Pharmacovigilance analysis of cardiac risks associated with Bruton tyrosine kinase inhibitors

ABSTRACT Background Bruton tyrosine kinase inhibitors (BTKIs) can be associated with several cardiac risks. Research design and methods The study was conducted based on records from a large spontaneous reporting database, the Food and Drug Administration Adverse Event Reporting System, for cardiac events reported for several BTKI agents. Reporting odds ratio and information components based on statistical shrinkage transformation were utilized to measure disproportionality. Results The final number of records for BTKI-related cardiac events was 10 320. Death or life-threatening events occurred in 17.63% of all associated cardiac records. Significant reporting was captured between BTKI (total/specific) and cardiac events, with the strongest association for ibrutinib. A total of 47 positive signals were evacuated for ibrutinib, with atrial fibrillation being the most commonly reported one. Concomitantly, cardiac failure, congestive, cardiac disorder, arrhythmia, pericardial effusion, and atrial flutter were also noticed for relatively stronger signal and disproportionality. Atrial fibrillation was over-reported in the three groups (ibrutinib, acalabrutinib, and zanubrutinib), and acalabrutinib had statistically significant lower reporting compared with ibrutinib. Conclusions Receiving ibrutinib, acalabrutinib, or zanubrutinib might increase the chance of cardiac complications, with ibrutinib posing the highest risk. The type of cardiotoxicity involved in ibrutinib was highly variable.


Introduction
Bruton tyrosine kinase inhibitors (BTKIs) are a class of effective medications that have resulted in dramatic improvements in the treatment of B-cell malignancies [1,2].
Ibrutinib was the first FDA-approved BTKI, the therapeutic efficacy of which has been demonstrated in various clinical trials [3][4][5][6][7][8][9]. Starting with ibrutinib, more-highly selective secondgeneration BTKIs (including acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib) have been developed, and several other third-generation agents (pirtobrutinib and nemtabrutinib) are also under active investigation [10]. Nevertheless, the emergence of BTKI-related cardiac adverse events (AEs) has been a safety concern and complicated the management decisions for the utilization of this class of therapy [2,11]. It has been reported, in the real-world setting, adverse effect is the most common reason for ibrutinib discontinuation, with cardiac side effects resulting in discontinuation in more than 10% of patients [2,12,13]. While the exact pathophysiology behind BTKI-induced cardiotoxicity remains unclear, inhibition of PI3K signaling, a crucial regulator of cardiac protection under stress that is regulated by BTK and TEC, may play a role [1,14]. The real-world cardiotoxicity profile of ibrutinib has been explored and described in several studies; however, it has not been fully characterized. Additionally, newer BTKIs appear to have lower cardiovascular risk risks, but current data are limited. The cardiotoxicity profiles of newer BTKIs and their relevant differences relative to ibrutinib remain unclear. There is growing recognition of the need to provide an overview of the risk and characteristics of cardiac AEs from realworld data to complement clinical trial information and fully assess the cardiac safety of these drugs. Herein, we conducted a disproportionality analysis leveraging a large spontaneous reporting database (Food and Drug Administration Adverse Event Reporting System, FAERS), with the final goal to contribute a comprehensive and in-depth understanding of this safety issue.

Study design and data sources
This real-world, pharmacovigilance study is a disproportionality analysis based on Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database of the United States. Input data for this study were taken from the FAERS database, and the time horizon was from January 2015 to June 2022. The FAERS database, established for national post-market surveillance for drug safety, contains anonymized information related to AEs and medication errors and is one of the largest spontaneous systems worldwide for health-care professionals, patients, and pharmaceutical manufacturers [15]. It is publicly available and is used regularly to evaluate safety concerns by the FDA. Substantial amount of data collected at a national level from the general population allows FAERS to be a useful tool in discovering early safety issues [16,17]. All data in this study can be downloaded from the FDA website: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Data cleaning
The following deduplication and standardization procedures were performed before the formal analysis. First, we scrutinized the extracted data based on similarities among sex, age, drug name, AE, starting date, reporting year, country of reporter, event date, end date, and outcome to ensure unique records. Second, we excluded aberrant records of which starting date of the drug was later than the occurring date of AE from the study. No imputations were conducted for missing data, as variables in the FAERS database were missing at a large proportion. Time to onset (TTO) was defined as the period between the start date of drug administration and the onset date of a cardiac event, which was calculated through the variables EVENT_DT and START_DT in the database. Severe outcomes were defined as causing any of the following situations: death, lifethreatening, hospitalization, disability, congenital anomaly, requiring intervention, and any other important medical events [18].
Five BTKI drugs (ibrutinib, acalabrutinib, zanubrutinib, orelabrutinib, and tirabrutinib) were involved in the present study, and the main focus is on the first three. Both generic and brand names were used to identify records related to BTKI. In the FAERS database, AEs are coded using the preferred term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). There are five levels in the MedDRA terminology: SOC (system organ class), HLGT (high-level group term), HLT (high-level term), PT (preferred term), and LLT (lowest level term) [19].
A specific PT can be categorized under one or more HLTs, HLGTs, and SOCs. The hierarchical and multiaxial nature of MedDRA allows flexibility in AE retrieval. In the present study, we captured all potential records of interest using all PTs involving the cardiac system (SOC code: 10007541) according to MedDRA (version 24.0).

