Cardiac adverse events associated with quetiapine: Disproportionality analysis of FDA adverse event reporting system

Abstract Objective Quetiapine, an atypical second‐generation antipsychotic drug, is approved for treatment of schizophrenia, bipolar disorder, and depression. Due to the limitations of clinical trials, the association between quetiapine and rare cardiac adverse events (AEs) is still unclear. This study is to evaluate quetiapine‐associated cardiac AEs through data mining of FDA Adverse Event Reporting System (FAERS). Methods Reporting odds ratio (ROR) was used to quantify the signals of quetiapine‐related cardiac AEs from the first quarter (Q1) of 2018–2022 Q1. Serious and nonserious cases were compared, and signals were prioritized using a rating scale. Results A total of 1004 cases of quetiapine‐associated cardiac AEs were identified, with 31 signals being detected, among which 13 AEs were identified as new and unexpected signals. Besides, nine and 22 cardiac AEs were identified as moderate and weak clinical priority. The median TTO for moderate and weak clinical priority signals were 0 and 4 days, respectively. All of the cardiac AEs had early failure type characteristics, suggesting that most of the patients developed cardiac AEs in a few days after quetiapine treatment, and that the risk of cardiac AEs occurrence would be gradually decreased over time. Conclusion Our study provided valuable evidence for health‐care professionals to mitigate the risk of quetiapine‐associated cardiac AEs based on an extensive analysis of a real‐world, large‐sample FAERS database, and prioritize cardiac AE signals.

new or serious adverse events (AEs) have been reported related to the long-term use of quetiapine. Particularly, studies have observed significant associations between quetiapine and metabolic and endocrine system (hyperglycemia, galactorrhea, dyslipidemia, etc.) and cardiovascular (cardiomyopathy, myocarditis, tachycardia, hypotension, prolonged QT interval, etc.) symptoms, although more serious consequences, including death, have been reported. [3][4][5][6] Evidence is accumulating from the reports and mechanism studies to support a possible association between quetiapine and cardiotoxicity. A case-crossover study using a nationwide population-based sample obtained from Taiwan's National Health Insurance Research Database reported that antipsychotic drug use such as quetiapine was associated with a 1.53-fold increased risk of ventricular arrhythmia and/or sudden cardiac death. 7 According to the International Drug Monitoring Program of the World Health Organization, quetiapineinduced myocarditis and cardiomyopathy have become the common manifestations in pathology. 8 Berge et al 6 reported that treatment with low-dose quetiapine/olanzapine for 6-12 months was significantly associated with an increased risk of cardiometabolic mortality Agency or the European Medicine Agency, which has therefore been cautious about expanding the use of quetiapine. 11,12 In particular, the FDA have warned in the instructions that elderly patients with dementia-related psychosis was associated with an increased risk of death from cardiovascular diseases (e.g., heart failure, sudden death) and infections (e.g., pneumonia) when treated with quetiapine.
Due to the limitations of clinical trials, such as specific population, relatively small sample size, limited duration of follow-ups, and strict inclusion and exclusion criteria, the association between quetiapine and rare cardiac AEs is still unclear, suggesting continuous post-marketing surveillance is urgent. 13 The long-term safety of drugs and the occurrence of rare or serious AEs are largely assessed using post-marketing surveillance data, which increases the value of spontaneous reporting systems such as Food and Drug Adverse Event Reporting System (FAERS). 14 The FAERS database is now widely used to identify pharmacovigilance risk signals in real-world clinical settings. 15 The purpose of this study was to utilize standardized information from the FAERS, to describe the characteristics of quetiapine-related cardiac AE reports from stratification analysis, clinical priority of signals, time-to-onset, and the serious outcomes.

| Study design and data sources
A disproportionality analysis, designed as a case/non-case study, was used to quantify the association between quetiapine and cardiological AEs. It calculated the proportion of occurring target AEs between a target drug (case) and all other drugs (non-case). 16 A significant safety signal occurs when a target drug is reported more frequently to induce a target AE than all other drugs. The data were sourced from the FAERS Quarterly Data Extract Files, available at https://fis.fda.gov/exten sions/ FPD-QDE-FAERS/ FPD-QDE-FAERS.
html. To get the latest reports, all reports recorded in FAERS covering the period between the first quarter (Q1) of 2018 and the 2022 Q1, were extracted in our study.

