Analysis of post-market adverse events of ivabradine: a real-world study base on FAERS database

Analysis of post-market adverse events of ivabradine: a real-world study base on FAERS database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Analysis of post-market adverse events of ivabradine: a real-world study base on FAERS database Yonghuo Ye, Yuxing Lai, Yuhao Lin, Xingjian Wang, Shaoli Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4451860/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Chronic heart failure (CHF) is a prevalent condition characterized by the heart's inability to effectively pump blood, leading to significant morbidity and mortality. Ivabradine, a medication targeting heart rate regulation, has emerged as a valuable therapy for managing CHF symptoms. However, comprehensive real-world data on ivabradine's adverse reactions are lacking. Our study utilized FAERS data and statistical algorithms to identify and characterize ivabradine-related adverse events, providing insights crucial for enhancing medication safety and informing clinical practice. Methods: This study utilized the FDA's Adverse Event Reporting System (FAERS) to analyze adverse drug reaction (ADR) reports associated with ivabradine over an eight-year period. Four statistical methodologies, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), were employed to assess the association between ivabradine and ADRs. Disproportionality analysis at both the System Organ Class (SOC) and Preferred Terms (PTs) levels was conducted to identify potential safety signals. Results: Analysis of 1,860 ADR reports revealed notable associations between ivabradine and various ADRs across different organ systems. Common AEs included cardiovascular events such as bradycardia and atrial fibrillation, as well as visual disturbances and autonomic dysfunction. The study also highlighted the importance of monitoring off-label use and potential interactions with other medications. Conclusions: This comprehensive pharmacovigilance analysis identified and characterized ADRs associated with ivabradine, providing valuable insights for healthcare professionals and regulatory authorities. Despite limitations inherent in spontaneous reporting systems, these findings underscore the importance of ongoing surveillance to ensure the safe use of ivabradine in clinical practice. Biological sciences/Drug discovery/Drug safety Biological sciences/Drug discovery/Drug screening Biological sciences/Drug discovery/Toxicology Chronic heart failure Ivabradine Adverse drug reactions Pharmacovigilance FAERS (FDA Adverse Event Reporting System). Introduction Chronic heart failure (CHF) is a complex clinical condition that occurs when the heart loses its ability to pump blood effectively due to various reasons, failing to meet the body's demands for blood and oxygen [1]. Globally, the prevalence of chronic heart failure is increasing, primarily due to an aging population and rising prevalence of cardiovascular diseases such as coronary artery disease and hypertension [2]. It is estimated that tens of millions of people are affected by CHF, making it one of the leading causes of hospitalization among middle-aged and older adults [3]. The main symptoms include shortness of breath, fluid retention, and fatigue, along with rapid and irregular heartbeats [4]. Treatment strategies for heart failure include lifestyle modifications, pharmacotherapy, and, when necessary, surgical interventions. Among these approaches, the control of heart rate stands out as particularly critical [5]. Effective management of heart rate not only diminishes the cardiac workload but also markedly enhances patient symptoms and overall quality of life [5]. This makes heart rate control an essential element of the holistic management plan for heart failure. Ivabradine was approved by the FDA in 2015, specifically sanctioned for the treatment of patients with chronic heart failure (CHF) to mitigate the risk of hospitalization due to exacerbations of the condition. It is indicated for use in adults with stable, symptomatic (NYHA Class II to IV) systolic heart failure, and is applicable at a resting heart rate of at least 70 beats per minute in the context of normal sinus rhythm, either as a standalone therapy or in conjunction with beta-blockers [6, 7]. Ivabradine acts as a selective heart rate-slowing agent by binding to the inner side of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the sinoatrial node, thereby inhibiting the If current within the node to reduce heart rate [8]. The administration of ivabradine significantly enhances survival rates and the quality of life for heart failure patients, reducing hospital admissions, and thus holds substantial importance in the management of chronic heart failure [9]. However, the paucity of large-scale real-world reports on adverse reactions within the patient population taking ivabradine raises concerns regarding its safety profile. The US Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS), formerly known as FAERS, serves as a central repository for adverse event reports and medication errors submitted to the FDA. It plays a crucial role in supporting the FDA's post-market safety surveillance efforts for drugs and therapeutic biologic products. Several commonly used analysis algorithms, such as ROR, PRR, BCPNN, and EBGM, play a crucial role in drug safety monitoring and pharmacovigilance, especially when analyzing data from adverse drug reaction reporting systems. ROR is a relatively simple method for drug safety signal detection, working by comparing the ratio of reports of a specific drug to a specific adverse event against the ratio of all drugs to that adverse event. PRR is another signal detection tool used in pharmacovigilance, which calculates by comparing the proportion of reports of a specific adverse event for a specific drug against the proportion of that adverse event in all other drug reports. BCPNN is a complex algorithm based on Bayesian statistical principles, using belief propagation networks to estimate the strength of association between drugs and adverse events. EBGM uses an empirical Bayesian approach to estimate the reporting frequency of drug-adverse event combinations and calculates the geometric mean to assess signal strength. These algorithms are crucial in medical research and drug regulation, helping researchers and healthcare professionals evaluate and monitor drug safety to ensure patient medication safety. The application of these methods enables the timely identification of potential drug safety issues, allowing for appropriate measures to be taken to mitigate adverse effects and protect public health. In this study, we utilized the ROR and PRR algorithms to calculate the association between Ivabradine and adverse events (AEs). Subsequently, we employed the BCPNN algorithm to construct a joint probability model between Ivabradine and the AEs identified by ROR and PRR. Finally, we applied the EBGM algorithm to transform the risk associations of adverse events (AEs) identified by the above three algorithms into corresponding risk indices. By integrating these four algorithms, this study detected and identified AEs associated with Ivabradine, including new AE signals not listed in the medication's label. Materials and methods 1.Data source and collection The FAERS data utilized in this study underwent collection and preprocessing procedures employing SAS and MySQL. Data related to ivabradine in FAERS were subjected to duplicate record removal and drug name standardization, with drug names mapped to RxNorm concepts and adverse drug reaction (ADR) outcomes mapped to Medical Dictionary for Regulatory Activities (MedDRA ® ) concepts. Ivabradine-related ADRs were collected over a eight-year period, spanning from April 20, 2015, to December 31, 2023. All preferred terms (PTs) targeting the system organ class (SOC), the highest level of MedDRA hierarchy, were extracted for analysis. 