Statistical analysis
Disproportionality analysis, also known as case/non-case analysis, was conducted to compare the proportion of selected AEs reported for a single drug or drug class with the proportion of that same AEs reported for a control drug group, e.g. the same AEs reported for other medications in the FAERS database [20].
Disproportionality emerged when the reporting frequency of a specific AE for a given medication is higher than that in the background data. In the present study, two established pharmacovigilance algorithms, reporting odds ratio (ROR) and information components (IC), were applied to assess disproportionality [21,22]. ROR and IC can estimate the strength of the association between a drug and an AE and have been widely used in pharmacovigilance research. The ROR is the pharmacovigilance equivalent of the Odds Ratio (OR) and is based on frequentist, while the IC is based on Bayesian and is calculated using Bayesian confidence propagation neural network [23][24][25][26].
Calculations for ROR and IC were both based on a 2 × 2 contingency table, through analysis of observed-to-expected reporting frequencies. And the expected frequency was calculated as: n Expected was the number of records expected for the target drug-AE combination,n Drug and n Event were the total number of records submitted for the selected drug and AE, respectively, and n total represented the total number of records involved.
Statistical shrinkage transformation was applied to address the shortcoming that these two algorithms were sensitive to random fluctuations for rare events [20]. The shrunk IC and ROR were calculated as: where n Observrd was the number of records observed for the target drug-AE combination. For the present study, a signal emerged if the lower limits of the 95% confidence intervals of ROR (ROR 025 ) and IC (IC 025 ) exceeded the predefined thresholds (1 and 0, respectively) in at least three records. Additionally, when comparing different drug strategies, only ROR was used to calculate disproportionality. All analyses were conducted using SAS 9.4 software (SAS Institute, Cary, NC).

Clinical characteristics
A total of 115,466 records related to BTKI were extracted, and 10,320 records were reported for cardiac disorders. Descriptive characteristics of the related records were summarized in Table 1. Orelabrutinib received its first approval in China in December 2020, and tirabrutinib received its first approval in March 2020 in Japan. The time-to-market of these medications was relatively late. In this study, only three cardiac records were found related to orelabrutinib or tirabrutinib use. Therefore, these two drugs were not listed despite being counted. Ibrutinib, acalabrutinib, and zanubrutinib were the three mainly investigated drugs in the present study.
Acalabrutinib (482, 4.67%) and zanubrutinib (74, 0.72%) accounted for a small proportion of total reporting. After the exclusion of records with unspecified age, the mean onset age across all records was 72.57 years. Excluding records with missing sex, males accounted for a larger proportion than females ( Table 2). Death accounted for 13.33% of all associated records when the final outcome was available. The corresponding proportion for life-threatening outcomes was 4.30%. After the exclusion of records with missing time, the overall median onset time of cardiac events was 95.

Comparison of the cardiotoxicity profiles of different BTKI agents
Importantly, we explored the cardiotoxicity spectrum of ibrutinib, acalabrutinib, and zanubrutinib by examining and quantifying all potential cardiac risks through further disproportionality analysis at PT level ( Figure 1). Positive signals were showed in Tables  Moreover, some overlap among the cardiotoxicities of these three medications was noticed. In this study, we further explored and compared these overlapping toxicities ( Figure 2). Significantly, acalabrutinib had lower reporting of atrial fibrillation and peripheral swelling, higher reporting of syncope, pericarditis, palpitations, dyspnea, chest pain, chest discomfort, cardiac tamponade, acute myocardial infraction, and acute coronary syndrome compared with ibrutinib. Zanubrutinib had higher reporting of presyncope when using ibrutinib as a reference.