| Data extraction and descriptive analysis
The database included seven data files, namely patient demographic information (DEMO), drug/biologic information (DRUG), adverse events (REAC), patient outcomes (OUTC), report sources (RPSR), start/end dates of drug therapy (THER), and indications for drug (INDI). 14 In the FAERS database architecture, a relation was built to connect each data file by some special identification numbers (such as caseid, primaryid). Moreover, the cases deleted by FDA or manufacturers for various reasons were collected in Deleted files.
Because multiple versions of a report would be reported, the deduplication process should be performed before statistical analysis, to ensure the uniqueness of the report. 17 The caseid and the primaryid were used as the key filters in our study to remove duplicate records.
First, the reports in the Deleted files were deleted. Then, the report with the higher primaryid was selected when the caseid was the same. We further removed reports where the data were not available, when we counted patient information (e.g., sex and age). We extracted reports using generic name (quetiapine in drugname and prod_ai columns) and trade name (SEROQUEL in drugname column) in the DRUG file. To improve the reported association between drug and AEs, only the role_cod as primary suspected (PS) was selected.
AEs in FAERS were coded using the preferred term (PT) according to standardized Medical Dictionary for Regulatory Activities (MedDRA 25.0), which were divided into five levels: system organ class (SOC), high level group term (HLGT), high level term (HLT), preferred term (PT), and lowest level term (LLT). 18 The quetiapine-associated AEs extracted from the REAC files, were used to calculate the frequency and intensity at PT and SOC levels. All the PTs under the SOC of cardiac disorders (SOC: 10007541) in the MedDRA 25.0 were calculated in our study. Further, because a PT can be normally affiliated to more than one SOC in MedDRA 25.0, the Aes in reports were classified to the corresponding PT and SOC levels. All data processing was Subsequently, descriptive analyses were carried out to summarize the clinical characteristics of all quetiapine-associated reports. Detailed information will be calculated if the data are available, such as gender, age, weight, reporting countries, indications, outcomes, and time-to-onset, etc. A flowchart including the multistep process of data extraction, processing, and analysis is shown in Figure 1.

| Statistical analysis
Based on the disproportionality analysis using a 2 × 2 table (Table S1), the reporting odds ratio (ROR) was employed to identify an association between a drug and an AE. All cardiological AE reports were selected to perform signal strength of reports of quetiapine at both PT (cardiological AEs) and SOC (cardiac disorders) levels in FAERS database. To reduce the likelihood of false positives, the threshold was set, and a significant signal was defined when the lower limit of the ROR 95% confidence interval (CI) exceeded 1 with at least five reports. 19 The outcomes of AE reports were classified as serious or nonserious in FAERS. The serious outcomes included death (DE), life-threatening (LT), inpatient hospitalization or prolongation of existing hospitalization (HO), disability (DS), congenital anomaly (CA), required intervention to prevent permanent impairment/ damage (RI), as well as other serious/important medical event (OT). Some reports might list more than one specific outcome (e.g., one report experienced DS, LT, and then DE), which recorded in the OUTC file. However, the serious and nonserious reports were also compared to clarify the severity of the detected safety signals and identify risk factors (gender, age, weight, and types of AEs) in patients. Proportions were compared using a Pearson's chi-squared (χ 2 ) or Fisher's exact test, and Mann-Whitney U test was applied for continuous non-normal distribution data, such as age and weight. Data were analyzed using SPSS (v22.0; IBM Corp., Armonk, NY, United States), and statistical significance was set at a two-tailed p < 0.05. To further explore the influence of different stratification regimens on the correlation between quetiapine and cardiac disorders, we performed subgroup analysis by gender (female and male), age (<18, 18 ≤ and ≤ 65, >65 years), weight (<80, 80 ≤ and ≤ 100, and >100 kg), and reporters (health-care professional and consumer) separately.