2.Statistical analysis Disproportionality analysis, a widely employed method in pharmacovigilance studies, was conducted to discern potential signals between Ivabradine and adverse drug reactions (ADRs). The study employed four primary statistical methodologies: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), derived from the Gamma-Poisson Shrinker (GPS) model. These methods were utilized to assess the association between Ivabradine and ADRs, aiming to identify potential safety concerns and contribute to the ongoing pharmacovigilance efforts. To be deemed effective, adverse drug reaction (ADR) results needed to satisfy the selection criteria of yielding a positive signal across all four methods concurrently. Data processing and statistical analyses related to Ivabradine were conducted using SAS, MySQL, WPS EXCEL, and R software. The prerequisites for the study are outlined in Table 1 , and the detailed formulas for the four methods employed are provided below: Results General characteristics: During the study period from April 20, 2015, to December 31, 2023, a comprehensive dataset comprising 1,336,915 case reports from FAERS was analyzed. Among these, 8,253,764 775 adverse events (AEs) and 84 adverse drug reactions (ADRs) were identified within 1,860 case reports specifically linked to Ivabradine after eliminating duplicate entries. The detailed clinical characteristics of events associated with Ivabradine are elucidated in Table 2 . Among the population experiencing all adverse events (AEs), females accounted for approximately half of the total population, representing 48.60%. Regarding age composition, individuals aged 40-49 years and 50-59 years showed the same proportion in adverse reactions, each accounting for 9.35% and representing the highest proportion. Conversely, individuals over 80 years old (>80 years) constituted the smallest proportion, representing 4.89% of the total population. Additionally, the top-ranked countries for the consumption of Ivabradine were America (1458, 78.39%), Japan (101, 5.43%), United Kingdom (51, 2.74%), France (44, 2.37%), Italy (40, 2.15%), and China (28, 1.51%). The most serious outcome of AEs was hospitalization, accounting for 258 cases (13.87%), compared to the other three outcomes: death (126, 6.78%), life-threatening (46, 2.47%), and disability (19, 1.02%). 3.2. System Organ Class Level-associated signal detections Table 3 presents the results of signal detection analysis for ivabradine at the System Organ Class (SOC) level. It is evident that adverse events (AEs) associated with ivabradine are widespread across 12 organ systems, suggesting a relatively common occurrence of ivabradine-related AEs. Notably, the highest numbers of AEs were observed in "Injury, poisoning, and procedural complications" (n=866), "Cardiac disorders" (n=501), and "Investigations" (n=149). These findings imply that while certain AEs, such as those related to cardiac function, are expected due to ivabradine's mechanism of action, others, like those in the category of "Injury, poisoning, and procedural complications", may be less commonly recognized and warrant further attention. Specifically, the significant number of AEs reported under "Injury, poisoning, and procedural complications" (n=866) at the SOC level highlights potential adverse reactions not previously documented in ivabradine's prescribing information. This underscores the importance of identifying and monitoring new and valuable adverse drug reactions (ADRs) associated with ivabradine usage, as they may have implications for patient safety and clinical management. 3.3 PT level-associated signal detections At the Preferred Terms (PTs) level, Table 4 provides detailed statistics on 59 ivabradine-related adverse drug reactions (ADRs) meeting specific selection criteria, ranked by case numbers. This further elucidates the specific AEs encountered with ivabradine therapy, offering valuable insights for healthcare professionals to anticipate, recognize, and manage potential adverse reactions associated with ivabradine use. The top five preferred terms (PTs) associated with ivabradine are as follows: injury, off-label use (n=866, IC025=3.38 (3.11)), bradycardia (n=76, IC025=4.23 (3.48)), increased heart rate (n=52, IC025=3.01 (2.11)), atrial fibrillation (n=50, IC025=2.88 (1.97)), and photopsia (n=46, IC025=6.81 (5.84)). Additionally, the top five PTs of ivabradine ranked by IC025 value are first trimester pregnancy (n=3, IC025=10.38 (6.77)), low cardiac output syndrome (n=4, IC025=7.01 (4.29)), photopsia (n=46, IC025=6.81 (5.84)), postural orthostatic tachycardia syndrome (n=7, IC025=6.4 (4.21)) and paroxysmal nocturnal dyspnea (n=3, IC025=6.11 (3.16)). Discussion This real-world evidence study included a comprehensive analysis of 1860 adverse drug reaction (ADR) reports linked to the use of Ivabradine. The number of cases among females is approximately double that of males. This numerical discrepancy may stem from various factors: divergent responses to medications between genders, with females being more susceptible to adverse reactions (including those to ivabradine) [ 10 – 12 ]. Females may also have a higher likelihood of underlying health conditions necessitating ivabradine usage, leading to a greater tendency to report adverse reactions [ 13 – 16 ]. The reported quantities of adverse reactions to ivabradine across different age groups reveal notable variations. Age groups ranging from 30–39 to 70–79 exhibit comparatively higher quantities (approximately around 150), whereas the 20–29 age group shows fewer reports (124), and those over 80 years old even fewer (91). Possible reasons for this disparity include vigorous metabolism and better physiological functions among younger individuals, resulting in fewer adverse reactions even at similar dosage levels. Conversely, individuals over 80 years old may have slower metabolism rates [ 17 ], leading to lower medication dosages or alternative treatments, thereby resulting in fewer reported adverse reactions. The disparities in reported adverse reactions to ivabradine among different countries reflect various factors, including medical practices, medication guidelines, physician preferences, medication availability, and healthcare policies. The United States reports significantly higher cases compared to other countries, possibly due to a more widespread usage of ivabradine for treating cardiovascular diseases, while other nations may prefer alternative treatments for heart failure [ 18 ].Furthermore, the data presented may also be influenced by reporting systems and cultural factors, with different countries having robust systems for reporting medication adverse effects and varying degrees of emphasis on medication safety and adverse reaction monitoring by regulatory authorities. Ivabradine primarily acts on the If channels of cardiac cells, modulating cardiac electrophysiological activity. The incidence of common adverse reactions is mainly concentrated in the cardiovascular system, especially affecting cardiac electrophysiology and the conduction system, including bradycardia, increased heart rate, and atrial fibrillation (AF) [ 6 , 19 – 21 ]. Although the expected side effect of ivabradine is sinus bradycardia, the side effect of causing tachycardia seems contradictory to its mechanism of action. It is speculated that it might trigger a reflex sympathetic response, potentially causing an increase in heart rate as the body attempts to compensate for the reduced cardiac output. Additionally, although