Drug-induced atrial fibrillation: A real-world pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System database

Drug-induced atrial fibrillation: A real-world pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System 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 Research Article Drug-induced atrial fibrillation: A real-world pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System database Jingsi Fu, Yixue Wu, Zheyu Guo, Jian Wu, Xin Su, Jiaxing Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6622422/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 Introduction Drug-induced atrial fibrillation is a serious adverse drug reaction (ADR) that occurs during the use of certain medications. The results of ADR signal detection derived from the analysis of a large number of reports, can help understand the safety profile of drugs and optimize clinical practice.Currently, there is a lack of comprehensive quantitative analysis of the major drugs that contribute to atrial fibrillation. Objective To identify the primary drugs associated with atrial fibrillation and provide information for clinical practice. Method We used disproportionality analyses to assess the association between medications and AF adverse events.Data were extracted from the U.S. Food and Drug Administration Adverse Event Reporting System database from January 2004 through December 2024. This study analyzed the distribution of drug types and related drug indications associated with drug-induced AF. Results From the first quarter of 2004 to the fourth quarter of 2024, there were a total of 118,074 adverse reaction reports on AF in the FAERS database. After setting screening criteria, we ultimately screened 80,289 AF-related reports and identified 156 medications associated with pharmacologic AF episodes.A wide range of drugs were reported, with cardiovascular system drugs, antineoplastic drugs and metabolic and endocrine drugs being the most common.Based on the number of reported cases,ibrutinib was the most commonly reported drug followed by rosiglitazone,sacubitril/valsartan,digoxin,dronedarone.Based on the ROR signal intensity,the highest signal intensity was dronedarone followed by eplantersen, propafenone,digoxin,dobutamine. Conclusion Our study provides a real-world overview of drug-induced AF and a list of potential culprit drugs. We examined ADR signals, and the results of ADR signal detection and ADR signal distribution characteristics help to understand the safety profile of a drug and optimize clinical practice. atrial fibrillation drug-induced atrial fibrillation FAERS disproportionality analyses Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Atrial fibrillation (AF) is a type of cardiac arrhythmia and the main clinical symptoms include palpitations, chest tightness, and shortness of breath. AF can lead to serious complications such as death, stroke, and peripheral embolism, and is one of the leading causes of cardiac hospitalization and death worldwide. It is estimated that by 2030, the number of AF patients in the United States will increase from 5.2 million in 2010 to 12.1 million [ 1 ].The pathogenesis of AF is not fully elucidated at present, and it is mainly an electrophysiological alteration of the heart, involving many factors such as changes in neural tone, myocardial injury, and oxidative stress. Meanwhile, genetic factors, unhealthy lifestyle and dietary habits are positively associated with the occurrence of AF [ 2 ].Notably, many widely used medications may cause or exacerbate atrial fibrillation, which we call drug-induced atrial fibrillation (DIAF). Similarly, there is no clear cause or pathogenesis of DIAF. Most DIAF is paroxysmal, but sometimes the disease persists. Since most cases of DIAF are short-lived, doctors and patients do not take this occurrence seriously. However, DIAF is a matter of concern because the occurrence of this phenomenon increases the risk of malignant events in the elderly and in patients with associated comorbidities. Therefore, it is crucial to identify medications that may be associated with DIAF.A large-scale retrospective study based on the years 2004 to 2019 analyzed drug-induced arrhythmias but was limited in its analysis of drug-induced atrial fibrillation[ 3 ]. The number of reported cases of drug-induced atrial fibrillation has increased substantially in the last 5 years, and there is a need to update and improve studies on drug-induced atrial fibrillation.A review[ 4 ]systematically summarized drug studies and mechanisms related to pharmacological atrial fibrillation according to drug class, but did not provide a comprehensive quantitative analysis from the perspective of active mining.Therefore, a systematic analysis is necessary to address the extent of the effects of various drugs.Big