| Clinical prioritization of signals
AEs with significant disproportionality were scored and ranked according to clinical priority in our study. A semiquantitative score was performed to prioritize disproportionality signals by assessing five different features, including number of AE reports, the lower limit of the ROR 95% CI (ROR 025 ) values, proportion of death, characterization as designated medical events (DMEs) or important medical events (IMEs), and evidence evaluation. 19,20 According to three levels of clinical importance, a composite score between 0-4, 5-7, or 8-10 was identified as AEs with weak, moderate, or strong clinical priority, respectively. The detailed information is shown in Table S2.

| Time-to-onset analysis and sensitivity analysis
Time-to-onset (TTO) was calculated as the duration between the occurrence date of AEs (EVENT_DT in DEMO file) and start date of quetiapine use (START_DT in THER file). 13 Only the reports with available TTO data were analyzed, and reports with input errors (EVENT_DT earlier than START_DT) were excluded before analysis, to ensure the accuracy of calculation. The incidence of AEs often varies over time, and the Weibull shape parameter (WSP) test is used for statistical analysis of TTO to describe the risk that the incidence of AEs increases or decreases over time. [21][22][23] The shape of Weibull distribution was described by two parameters: scale (α) and shape (β). In the analysis of WSP test, the shape parameter β of the Weibull distribution will be considered and discussed to forecast the hazard without a reference population. However, three hazard types are described in WSP test: early failure type means the hazard of the AEs decreases over time (β < 1 and 95% CI < 1); random failure type means the hazard of the AEs constantly occurs over time (β was equal to or nearly 1 and its 95% CI included the value 1); wear-out failure type means the hazard of the AEs increases over time (β > 1 and 95% CI > 1).
In order to predict the risk of increase or decrease of these quetiapine-associated cardiological AEs over time, we calculated the median TTO and WSP of signals with moderate or weak clinical priority after quetiapine use. The WSP tests were performed using Minitab statistical software (v20.0; Minitab LLC).
Moreover, we also considered the effect of concomitant drugs on quetiapine-related cardiac AEs, and concomitant therapy was defined as quetiapine being the "primary suspect." and other drugs were listed as "second suspect," "concomitant," or "interacting." Subsequently, the sensitivity analysis was performed after the exclusion of the reports associated with potential suspicious drugs. 24 F I G U R E 1 Multistep process of data extraction, processing, and analysis from Food and Drug Administration adverse event reporting system (FAERS) database.

| Descriptive analysis
From January 2018 to March 2022, the FAERS database has recorded 6,437,182 AE reports after exclusion of duplicates, including 1415 quetiapine-associated cardiac AEs in 1004 patients. The clinical characteristics of quetiapine-induced AEs are described in Table 1. Among all reports, females accounted for a larger proportion than males (61.89% vs 38.11%). Patients were mainly aged

| Disproportionality analysis
During the study period, a total of 31 different PTs of quetiapineassociated cardiac AEs were identified in FAERS database in at least five cases ( Figure 2). The most commonly reported cardiac AEs were dizziness (n = 205), tachycardia (n = 138), palpitations (n = 57), and cardiorespiratory arrest (n = 57). Figure 2 presented a full list of disproportionality analysis results. In the entire database, quetiapine-related cardiac disorders were reported significantly more frequently than non-quetiapine, with an ROR 025

| Serious vs. Nonserious cases
Data in Table 2 showed that there were no statistically signifi-

| Subgroup analysis
As shown in Figure 3, cardiac disorders were separately assessed stratifying by sex, age, weight, and type of reporters. Results demonstrated that the lower limits of ROR values were >1 when stratified by sex and reporters' type, indicating there was still a strong statistical correlation between quetiapine and cardiac disorders. In females, ROR 025 was found to be 1.48, whereas it was 1.20 in males, indicating a significant association of quetiapine with cardiac AEs in both male and females. Moreover, it suggested that women were more likely to experience cardiotoxicity with quetiapine than men.
The majority of quetiapine-associated cardiac AEs cases were found in the 18-65 years age groups. However, it did not show significant association between cardiac disorders and quetiapine treatment when stratified by age and body weight, primarily in subgroups of patients >65 years old and body weight <80 kg and >100 kg.

| Time-to-onset analysis and sensitivity analysis
As shown in Table 4, the median onset time of moderate and weak AE signals associated with quetiapine was 0 (IQR 0-8) and 4 (IQR 0-59.5) days, respectively. In the WSP analysis, the upper limits of 95% CI of the shape parameters β were <1, suggesting these moderate TA B L E 1 Clinical characteristics of patients with quetiapine-associated cardiac adverse events.