ivabradine is selective for the If channels, its electrophysiological effects might extend in ways that are not fully understood, potentially causing tachycardia in susceptible individuals. Another common arrhythmia is AF, which is often associated with heart failure and ischemic heart disease, the current two clinical indications for the use of ivabradine, hence AF in this patient population may be an association rather than a drug-induced effect. However, the largest randomized controlled trial (the SIGNIFY study) conducted in patients with coronary artery disease without heart failure showed that the incidence of AF was significantly higher in the ivabradine group compared to the placebo group [ 22 ]. Furthermore, a meta-analysis involving 36,501 participants showed that the incidence of AF was 5.34% in the ivabradine group and 4.56% in the placebo group, with a significantly higher incidence of AF in the ivabradine group compared to placebo (24% increased relative risk) [ 23 ]. Mahmoud's review article also suggests this phenomenon, noting that the If channels affected by ivabradine were found in the pulmonary vein myocardial sleeves, the recognized triggers for AF, which may explain the risk of AF in patients receiving this medication [ 24 ]. Moreover, the interaction of ivabradine with other drugs could exacerbate instability in cardiac electrophysiology, leading to adverse reactions such as arrhythmias [ 25 ]. Although Ivabradine is widely acknowledged not to affect myocardial ejection function, observations of adverse reactions indicating changes in ejection fraction, such as decreased ejection fraction, acute and chronic heart failure, cardiomyopathy, as well as severe cardiac arrest and sudden death, have been noted. Ivabradine serves as a commonly utilized medication for regulating heart rate in the treatment of angina and chronic heart failure [ 26 ]. Despite its direct mechanism of action not impacting myocardial contractility or ejection fraction, it regulates cardiac function by modulating heart rate [ 26 ]. Specifically, it acts on the heart's "funny" or "slow response" calcium channels, thereby reducing cardiac oxygen consumption, improving the balance between cardiac supply and demand, and alleviating angina while reducing symptoms of chronic heart failure [ 27 ].However, despite its apparent efficacy, Ivabradine is associated with adverse reactions [ 28 ]. For instance, bradycardia induced by Ivabradine may lead to excessive cardiac suppression in certain circumstances, resulting in reduced cardiac output, possibly leading to decreased ejection fraction, inadequate myocardial perfusion, exacerbation of heart failure, or precipitating angina [ 29 , 30 ]. Though Ivabradine does not directly impact myocardial contractility, in some individuals, particularly those with preexisting cardiac conditions, impaired cardiac function and adverse reactions such as myocardial disease may manifest [ 31 ]. Additionally, Ivabradine's action can affect cardiac rhythm, potentially leading to arrhythmias, including severe bradycardia, which may result in sudden death [ 32 ].These observed adverse reactions may be associated with Ivabradine's mechanism of action, particularly its effects on heart rate regulation. Therefore, close monitoring of cardiac function, especially heart rate and ejection fraction, and any potential adverse reactions, is crucial when using Ivabradine, especially in patients with preexisting cardiac disease or other relevant risk factor. Another common and notable adverse effect is issues related to the visual system, such as flashes of light, hallucinations, phosphenes and photophobia [ 33 ]. These visual symptoms may be associated with the mechanism of action of ivabradine, particularly its effects on heart rate regulation and ion channels. Ivabradine slows the heart rate by selectively blocking the "funny" sodium channels (If channels) in the heart [ 34 , 35 ]. However, aside from the heart, If channels are also present in other tissues, including the retina [ 34 , 35 ]. Therefore, ivabradine may affect ion channels in retinal cells, leading to changes in visual perception, such as flashes of light and hallucinations [ 36 ].In clinical trials, some patients discontinued ivabradine due to bradycardia, while visual symptoms led to withdrawal in a small percentage of cases. However, the majority of patients were able to continue treatment, indicating that ivabradine is generally well-tolerated. Autonomic dysfunction has also been noted as an observed adverse reaction. Ivabradine primarily targets cardiovascular diseases by modulating heart rate, instances of heart rate instability might inadvertently affect the autonomic nervous system, potentially leading to symptoms of autonomic dysfunction [ 37 ], which could manifest as postural orthostatic tachycardia syndrome. Furthermore, interactions with other medications, especially those affecting heart rate or blood pressure, could exacerbate autonomic imbalance during Ivabradine therapy. Patients with concurrent cardiovascular disorders might be particularly vulnerable to such interactions, further complicating autonomic regulation [ 37 ]. Additionally, we observed that injuries, poisonings, and procedural complications are the most common complications, with the corresponding Preferred Term (PT) being off-label use. The frequent reports of off-label use underscore the necessity for more cautious monitoring and management of this practice. It highlights the importance of enhancing drug use research, improving education for patients and healthcare professionals, updating policies and guidelines, and strengthening the drug adverse reaction monitoring system. Conversely, categories such as general disorders and administration site conditions, eye disorders, and psychiatric disorders have fewer cases, indicating potentially lower risks associated with Ivabradine adverse reactions in these organ systems. Furthermore, notably fewer cases in some organ systems, including surgical and medical procedures, immune system disorders, pregnancy, puerperium, and perinatal conditions, as well as respiratory, thoracic, and mediastinal disorders, suggest the need for further research to ascertain their true risks and impacts with Ivabradine use. Overall, these findings provide insights into the adverse reaction profile of Ivabradine across different organ systems, aiding healthcare professionals and researchers in better understanding and managing the safety and risks associated with this medication. While large-scale population studies and data mining techniques employed in this research present several benefits, it's crucial to consider certain limitations. FAERS, acting as an open spontaneous reporting system database, often receives information that may lack completeness and is susceptible to inaccuracies, leading to data of non-standardized quality that could bias analysis. Furthermore, managing confounding factors such as dosage, usage duration, comorbidities, drug combinations, and variables affecting adverse events presents a challenge. Additionally, the absence of comprehensive patient data on Ivabradine usage complicates the accurate determination of each adverse event's incidence rate. Importantly, this study didn't establish a causal link between Ivabradine and adverse drug reactions (ADRs), as the analysis of imbalance only offers a statistical indication of signal strength without quantifying risks or proving causality. Despite these challenges, the extensive data collected internationally aids in assessing the potential risks associated with ADRs. Nonetheless, prospective studies are needed to accurately gauge these ADRs' true risks. Conclusion This study conducted a comprehensive analysis of adverse drug reactions (ADRs) related to the use of Ivabradine, finding that Ivabradine's side effects are mainly concentrated in the cardiac system. However, it can also lead to non-cardiovascular adverse reactions, such as visual disturbances and autonomic dysfunction, highlighting the importance of monitoring and managing these potential risks. The analysis based on the FAERS database has its limitations regarding data sources. Future research is needed to accurately assess the safety of Ivabradine, ensuring patients receive effective and safe treatment. Declarations CRediT authorship contribution statement Yonghuo Ye : Writing – review & editing, Writing – original draft, Supervision. Yuxing Lai : Writing – original draft, Formal analysis. Yuhao Lin : Validation, Data curation. Xingjian Wang : Validation, Data curation. Shaoli Wang : Supervision, Methodology. Declaration of competing interest 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. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Author Contribution Yonghuo Ye: Writing – review & editing, Writing – original draft, Supervision. Yuxing Lai: Writing – original draft, Formal analysis. Yuhao Lin: Validation, Data curation. Xingjian Wang: Validation, Data curation. Shaoli Wang: Supervision, Methodology. References Edelman IS, Zweifach BW, Escher DJ, Grossman J, Mokotoff R, Weston RE, et al. Studies on VEM and VDM in blood in relation to renal hemodynamics and renal oxygen extraction in chronic congestive heart failure. J Clin Invest. 1950;29:925-34. Roger VL. Epidemiology of Heart Failure: A Contemporary Perspective. Circ Res. 2021;128:1421-34. Zhou Y, Sun X, Yang G, Ding N, Pan X, Zhong A, et al. 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Cellular mechanisms underlying the pharmacological induction of phosphenes. Br J Pharmacol. 2007;150:383-90. Baka T, Simko F. Ivabradine modulates the autonomic nervous system by affecting the "little brain" of the heart: A hypothesis. Med Hypotheses. 2019;129:109253. Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4451860","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":310254374,"identity":"b563e5de-949d-4316-b19e-1386360724ae","order_by":0,"name":"Yonghuo Ye","email":"","orcid":"","institution":"Fujian Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yonghuo","middleName":"","lastName":"Ye","suffix":""},{"id":310254375,"identity":"60efeecd-da64-430a-928c-bdeb65779ac7","order_by":1,"name":"Yuxing Lai","email":"","orcid":"","institution":"The First Affiliated Hospital of Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuxing","middleName":"","lastName":"Lai","suffix":""},{"id":310254376,"identity":"13178d51-fb22-4361-8b05-b95c390a400b","order_by":2,"name":"Yuhao Lin","email":"","orcid":"","institution":"Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuhao","middleName":"","lastName":"Lin","suffix":""},{"id":310254377,"identity":"c032f255-d861-44d2-ad8f-ccb7167d3150","order_by":3,"name":"Xingjian Wang","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xingjian","middleName":"","lastName":"Wang","suffix":""},{"id":310254378,"identity":"c1edf842-b81f-4929-b6b4-5c7b2c13b23e","order_by":4,"name":"Shaoli Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYNCCAgYGfmbmgw9I0GLAwCDZzpZsQJoWg/M8ZgLEKT5+9vDLHwZ1iZsPM5gxMNTYRBPWciYvzZrHgC1x22GGtAcMx9JyGwhpMTuQY2bMYMAD0nLcgLHhMBFazr8xM/xhIJG4uZmxTYI4LTdyjB/wGBgkbmBmZiNOi/2NN2bMPAYJxjMOszEbJBDjF8n+HOOPPyrqZPv7z3988KHGhrAWIGCTABKOYJUJRCgHAeYPIAcSqXgUjIJRMApGIgAAN14+Uwygl6gAAAAASUVORK5CYII=","orcid":"","institution":"Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shaoli","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-05-21 03:15:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4451860/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4451860/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74892772,"identity":"be93e5f0-0aaf-42ae-a70b-ceb92c97fac2","added_by":"auto","created_at":"2025-01-28 05:33:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":503416,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4451860/v1/c23335fd-c094-4970-bdf1-cdfe218ba20f.pdf"},{"id":57843915,"identity":"948f2fe6-1e2f-4afb-b49e-cf0c75628a41","added_by":"auto","created_at":"2024-06-06 10:26:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33922,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4451860/v1/c967c0dc1a9b71e5b4915539.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of post-market adverse events of ivabradine: a real-world study base on FAERS database","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic heart failure (CHF) is a complex clinical condition that occurs when the heart loses its ability to pump blood effectively due to various reasons, failing to meet the body's demands for blood and oxygen [1]. Globally, the prevalence of chronic heart failure is increasing, primarily due to an aging population and rising prevalence of cardiovascular diseases such as coronary artery disease and hypertension [2]. It is estimated that tens of millions of people are affected by CHF, making it one of the leading causes of hospitalization among middle-aged and older adults [3]. The main symptoms include shortness of breath, fluid retention, and fatigue, along with rapid and irregular heartbeats [4]. Treatment strategies for heart failure include lifestyle modifications, pharmacotherapy, and, when necessary, surgical interventions. Among these approaches, the control of heart rate stands out as particularly critical [5]. Effective management of heart rate not only diminishes the cardiac workload but also markedly enhances patient symptoms and overall quality of life\u0026nbsp;[5]. This makes heart rate control an essential element of the holistic management plan for heart failure.\u003c/p\u003e\n\u003cp\u003eIvabradine\u0026nbsp;was approved by the FDA in 2015, specifically sanctioned for the treatment of patients with chronic heart failure (CHF) to mitigate the risk of hospitalization due to exacerbations of the condition. It is indicated for use in adults with stable, symptomatic (NYHA Class II to IV) systolic heart failure, and is applicable at a resting heart rate of at least 70 beats per minute in the context of normal sinus rhythm, either as a standalone therapy or in conjunction with beta-blockers [6, 7]. Ivabradine acts as a selective heart rate-slowing agent by binding to the inner side of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the sinoatrial node, thereby inhibiting the If current within the node to reduce heart rate [8]. The administration of ivabradine significantly enhances survival rates and the quality of life for heart failure patients, reducing hospital admissions, and thus holds substantial importance in the management of chronic heart failure [9]. However, the paucity of large-scale real-world reports on adverse reactions within the patient population taking ivabradine raises concerns regarding its safety profile.