data analytics have promising applications in the prevention and treatment of drug-induced diseases. The U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) is the largest public drug safety database for spontaneous reporting of adverse events, and is the primary source for post-marketing safety monitoring and evaluation of chemical drugs and therapeutic biologics.Therefore, in this study, we reviewed reports related to the occurrence of AF in the FAERS database and detected the ADR signals of AF-related drugs using disproportionality analysis, aiming to comprehensively uncover drugs that may induce AF from a pharmacovigilance point of view and to provide a reference for clinical practice. Methods Data source This retrospective pharmacovigilance study was conducted based on the FAERS database.FAERS is an is an open database where healthcare professionals, consumers, and drug manufacturers from around the world can report adverse drug information to FAERS.It collects information on adverse events and medication errors, including DEMO (patient demographics and management information), DRUG (drug/biologic information), REAC (all coded terms for adverse events), OUTC (patient outcomes), RPSR (reporting source), THER (date of initiation and end of drug therapy), and INDI (all coded terms for indications)[ 5 ].This study retrospectively analyzed adverse event information in the FAERS system from January 2004 to December 2024, yielding a total of 21,890,177 reports. Removal of duplicate information resulted in 18,282,801 actual reports.(Fig. 1 ) Data cleaning Adverse reports (AEs) in the REAC file were coded by the Preferred Term (PT) in the Medical Dictionary of Regulatory Activities (MedDRA) nomenclature, and we searched the PT column for “atrial fibrillation” (MedDRA code: 10003658) to find medications that may induce atrial fibrillation[ 6 , 7 ].Role codes for AEs were assigned by the reporter and included primary suspect (PS), secondary suspect drug (SS), concomitant (C), and interaction (I).We screened the primary suspect drugs (PS) for analysis.All reports on AF were subsequently downloaded and analyzed using the drug's generic name as a unique identifier for statistical analysis. For some FAERS database reports of drugs with trade names, we converted them to generic names based on their active ingredient composition and drug name.In addition, some reporters may have confused the concepts of adverse reactions and indications, reporting indications for some drugs as adverse reactions.Therefore, we deleted some drugs (DOAC, warfarin and heparin) based on previous studies to exclude the influence of related drugs on the results. Data mining and statistical analysis We performed a descriptive evaluation of all AE characteristics and outcome indicators associated with AF. Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as medians and interquartile spacing.The analytical approach uses disproportionality analysis to detect potential signals of drug-induced adverse events in AF.Higher values are usually obtained when the target drug is more likely to trigger a specific adverse event than all other drugs. We prioritized the use of two frequency methods, reporting ratio of ratios (ROR)[ 8 ] and proportional reporting rate (PRR)[ 9 ], to rapidly identify potential signals. We also verified the signal reliability by combining Bayesian methods (BCPNN and EBGM)[ 10 , 11 ].The formulas of the four disproportionality algorithms and their corresponding criteria are listed in Table 1. Table 1. Data mining methods and specific formulas(Table 1 is provided as a supplementary file) Results Basic information for AE reports From the first quarter of 2004 through the fourth quarter of 2024, we conducted a narrow search using “AF” and retrieved a total of 118,074 AE reports related to AF in the FAERS database.We set medications as the “primary suspected medications” causing DIAF and excluded anticoagulants used for AF (e.g., rivaroxaban, dabigatran, heparin, etc.), resulting in 80,289 targeted AE reports. The annual distribution of AE reports related to DIAF is shown, with the highest number of reports received in 2024(Fig.2). In terms of source and type of report, the top three were consumers, physicians, and pharmacists, with AE reports coming primarily from the United States.In terms of patients, the prevalence was higher in men than in women, with 65 years of age or older being the age group with the highest number of cases. In terms of patient outcomes, hospitalization for AF events accounted for 41.43% of cases and death accounted for 7.95% of cases.(Table 2)In terms of drug indications, the highest percentage of drugs were indicated for chronic lymphocytic leukaemia, followed by pulmonary arterial hypertension, rheumatoid arthritis, atrial fibrillation, plasma cell myeloma, diabetes mellitus, and so on.