Comparison of the outcomes of cardiac AEs following different BTKI drugs
We also assessed the proportion of death and lifethreatening outcomes of class-specific cardiac AEs stratified
In addition to the significant survival benefits, BTKIs can also lead to an unfortunate rise in targeted therapy-associated cardiac complications, which could lead to severe and even fatal outcomes [33]. Despite increasing usage in clinical settings, there is a paucity of the study describing the postmarketing safety profile of BTKI in cardiac system, and the whole picture of the profile was not fully characterized.
Herein, we conducted a pharmacovigilance study taking advantage of large-scale pharmacovigilance data from the FAERS, aimed to gain further insight into the frequency, spectrum, clinical features, timing, and outcomes of BTKIrelated cardiac toxicities. To our knowledge, this study reports the latest and most comprehensive assessment of cardiac AEs after BTKI therapy by analyzing a large quantity of FAERS data. We have enumerated the notable and interesting findings as follows: First, this study contributed to the clarification of the characteristics of cardiac AEs associated with BTKIs. A comprehensive understanding of these characteristics is necessary to enhance cardiotoxicity management and optimize the delivery of care. We showed that BTKI-related cardiac events occurred mainly in males and the mean age of affected patients was above 70. The younger population (age < 60) had a significantly lower reporting of cardiac events compared with the older (age ≥ 60). Overall, the median onset time of cardiac AEs was 95.5 days after BTKI initiation, and acalabrutinib was associated with a later onset of cardiac AEs. Totally, death or life-threatening events occurred in approximately 17.63% of all associated cardiac records indicating the potentially fatal and life-threatening nature of BTKI-related cardiotoxicity. It is worthwhile to recognize the difference in time-to-onset between different BTKI agents; furthermore, our findings underscored a need for close cardiac monitoring after BTKI treatment, to ensure early intervention in the affected population. It should be noted that, due to the nonignorable impact of missing data, reporting bias, and the low number of records for acalabrutinib and zanubrutinib, these results might be subject to bias and should be interpreted with caution. Future studies using active surveillance data or clinical trial data are needed to update and verify our results.
Second, our analysis revealed that BTKI use was associated with higher odds of cardiac complications, with ibrutinib therapy posing the highest risk. Ibrutinib contributed to the vast majority of reported cardiac records, exhibiting the strongest association with cardiotoxicity. Similarly, results from subgroup analysis also supported this. Indeed, both acalabrutinib and zanubrutinib were second-generation BTK inhibitors, and it has been postulated that these more selective BTKIs may result in less off-target cardiovascular adverse effects and improve continuous therapy tolerability [34,35]. It was supported by the recently reported results from two head-tohead trials, the ELEVATE-RR trial and ALPINE trial, which demonstrated at least equivalency among the 3 BTK inhibitors in terms of efficacy, but with diminished cardiovascular AEs for acalabrutinib and zanubrutinib compared with ibrutinib [36,37]. Our finding was that ibrutinib was persistent with greater disproportionality compared with the other two drugs regardless of sex or age, in accordance with the evidence provided by these clinical trials. Interestingly, we noticed that, unlike ibrutinib and acalabrutinib, which had disproportionate reporting of cardiac AEs in all subgroups, zanubrutinib was only in the younger subgroup. It was important to note that we could not exclude the possibility that the negative signals detected for zanubrutinib were due to the random variation and a small number of records. Future studies using FAERS in conjunction with other data sources would be vital for the ongoing monitoring and comprehensive assessment of the cardiotoxicity of these newer BTKIs. Additionally, we found the males had a significant higher reporting of cardiac AEs compared with the females and younger subgroup (age < 60) was disproportionately at higher reporting of these AEs compared with older (age ≥ 60). These observations also highlight the need for continued efforts with regard to the identification and quantification of sex and age differences in cardiac-associated events with BTKI as well as to understand their underlying mechanisms, to monitor and manage patients in this subgroup more efficiently. Preassessment of baseline clinical risk of cardiovascular risk factors before initiating BTKI therapy is vital [1]. The natural compound polydatin has been reported to improve cardiac functions reduced by sunitinib, a multi-targeted tyrosine kinase inhibitor. Further research is needed to investigate the potential of natural compounds in mitigating BTKI-related cardiotoxicity [38].
Third, we conducted a comprehensive and comparative assessment of the cardiotoxicity profiles of three individual BTKI agents (ibrutinib, acalabrutinib, and zanubrutinib). There were some differences in cardiotoxicity of these three BTKIs and several major ones warranting further attention were prioritized. Ibrutinib, the first authorized and most commonly prescribed BTKI drug, was corresponding to a wide variety of cardiac AEs, which should be prescribed with caution. A total of 47 cardiac signals were excavated with significant disproportionality after ibrutinib, ranging from supraventricular tachycardia (weakest signal) to arrhythmia supraventricular (strongest signal), highlighting several possible new complications of ibrutinib that needs to be monitored, while patients receive this medication.