\u003c/p\u003e\n\u003cp\u003eThe US Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS), formerly known as FAERS, serves as a central repository for adverse event reports and medication errors submitted to the FDA. It plays a crucial role in supporting the FDA's post-market safety surveillance efforts for drugs and therapeutic biologic products. Several commonly used analysis algorithms, such as ROR, PRR, BCPNN, and EBGM, play a crucial role in drug safety monitoring and pharmacovigilance, especially when analyzing data from adverse drug reaction reporting systems. ROR is a relatively simple method for drug safety signal detection, working by comparing the ratio of reports of a specific drug to a specific adverse event against the ratio of all drugs to that adverse event. PRR is another signal detection tool used in pharmacovigilance, which calculates by comparing the proportion of reports of a specific adverse event for a specific drug against the proportion of that adverse event in all other drug reports. BCPNN is a complex algorithm based on Bayesian statistical principles, using belief propagation networks to estimate the strength of association between drugs and adverse events. EBGM uses an empirical Bayesian approach to estimate the reporting frequency of drug-adverse event combinations and calculates the geometric mean to assess signal strength. These algorithms are crucial in medical research and drug regulation, helping researchers and healthcare professionals evaluate and monitor drug safety to ensure patient medication safety. The application of these methods enables the timely identification of potential drug safety issues, allowing for appropriate measures to be taken to mitigate adverse effects and protect public health.\u003c/p\u003e\n\u003cp\u003eIn this study, we utilized the ROR and PRR algorithms to calculate the association between Ivabradine and adverse events (AEs). Subsequently, we employed the BCPNN algorithm to construct a joint probability model between Ivabradine and the AEs identified by ROR and PRR. Finally, we applied the EBGM algorithm to transform the risk associations of adverse events (AEs) identified by the above three algorithms into corresponding risk indices. By integrating these four algorithms, this study detected and identified AEs associated with Ivabradine, including new AE signals not listed in the medication's label.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003e1.Data source and collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe FAERS data utilized in this study underwent collection and preprocessing procedures employing SAS and MySQL. Data related to ivabradine in FAERS were subjected to duplicate record removal and drug name standardization, with drug names mapped to RxNorm concepts and adverse drug reaction (ADR) outcomes mapped to Medical Dictionary for Regulatory Activities (MedDRA\u003csup\u003e\u0026reg;\u003c/sup\u003e) concepts. Ivabradine-related ADRs were collected over a eight-year period, spanning from April 20, 2015, to December 31, 2023. All preferred terms (PTs) targeting the system organ class (SOC), the highest level of MedDRA hierarchy, were extracted for analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDisproportionality analysis, a widely employed method in pharmacovigilance studies, was conducted to discern potential signals between Ivabradine and adverse drug reactions (ADRs). The study employed four primary statistical methodologies: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), derived from the Gamma-Poisson Shrinker (GPS) model. These methods were utilized to assess the association between Ivabradine and ADRs, aiming to identify potential safety concerns and contribute to the ongoing pharmacovigilance efforts. To be deemed effective, adverse drug reaction (ADR) results needed to satisfy the selection criteria of yielding a positive signal across all four methods concurrently. Data processing and statistical analyses related to Ivabradine were conducted using SAS, MySQL, WPS EXCEL, and R software. The prerequisites for the study are outlined in \u003cstrong\u003eTable 1\u003c/strong\u003e, and the detailed formulas for the four methods employed are provided below:\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eGeneral characteristics:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period from April 20, 2015, to December 31, 2023, a comprehensive dataset comprising 1,336,915 case reports from FAERS was analyzed. Among these, 8,253,764 775 adverse events (AEs) and 84 adverse drug reactions (ADRs) were identified within 1,860 case reports specifically linked to Ivabradine after eliminating duplicate entries. The detailed clinical characteristics of events associated with Ivabradine are elucidated in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eAmong the population experiencing all adverse events (AEs), females accounted for approximately half of the total population, representing 48.60%. Regarding age composition, individuals aged 40-49 years and 50-59 years showed the same proportion in adverse reactions, each accounting for 9.35% and representing the highest proportion. Conversely, individuals over 80 years old (\u0026gt;80 years) constituted the smallest proportion, representing 4.89% of the total population.\u003c/p\u003e\n\u003cp\u003eAdditionally, the top-ranked countries for the consumption of Ivabradine were America (1458, 78.39%), Japan (101, 5.43%), United Kingdom (51, 2.74%), France (44, 2.37%), Italy (40, 2.15%), and China (28, 1.51%).\u003c/p\u003e\n\u003cp\u003eThe most serious outcome of AEs was hospitalization, accounting for 258 cases (13.87%), compared to the other three outcomes: death (126, 6.78%), life-threatening (46, 2.47%), and disability (19, 1.02%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. System Organ Class Level-associated signal detections\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003epresents the results of signal detection analysis for ivabradine at the System Organ Class (SOC) level. It is evident that adverse events (AEs) associated with ivabradine are widespread across 12 organ systems, suggesting a relatively common occurrence of ivabradine-related AEs. Notably, the highest numbers of AEs were observed in \u0026quot;Injury, poisoning, and procedural complications\u0026quot; (n=866), \u0026quot;Cardiac disorders\u0026quot; (n=501), and \u0026quot;Investigations\u0026quot; (n=149). These findings imply that while certain AEs, such as those related to cardiac function, are expected due to ivabradine\u0026apos;s mechanism of action, others, like those in the category of \u0026quot;Injury, poisoning, and procedural complications\u0026quot;, may be less commonly recognized and warrant further attention. Specifically, the significant number of AEs reported under \u0026quot;Injury, poisoning, and procedural complications\u0026quot; (n=866) at the SOC level highlights potential adverse reactions not previously documented in ivabradine\u0026apos;s prescribing information. This underscores the importance of identifying and monitoring new and valuable adverse drug reactions (ADRs) associated with ivabradine usage, as they may have implications for patient safety and clinical management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 PT level-associated signal detections\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the Preferred Terms (PTs) level, \u003cstrong\u003eTable 4\u003c/strong\u003e provides detailed statistics on 59 ivabradine-related adverse drug reactions (ADRs) meeting specific selection criteria, ranked by case numbers. This further elucidates the specific AEs encountered with ivabradine therapy, offering valuable insights for healthcare professionals to anticipate, recognize, and manage potential adverse reactions associated with ivabradine use.\u003c/p\u003e\n\u003cp\u003eThe top five preferred terms (PTs) associated with ivabradine are as follows: injury, off-label use (n=866, IC025=3.38 (3.11)), bradycardia (n=76, IC025=4.23 (3.48)), increased heart rate (n=52, IC025=3.01 (2.11)), atrial fibrillation (n=50, IC025=2.88 (1.97)), and photopsia (n=46, IC025=6.81 (5.84)). Additionally, the top five PTs of ivabradine ranked by IC025 value are first trimester pregnancy (n=3, IC025=10.38 (6.77)), low cardiac output syndrome (n=4, IC025=7.01 (4.29)), photopsia (n=46, IC025=6.81 (5.84)), postural orthostatic tachycardia syndrome (n=7, IC025=6.4 (4.21)) and paroxysmal nocturnal dyspnea (n=3, IC025=6.11 (3.16)).