitant AEs and could not determine the effect of concomitant AEs on ppAEs; Fourth, we did not provide strong evidence of the underlying biological mechanisms of ppAEs.In conclusion, this pharmacovigilance study comprehensively investigates and identifies 18 psychiatric AEs highly associated with PCSK9i and explores their clinical characteristics by performing disproportionality analyses based on real-world data from the FAERS.The results of this study will help clinicians to recognize the different features of the psychiatric toxicity spectrum and to intervene early.As our study is exploratory, large-scale prospective studies are needed for validation.In the future, we will consider clinical trials to further validate our findings.AUTH O R CO NTR I B UTI O N SWenqi Gao, Zhifang Deng, and Han Xiao were involved in the conceptualization and study design.Jue Liu, Hongjian Gong, and Xiaonan Cai were responsible for the collection, completeness, and accuracy of the data; Zhifang Deng wrote the draft of the article; Wenqi Gao revised the manuscript.All the authors were involved in drafting the article, analyzing and interpreting the data, and revising the article, and approved the final version.FU N D I N G I N FO R M ATI O NThis work was supported in part by grants from the Top Medical Young Talents of Hubei Province (2019), and the Wuhan Yellow Crane Talent-Outstanding Young Talents Program (Wenqi Gao, Zhifang Deng, and Hongjian Gong).
Number of different PTs among cases treated with PCSK9i during 2015-2023.
TA B L E 2 FAERS was scanned for ppAEs.(A) ROR of psychiatric AEs under the two PCKS9i treatment strategies (cases not less than 3).Red indicates a ROR value greater than 1, green indicates a ROR value less than 1, and gray indicates a ROR value that could not be calculated.(B) Number of reported cases of PCSK9i-relared psychiatric AEs under the two PCKS9i treatment strategies.(C) Sankey diagram depicting the hierarchical relationship of PTs for ppAEs.PT denotes preferred terminology, HLT denotes high-level terminology, HLGT denotes high-level group terminology, and SOC denotes systemic organ class.(D-E) Forest plots showing the subgroup ROR of ppAEs under two PCKS9i treatment strategies.
ment, 11 (61.11%),seven (38.89%), and zero psychiatric AEs were identified as weak, moderate, and strong levels of clinical priority, F I G U R E 4 Signal detection of PCSK9i associated psychiatric AEs.
TA B L E 3 Differences in clinical characteristics of severe and non-severe reports.The chi-square (χ 2 ) statistic of the Pearson chi-square test.
effective measures to prevent and manage these side effects are needed to improve the acceptability and effectiveness of treatment.First, a thorough assessment of the patient by the healthcare provider before prescribing, extra caution when using PCSK9i therapy in patients with pre-existing language or memory disorders, patient education and instruction, and skilled nursing practice are TA B L E 9 a b Proportions were compared using Pearson chi-square test.c The Z statistic of the Mann-Whitney U test.d The Mann-Whitney U test.