| DISCUSS ION
This pharmacovigilance study comprehensively and systemati-  Figure 2.
This study suggests that there are significant differences found that although women were at a lower risk of sudden cardiac death, they had a higher risk of induced long QT syndrome from antipsychotic drugs. To date, sex differences in quetiapine-induced AEs have not been well studied, but some AEs, such as weight gain, elevated lipids, and cardiac effects, have been reported to be particularly associated with women. 30 The present subgroup analysis revealed that females were associated with more cardiac AEs than males with a higher ROR value (1.62 vs. 1.35). The mechanism of gender-specific effects on quetiapine-related cardiotoxicity may be related to hormones and pharmacokinetic properties. 33 In our study, patients aged 18-65 years reported more frequently cardiac AEs (n = 575, 72.60%) than those aged >65 years (n = 157, 19.82%) and <18 years (n = 60, 7.58%), which were consistent with a FAERS study that the median patient age among quetiapine abuse-related event reports was 44 years (IQR = 31-55). 34 On the contrary, younger patients generally had numerically higher ROR estimates than older adults (2.34 vs. 1.43) in the subgroup analysis ( Figure 2), suggesting youths taking quetiapine might be more likely to have cardiac AEs. Moreover, severe cases were also reported at younger ages than non-severe cases (median age 43 vs 51 years), but there was no statistical difference among the two groups (p = 0.093).
However, Yunusa et al 35 reported the opposite results that antipsychotics were associated with potentially serious AEs in vulnerable older adults with higher RORs of hospitalization due to age-related reduction in the ability to metabolize and excrete drugs, thus leading to a higher plasma concentration of quetiapine. Another study also demonstrated an increased risk of cardiovascular events in older patients with antipsychotic drugs, including quetiapine. 36 Therefore, cautions are necessary when prescribing quetiapine to older women and children.
We conducted subgroup analysis by body weight (<80, 80-100, and >100 kg), and found that only the subgroup of body weight 80-100 kg presented significant signal strength with ROR 025 = 1.
The other two groups (<80 and >100 kg) did not show an association between quetiapine and cardiac AEs because of ROR 025 < 1. A Bayesian meta-analysis of 41 short-term trials of second-generation antipsychotics found a significant mean weight gain (1.74 kg; 95% CI, 0.99-2.50) during treatment with quetiapine. 37 Jensen et al 38 also reported that quetiapine was associated with significantly greater weight gain and adverse changes in cardiometabolic outcomes in youths. Results suggested body weight might, in part, be associated with quetiapine-induced cardiac AEs.

F I G U R E 3 Subgroup analysis of quetiapine-related cardiac disorders.
TA B L E 3 Clinical priority assessing results of disproportionality signals. Therefore, we cannot exclude the possibility that quetiapine combined with other drugs may increase the risk of cardiac AEs.
There are some limitations inherently shared by all pharmacovigilance databases. First, due to the nature of spontaneous reporting mechanism of the FAERS database (e.g., false, overreported, inaccurate, incomplete, and delayed reports), our analysis is subject to inevitable and unquantifiable biases. Second, because the total number of patients using quetiapine is not available in FAERS, we cannot calculate AE incidence and establish causality. Third, we focus only on AEs in cardiac disorders, and the deep relationship between quetiapine and other systemic organ classes remain unknown.
Notwithstanding the above limitations, we systematically and comprehensively reveal the association between quetiapine and cardiotoxicity through an extensive analysis of a real-world, large-sample FAERS database, and prioritize cardiac AE signals, which provides valuable evidence for healthcare professionals to mitigate the risk of quetiapine-associated cardiac AEs.

AUTH O R CO NTR I B UTI O N S
Qilin Zhang and Yamin Shu contributed to conception and study design, and took responsibility for the collection, integrity, and accuracy of the data. All authors drafted the article, participated in data analyses and interpretation, and revisions of the article, and approved the final version.

FU N D I N G I N FO R M ATI O N
This study was supported by grants from National Natural Science Foundation of China (No. 82104476).

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that they have no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.