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis real-world evidence study included a comprehensive analysis of 1860 adverse drug reaction (ADR) reports linked to the use of Ivabradine. The number of cases among females is approximately double that of males. This numerical discrepancy may stem from various factors: divergent responses to medications between genders, with females being more susceptible to adverse reactions (including those to ivabradine) [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Females may also have a higher likelihood of underlying health conditions necessitating ivabradine usage, leading to a greater tendency to report adverse reactions [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The reported quantities of adverse reactions to ivabradine across different age groups reveal notable variations. Age groups ranging from 30\u0026ndash;39 to 70\u0026ndash;79 exhibit comparatively higher quantities (approximately around 150), whereas the 20\u0026ndash;29 age group shows fewer reports (124), and those over 80 years old even fewer (91). Possible reasons for this disparity include vigorous metabolism and better physiological functions among younger individuals, resulting in fewer adverse reactions even at similar dosage levels. Conversely, individuals over 80 years old may have slower metabolism rates [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], leading to lower medication dosages or alternative treatments, thereby resulting in fewer reported adverse reactions. The disparities in reported adverse reactions to ivabradine among different countries reflect various factors, including medical practices, medication guidelines, physician preferences, medication availability, and healthcare policies. The United States reports significantly higher cases compared to other countries, possibly due to a more widespread usage of ivabradine for treating cardiovascular diseases, while other nations may prefer alternative treatments for heart failure [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].Furthermore, the data presented may also be influenced by reporting systems and cultural factors, with different countries having robust systems for reporting medication adverse effects and varying degrees of emphasis on medication safety and adverse reaction monitoring by regulatory authorities.\u003c/p\u003e \u003cp\u003eIvabradine primarily acts on the If channels of cardiac cells, modulating cardiac electrophysiological activity. The incidence of common adverse reactions is mainly concentrated in the cardiovascular system, especially affecting cardiac electrophysiology and the conduction system, including bradycardia, increased heart rate, and atrial fibrillation (AF) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although the expected side effect of ivabradine is sinus bradycardia, the side effect of causing tachycardia seems contradictory to its mechanism of action. It is speculated that it might trigger a reflex sympathetic response, potentially causing an increase in heart rate as the body attempts to compensate for the reduced cardiac output. Additionally, although ivabradine is selective for the If channels, its electrophysiological effects might extend in ways that are not fully understood, potentially causing tachycardia in susceptible individuals. Another common arrhythmia is AF, which is often associated with heart failure and ischemic heart disease, the current two clinical indications for the use of ivabradine, hence AF in this patient population may be an association rather than a drug-induced effect. However, the largest randomized controlled trial (the SIGNIFY study) conducted in patients with coronary artery disease without heart failure showed that the incidence of AF was significantly higher in the ivabradine group compared to the placebo group [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Furthermore, a meta-analysis involving 36,501 participants showed that the incidence of AF was 5.34% in the ivabradine group and 4.56% in the placebo group, with a significantly higher incidence of AF in the ivabradine group compared to placebo (24% increased relative risk) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Mahmoud's review article also suggests this phenomenon, noting that the If channels affected by ivabradine were found in the pulmonary vein myocardial sleeves, the recognized triggers for AF, which may explain the risk of AF in patients receiving this medication [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Moreover, the interaction of ivabradine with other drugs could exacerbate instability in cardiac electrophysiology, leading to adverse reactions such as arrhythmias [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough Ivabradine is widely acknowledged not to affect myocardial ejection function, observations of adverse reactions indicating changes in ejection fraction, such as decreased ejection fraction, acute and chronic heart failure, cardiomyopathy, as well as severe cardiac arrest and sudden death, have been noted. Ivabradine serves as a commonly utilized medication for regulating heart rate in the treatment of angina and chronic heart failure [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Despite its direct mechanism of action not impacting myocardial contractility or ejection fraction, it regulates cardiac function by modulating heart rate [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Specifically, it acts on the heart's \"funny\" or \"slow response\" calcium channels, thereby reducing cardiac oxygen consumption, improving the balance between cardiac supply and demand, and alleviating angina while reducing symptoms of chronic heart failure [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].However, despite its apparent efficacy, Ivabradine is associated with adverse reactions [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. For instance, bradycardia induced by Ivabradine may lead to excessive cardiac suppression in certain circumstances, resulting in reduced cardiac output, possibly leading to decreased ejection fraction, inadequate myocardial perfusion, exacerbation of heart failure, or precipitating angina [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Though Ivabradine does not directly impact myocardial contractility, in some individuals, particularly those with preexisting cardiac conditions, impaired cardiac function and adverse reactions such as myocardial disease may manifest [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Additionally, Ivabradine's action can affect cardiac rhythm, potentially leading to arrhythmias, including severe bradycardia, which may result in sudden death [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].These observed adverse reactions may be associated with Ivabradine's mechanism of action, particularly its effects on heart rate regulation. Therefore, close monitoring of cardiac function, especially heart rate and ejection fraction, and any potential adverse reactions, is crucial when using Ivabradine, especially in patients with preexisting cardiac disease or other relevant risk factor.\u003c/p\u003e \u003cp\u003eAnother common and notable adverse effect is issues related to the visual system, such as flashes of light, hallucinations, phosphenes and photophobia [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. These visual symptoms may be associated with the mechanism of action of ivabradine, particularly its effects on heart rate regulation and ion channels. Ivabradine slows the heart rate by selectively blocking the \"funny\" sodium channels (If channels) in the heart [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, aside from the heart, If channels are also present in other tissues, including the retina [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Therefore, ivabradine may affect ion channels in retinal cells, leading to changes in visual perception, such as flashes of light and hallucinations [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].In clinical trials, some patients discontinued ivabradine due to bradycardia, while visual symptoms led to withdrawal in a small percentage of cases. However, the majority of patients were able to continue treatment, indicating that ivabradine is generally well-tolerated.