(Fig.3) Table 2 . Characteristic table（Table2 is located at the end of the file） Disproportionality analysis From the 80,289 targeted AE reports collected, we identified 156 drugs associated with the occurrence of DIAF, and a total of 22,255 adverse reaction reports were eligible for screening after setting the signaling detection conditions (ROR ≥ 3,PRR ≥ 2,IC025 > 0,EBGM05 > 2). For AE reports associated with specific PTs and their contained drugs, we ranked the top 50 drugs by number of cases and signal intensity respectively. The top fifty drugs in order of the number of adverse reaction reports are shown in Fig.4 and Table 3.The top ten drugs are as follows:ibrutinib(2906),rosiglitazone(2015), Table 3. Top 50 drugs in terms of number (Table 3 is located at the end of the file) sacubitril/valsartan(1712),digoxin(1121),dronedarone(1050),amiodarone(771),metoprolol(758),bosentan(671),and dofetilide(668).The top 50 drugs mainly contained cardiovascular system drugs, antineoplastic drugs, metabolic and endocrine drugs, respiratory system drugs, anti-infective and immunomodulatory drugs, with cardiovascular system drugs being the most reported(26/50). Based on the magnitude of ROR values, we ranked the top 50 drugs in terms of ROR values as shown in Fig.5 and Table 4.Among them, the top 10 drugs were as follows: Table 4. Top 50 drugs in terms of ROR (Table 4 is located at the end of the file) dronedarone(ROR53.09,95%CI49.62,56.8),eplontersen(ROR42.48,95%CI12.38,145.79), propafenone(ROR32.87,95%CI29.04,37.21),digoxin(ROR27.75,95%CI26.07,29.54),dobutamine(ROR25.74,95%CI21.39,30.97),dofetilide(ROR23.57,95%CI21.76,25.54),recombinant human-interleukin-11(ROR19.87,95%CI7.97,49.58),sotalol(ROR19.13,95%CI16.31,22.44),mavacamten(ROR18.71,95%CI15.96,21.93),flecainide(ROR18.31,95%CI15.67,21.4).We ranked them according to PRR values and the results were consistent with the order of drugs by ROR.The top fifty drugs mainly contain cardiovascular system drugs, antineoplastic drugs,metabolic and endocrine drugs,respiratory drugs,anti-infective and immunomodulatory drugs,with the most reported being cardiovascular system drugs(22/50). Discussion DIAF has a significant impact on the health and quality of life of patients and requires attention in the clinical setting, and it can lead to serious consequences such as sudden cardiac death. This study comprehensively evaluated real-world AE reports of DIAF based on the FAERS database. We described the basic features of AE reports of DIAF and summarized a list of drugs that can cause AF and are potential culprits for AF. Also, based on this list of drugs, we counted the proportion of reports for different drugs and drug classes, and integrated ADR signal detection and signal distribution for each drug. From 2004 to 2024, the number of DIAF reports shows an upward trend. The reasons for this situation may be multifactorial. First, the public and the pharmaceutical industry are becoming more aware of medication safety, leading to a greater focus on adverse events. The source of reports shows that the proportion of consumer reports is higher than that of physicians and is the most frequent source of all reporters, which may be related to the fact that DIAFs tend to be paroxysmal and transient in nature. Atrial fibrillation involves a number of pathogenetic mechanisms that are fundamentally dependent on electrophysiological abnormalities[ 2 ], involving electrophysiological changes in the atria (increased atrial arrhythmia, ectopic activity of the pulmonary veins, slow intra-atrial conduction, decrease in the ratio of duration of the action potential to the effective response time, changes in the regulation of ion channels, and intracellular changes in calcium ions, etc.), changes in cardiac autonomic tone (increased vagal tone, increased sympathetic tone, etc.), myocardial damage (myocardial ischemia, cardiac fibrosis, myocarditis, etc.),In addition, DIAF involves mechanisms such as increased oxidative stress, mitochondrial damage, hyperthyroidism, increased sympathetic tone, myocardial injury (e.g., myocardial ischemia, cardiac fibrosis, myocarditis, etc.) and inhibition of cardiac signaling pathways. All of these factors affect the normal electrophysiologic activity of the heart, ultimately leading to atrial fibrillation. During the study period, we observed a correlation between DIAF cases submitted to the FDA and age and gender. From the data, 48.03% of DIAF reports were aged ≥ 65 years, and men reported more frequently than women. Smoking is an important risk factor for AF patients, and men have more smoking preference than women, which may explain the higher frequency of reporting in men[ 12 ].The number of DIAF increases with age, which may be related to several