Atrial fibrillation was the first recognized cardiac adverse effect of ibrutinib, and it is the most common reason for toxicityrelated drug discontinuation in patients on ibrutinib [2,39]. Mounting clinical data have suggested ibrutinib usage increases the risk of atrial fibrillation [11,14,[40][41][42]. With its widespread use in clinical practice, some of its uncommon cardiac AEs reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. Serious and fatal events of cardiac arrhythmia or cardiac failure, as well as cardiac arrest and sudden cardiac death, also have occurred in patients treated with this medication [2,43,44]. Several emerging potential safety signals, including cardiac tamponade, pleural effusion, and pericarditis have been reported in case report and pharmacovigilance study [45]. As expected, in the present study, atrial fibrillation is the most commonly reported cardiac problem after ibrutinib treatment with significant disproportionality. Concomitantly, cardiac failure congestive, cardiac disorder, arrhythmia, pericardial effusion, and atrial flutter, were highlighted for relatively stronger signals and disproportionately higher reporting. It is worth noting that significant associations between ibrutinib and these toxicities were consistently maintained over the study period. It is critical that clinicians should recognize the broad spectrum of cardiotoxicity after ibrutinib and patients should be informed about these potential risks that might be encountered in real-world practice. Contrastingly, regarding acalabrutinib, 10 PTs were detected as signals, ranging from angina pectoris (weakest signal) to cardiac tamponade (strongest signal); for zanubrutinib, only two PTs were detected as signals, atrial fibrillation, and presyncope.
Moreover, the study identified sudden death and ventricular arrhythmia as positive signals for ibrutinib, further validating the growing concern regarding the increased risk of these events in patients receiving ibrutinib. Although the occurrence of these events was uncommon in patients undergoing ibrutinib, they posed a substantial threat due to their high mortality rate. Recently, unexplained ventricular arrhythmias with next-generation BTKIs have been reported. Published data from a large cohort has shown that patients treated with acalabrutinib were linked with a more than eightfold risk of ventricular arrhythmia and sudden death events [46]. Both acalabrutinib and zanubrutinib have much fewer data compared with ibrutinib in the database, mainly owing to their much later approval. Therefore, the cardiotoxicity profiles assessment was limited by the number of included records. To better evaluate the risk of ventricular arrhythmia and sudden death with these newer BTKIs, additional data is required, and increased vigilance is warranted. Fourth, several AEs overlapped among BTKI medications with varied reporting frequencies were compared and evaluated. We noticed that atrial fibrillation and peripheral swelling were statistically significantly less frequent for acalabrutinib versus ibrutinib, while syncope, pericarditis, palpitations, dyspnea, chest pain, chest discomfort, cardiac tamponade, acute myocardial infraction, and acute coronary syndrome were statistically disproportionately over-reported for acalabrutinib versus ibrutinib. Concomitantly, regarding zanubrutinib, significantly higher reporting of presyncope was observed when taking ibrutinib as a reference. These findings may provide insight into whether the risk of a specific cardiac event is lower with acalabrutinib or zanubrutinib than with ibrutinib. For example, it appeared that acalabrutinib was associated with significantly lower odds of atrial fibrillation events compared with ibrutinib, which was in line with the evidence from the Randomized Phase III Trial [36].
Fifth, our study evaluated and compared the outcome of AEs after taking different BTKIs through analysis of death and life-threatening proportions, providing insight into the burden of different cardiac events imposed on BTKI users. Among emerging signals for ibrutinib, sudden death and cardiac arrest were highlighted carrying substantial mortality, corresponding to relatively higher death count and death proportion. Additionally, several AEs although not detected as positive signals, like ventricular fibrillation and Torsade De Pointes were very likely developing into life-threatening outcomes. Regarding positive signals for acalabrutinib, pericarditis and cardiac tamponade were noticed for nearly 100% of life-threatening outcomes.
Our study suffers from several limitations. First, some shortcomings inherent to the spontaneous reporting nature and the FAERS database, including under-reporting, Weber effect, awareness bias, confounding, and missing [47,48]. Second, the absence of clinical and laboratory data in FAERS precluding a complete assessment for alternative causes of BTKI-associated cardiotoxicity. Third, a lack of exposure data, we are unable to determine the incidence of cardiac AEs using FAERS. Fourth, relatively few data on newer BTKIs during the study period limited the ability to identify all possible signals. We hope the generated signals for acalabrutinib and zanubrutinib from our exploratory study should be considered as initial warnings worth further investigation. Future studies employing more monitoring data or clinical trial data are needed to update and validate our findings.

Conclusions
BTKI administration should be carefully evaluated to avoid potentially increasing cardiac risk. Patients exposed to ibrutinib might fall victim to a range of cardiac events. Constant vigilance was needed to exercise on the cardiotoxicity profile of both ibrutinib and non-ibrutinib BTKIs. More postmarketing data are needed to improve current knowledge of cardiac risk profiles of more selective BTKIs and the cardiotoxicity profiles of these newer BTKIs in comparison with ibrutinib require further investigation.