\u003c/p\u003e \u003cp\u003eAutonomic dysfunction has also been noted as an observed adverse reaction. Ivabradine primarily targets cardiovascular diseases by modulating heart rate, instances of heart rate instability might inadvertently affect the autonomic nervous system, potentially leading to symptoms of autonomic dysfunction [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], which could manifest as postural orthostatic tachycardia syndrome. Furthermore, interactions with other medications, especially those affecting heart rate or blood pressure, could exacerbate autonomic imbalance during Ivabradine therapy. Patients with concurrent cardiovascular disorders might be particularly vulnerable to such interactions, further complicating autonomic regulation [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Additionally, we observed that injuries, poisonings, and procedural complications are the most common complications, with the corresponding Preferred Term (PT) being off-label use. The frequent reports of off-label use underscore the necessity for more cautious monitoring and management of this practice. It highlights the importance of enhancing drug use research, improving education for patients and healthcare professionals, updating policies and guidelines, and strengthening the drug adverse reaction monitoring system. Conversely, categories such as general disorders and administration site conditions, eye disorders, and psychiatric disorders have fewer cases, indicating potentially lower risks associated with Ivabradine adverse reactions in these organ systems. Furthermore, notably fewer cases in some organ systems, including surgical and medical procedures, immune system disorders, pregnancy, puerperium, and perinatal conditions, as well as respiratory, thoracic, and mediastinal disorders, suggest the need for further research to ascertain their true risks and impacts with Ivabradine use. Overall, these findings provide insights into the adverse reaction profile of Ivabradine across different organ systems, aiding healthcare professionals and researchers in better understanding and managing the safety and risks associated with this medication.\u003c/p\u003e \u003cp\u003eWhile large-scale population studies and data mining techniques employed in this research present several benefits, it's crucial to consider certain limitations. FAERS, acting as an open spontaneous reporting system database, often receives information that may lack completeness and is susceptible to inaccuracies, leading to data of non-standardized quality that could bias analysis. Furthermore, managing confounding factors such as dosage, usage duration, comorbidities, drug combinations, and variables affecting adverse events presents a challenge. Additionally, the absence of comprehensive patient data on Ivabradine usage complicates the accurate determination of each adverse event's incidence rate. Importantly, this study didn't establish a causal link between Ivabradine and adverse drug reactions (ADRs), as the analysis of imbalance only offers a statistical indication of signal strength without quantifying risks or proving causality. Despite these challenges, the extensive data collected internationally aids in assessing the potential risks associated with ADRs. Nonetheless, prospective studies are needed to accurately gauge these ADRs' true risks.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study conducted a comprehensive analysis of adverse drug reactions (ADRs) related to the use of Ivabradine, finding that Ivabradine's side effects are mainly concentrated in the cardiac system. However, it can also lead to non-cardiovascular adverse reactions, such as visual disturbances and autonomic dysfunction, highlighting the importance of monitoring and managing these potential risks. The analysis based on the FAERS database has its limitations regarding data sources. Future research is needed to accurately assess the safety of Ivabradine, ensuring patients receive effective and safe treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYonghuo Ye\u003c/strong\u003e: Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft, Supervision. \u003cstrong\u003eYuxing Lai\u003c/strong\u003e: Writing \u0026ndash; original draft, Formal analysis. \u003cstrong\u003eYuhao Lin\u003c/strong\u003e: Validation, Data curation. \u003cstrong\u003eXingjian Wang\u003c/strong\u003e: Validation, Data curation. \u003cstrong\u003eShaoli Wang\u003c/strong\u003e: Supervision, Methodology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYonghuo Ye: Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft, Supervision. Yuxing Lai: Writing \u0026ndash; original draft, Formal analysis. Yuhao Lin: Validation, Data curation. Xingjian Wang: Validation, Data curation. Shaoli Wang: Supervision, Methodology.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eEdelman IS, Zweifach BW, Escher DJ, Grossman J, Mokotoff R, Weston RE, et al. Studies on VEM and VDM in blood in relation to renal hemodynamics and renal oxygen extraction in chronic congestive heart failure. J Clin Invest. 1950;29:925-34.\u003c/li\u003e\n \u003cli\u003eRoger VL. Epidemiology of Heart Failure: A Contemporary Perspective. Circ Res. 2021;128:1421-34.\u003c/li\u003e\n \u003cli\u003eZhou Y, Sun X, Yang G, Ding N, Pan X, Zhong A, et al. Sex-specific differences in the association between steps per day and all-cause mortality among a cohort of adult patients from the United States with congestive heart failure. Heart Lung. 2023;62:175-9.\u003c/li\u003e\n \u003cli\u003eOriani A, Guo P, Gadoud A, Dunleavy L, Kane P, Murtagh FEM. What are the main symptoms and concerns reported by patients with advanced chronic heart failure?-a secondary analysis of the Palliative care Outcome Scale (POS) and Integrated Palliative care Outcome Scale (IPOS). Ann Palliat Med. 2019;8:775-80.\u003c/li\u003e\n \u003cli\u003eJha MK, Qamar A, Vaduganathan M, Charney DS, Murrough JW. Screening and Management of Depression in Patients With Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73:1827-45.\u003c/li\u003e\n \u003cli\u003ePonikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-200.\u003c/li\u003e\n \u003cli\u003eMarciszek M, Paterek A, Oknińska M, Zambrowska Z, Mackiewicz U, Mączewski M. Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic? Heart Rhythm. 2021;18:1230-8.\u003c/li\u003e\n \u003cli\u003eCao Y, Pang J, Zhou P. HCN Channel as Therapeutic Targets for Heart Failure and Pain. Curr Top Med Chem. 2016;16:1855-61.\u003c/li\u003e\n \u003cli\u003eSimko F, Baka T, Repova K, Aziriova S, Krajcirovicova K, Paulis L, et al. Ivabradine improves survival and attenuates cardiac remodeling in isoproterenol-induced myocardial injury. Fundam Clin Pharmacol. 2021;35:744-8.\u003c/li\u003e\n \u003cli\u003eRosano GM, Lewis B, Agewall S, Wassmann S, Vitale C, Schmidt H, et al. Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC. Eur Heart J. 2015;36:2677-80.\u003c/li\u003e\n \u003cli\u003eSoldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48:143-57.\u003c/li\u003e\n \u003cli\u003eHudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure--a population study. Eur J Heart Fail. 2007;9:602-9.\u003c/li\u003e\n \u003cli\u003eMelloni C, Berger JS, Wang TY, Gunes F, Stebbins A, Pieper KS, et al. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135-42.\u003c/li\u003e\n \u003cli\u003eScott PE, Unger EF, Jenkins MR, Southworth MR, McDowell TY, Geller RJ, et al. Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs. J Am Coll Cardiol. 2018;71:1960-9.\u003c/li\u003e\n \u003cli\u003eTahhan AS, Vaduganathan M, Greene SJ, Fonarow GC, Fiuzat M, Jessup M, et al. Enrollment of Older Patients, Women, and Racial and Ethnic Minorities in Contemporary Heart Failure Clinical Trials: A Systematic Review. JAMA Cardiol. 2018;3:1011-9.\u003c/li\u003e\n \u003cli\u003eYang Y, Carlin AS, Faustino PJ, Motta MI, Hamad ML, He R, et al. Participation of women in clinical trials for new drugs approved by the food and drug administration in 2000-2002. J Womens Health (Larchmt). 2009;18:303-10.\u003c/li\u003e\n \u003cli\u003eKlotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41:67-76.\u003c/li\u003e\n \u003cli\u003eHeidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606-19.\u003c/li\u003e\n \u003cli\u003eKomajda M. Ivabradine. Handb Exp Pharmacol. 2017;243:167-75.\u003c/li\u003e\n \u003cli\u003eMaskell K, Tse A, Wolf CE, Troendle M. Acute on Chronic Ivabradine Overdose: a Case Report. J Med Toxicol. 2016;12:189-91.\u003c/li\u003e\n \u003cli\u003eDoctor P, Scott WA, Tindel K, Nguyen HH. Ivabradine Overdose in a Newborn: Precautions of Dispensing in Infants. Cardiol Res. 2022;13:242-5.\u003c/li\u003e\n \u003cli\u003eLu Y, Li K, Liu XS, Zhang N, Li G, Liu T. Ivabradine and atrial fibrillation: A double-edged sword. Int J Cardiol. 2016;223:182-5.\u003c/li\u003e\n \u003cli\u003eTong X, Shen L, Zhou X, Wang Y, Chang S, Lu S. Comparative Efficacy of Different Drugs for the Treatment of Dilated Cardiomyopathy: A Systematic Review and Network Meta-analysis. Drugs R D. 2023;23:197-210.\u003c/li\u003e\n \u003cli\u003eAbdelnabi M, Ahmed A, Almaghraby A, Saleh Y, Badran H. Ivabradine and AF: Coincidence, Correlation or a New Treatment? Arrhythm Electrophysiol Rev. 2020;8:300-3.\u003c/li\u003e\n \u003cli\u003eLang J, Vincent L, Chenel M, Ogungbenro K, Galetin A. Impact of Hepatic CYP3A4 Ontogeny Functions on Drug-Drug Interaction Risk in Pediatric Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling: Critical Literature Review and Ivabradine Case Study. Clin Pharmacol Ther. 2021;109:1618-30.\u003c/li\u003e\n \u003cli\u003eReed M, Kerndt CC, Nicolas D. Ivabradine. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright \u0026copy; 2024, StatPearls Publishing LLC.; 2024.\u003c/li\u003e\n \u003cli\u003eTardif JC. Clinical results of I(f) current inhibition by ivabradine. Drugs. 2007;67 Suppl 2:35-41.\u003c/li\u003e\n \u003cli\u003eStieber J. Ivabradine: pharmacodynamic aspects of its clinical use. Methods Find Exp Clin Pharmacol. 2008;30:633-41.\u003c/li\u003e\n \u003cli\u003eYaniv Y, Sirenko S, Ziman BD, Spurgeon HA, Maltsev VA, Lakatta EG. New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca\u0026sup2;⁺ cycling. J Mol Cell Cardiol. 2013;62:80-9.\u003c/li\u003e\n \u003cli\u003eSavelieva I, Camm AJ. I f inhibition with ivabradine : electrophysiological effects and safety. Drug Saf. 2008;31:95-107.\u003c/li\u003e\n \u003cli\u003eNguyen LS, Squara P, Amour J, Carbognani D, Bouabdallah K, Thierry S, et al. Intravenous ivabradine versus placebo in patients with low cardiac output syndrome treated by dobutamine after elective coronary artery bypass surgery: a phase 2 exploratory randomized controlled trial. Crit Care. 2018;22:193.\u003c/li\u003e\n \u003cli\u003eFalconer D, Yousfani S, Herrey AS, Lambiase P, Captur G. Therapeutic Dilemmas Faced When Managing a Life-Threatening Presentation of a Myocardial Bridge. Case Rep Cardiol. 2022;2022:8148241.\u003c/li\u003e\n \u003cli\u003eLancellotti P. [Ivabradine (Procoralan)]. Rev Med Liege. 2008;63:220-4.\u003c/li\u003e\n \u003cli\u003eIde T, Ohtani K, Higo T, Tanaka M, Kawasaki Y, Tsutsui H. Ivabradine for the Treatment of Cardiovascular Diseases. Circ J. 2019;83:252-60.\u003c/li\u003e\n \u003cli\u003eBocchi EA, Salemi VMC. Ivabradine for treatment of heart failure. Expert Opin Drug Saf. 2019;18:393-402.\u003c/li\u003e\n \u003cli\u003eCervetto L, Demontis GC, Gargini C. Cellular mechanisms underlying the pharmacological induction of phosphenes. Br J Pharmacol. 2007;150:383-90.\u003c/li\u003e\n \u003cli\u003eBaka T, Simko F. Ivabradine modulates the autonomic nervous system by affecting the \u0026quot;little brain\u0026quot; of the heart: A hypothesis. Med Hypotheses. 2019;129:109253.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic heart failure, Ivabradine, Adverse drug reactions, Pharmacovigilance, FAERS (FDA Adverse Event Reporting System).","lastPublishedDoi":"10.21203/rs.3.rs-4451860/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4451860/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eChronic heart failure (CHF) is a prevalent condition characterized by the heart's inability to effectively pump blood, leading to significant morbidity and mortality. Ivabradine, a medication targeting heart rate regulation, has emerged as a valuable therapy for managing CHF symptoms. However, comprehensive real-world data on ivabradine's adverse reactions are lacking. Our study utilized FAERS data and statistical algorithms to identify and characterize ivabradine-related adverse events, providing insights crucial for enhancing medication safety and informing clinical practice.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study utilized the FDA's Adverse Event Reporting System (FAERS) to analyze adverse drug reaction (ADR) reports associated with ivabradine over an eight-year period. Four statistical methodologies, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), were employed to assess the association between ivabradine and ADRs. Disproportionality analysis at both the System Organ Class (SOC) and Preferred Terms (PTs) levels was conducted to identify potential safety signals.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAnalysis of 1,860 ADR reports revealed notable associations between ivabradine and various ADRs across different organ systems. Common AEs included cardiovascular events such as bradycardia and atrial fibrillation, as well as visual disturbances and autonomic dysfunction. The study also highlighted the importance of monitoring off-label use and potential interactions with other medications.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis comprehensive pharmacovigilance analysis identified and characterized ADRs associated with ivabradine, providing valuable insights for healthcare professionals and regulatory authorities. Despite limitations inherent in spontaneous reporting systems, these findings underscore the importance of ongoing surveillance to ensure the safe use of ivabradine in clinical practice.\u003c/p\u003e","manuscriptTitle":"Analysis of post-market adverse events of ivabradine: a real-world study base on FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-06 10:26:48","doi":"10.21203/rs.3.rs-4451860/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5386f55b-a010-48a3-8f51-63176ba0d3d1","owner":[],"postedDate":"June 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":32784064,"name":"Biological sciences/Drug discovery/Drug safety"},{"id":32784065,"name":"Biological sciences/Drug discovery/Drug screening"},{"id":32784066,"name":"Biological sciences/Drug discovery/Toxicology"}],"tags":[],"updatedAt":"2025-01-28T05:23:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-06 10:26:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4451860","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4451860","identity":"rs-4451860","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}