factors. Elderly people usually have altered atrial structure, in which oxidative stress is thought to be the central pathological mechanism triggering the process of atrial electrical remodeling and fibrosis.With age, the body's antioxidant defense system exhibits a significant decline, manifested as a decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), leading to ROS scavenging ability is weakened.Excessive ROS can disrupt the oxidative-antioxidant homeostasis of atrial myocytes, inducing apoptosis and fibrosis through activation of calcium overload, mitochondrial dysfunction and other pathways, leading to the development of atrial fibrillation[ 13 ].At the same time, the activity of drug metabolizing enzyme systems (e.g., CYP450 family) is reduced in the elderly population, which delays the clearance of some drugs and their active metabolites and aggravates the accumulation of toxicity in atrial tissues[ 14 ]. It is worth noting that the anti-inflammatory response and repair mechanisms in elderly individuals present dual obstacles: on the one hand, inflammatory signaling pathways such as NF-κB are abnormally activated, and pro-inflammatory factors (e.g., TNF-α, IL-6) are persistently released; on the other hand, the diminished ability of atrial stem cells to proliferate and differentiate, and the imbalance of extracellular matrix repair, accelerate the irreversible development of the fibrotic lesions[ 15 , 16 ]. In addition, underlying diseases in the elderly are an important cause of DIAF, and their effects are more complex. For example, in hypertensive patients, elevated levels of angiotensin II can activate NADPH oxidase, leading to overproduction of ROS[ 17 , 18 ].In patients with chronic kidney disease, impaired drug excretion may allow toxic metabolites (e.g. anthracycline chemotherapeutic agents) to accumulate in atrial tissues and then trigger DIAF[ 19 ].Epidemiological data show that the incidence of AF in the elderly has increased exponentially during the global aging process, and its high lethality and treatment complexity pose a serious challenge to the public health system. The current study showed that death accounted for 7.95% of the prognosis of drug-induced atrial fibrillation, suggesting that DIAF has a serious adverse prognosis and requires great attention from clinicians and patients[ 20 ]. Based on the number of reported cases and signal strength, we categorized the respective top 50 drugs by indication, as shown in Table 5. Table 5. List of top 50 drugs by number and ROR strength by indication(Table 5 is provided as a supplementary file) Among the top 50 drugs ordered according to the number of ROR and adverse reaction reports, cardiovascular-related drugs occupy a major portion of the list, including blood pressure control drugs,rhythm regulators, antiplatelet drugs, and some anticoagulants(There is no evidence in previous studies that direct oral anticoagulants (DOAC), warfarin, and heparin can cause arrhythmias, and these medications were excluded from the study to exclude any confounding of adverse reactions and indications that might have affected the accuracy of the results by those completing the adverse reaction reports.), which affect cardiac electrophysiology through a series of changes such as altering hemodynamics and direct modulation of the heart's electrical activity to ultimately induce atrial fibrillation.For example, when the heart is ischemic, the atrial electrical conduction velocity decreases and the duration of AF increases. And the use of antihypertensive drugs may lead to inadequate cardiac perfusion, which in turn induces AF[ 21 ].Another example is the hypertensive state that decreases atrial conduction velocity and wavelength and increases the dispersion of conduction velocity[ 22 ],especially in enlarged or fibrotic atria[ 23 ], which can promote atrial fibrillation. And some medications used to treat heart failure may elevate blood pressure and induce atrial fibrillation.These seemingly contradictory results suggest that the occurrence of AF may be associated with hemodynamics that are different from the usual state, and therefore it is important to maintain stable hemodynamics in the treatment of cardiovascular disease. Therefore, in the clinic, we need to select clinical medications based on the patient's specific situation and conduct intensive monitoring to minimize the risk. It is noteworthy that antineoplastic drugs also occupied a major portion of this study, which was especially dominated by the types used for the treatment of lymphoma. There have been previous studies of antineoplastic drugs for AF based on the faers database, but most were single-drug taps, such as studies of ponatinib causing arrhythmias[ 24 ].Cancer patients have a higher incidence of AF than the healthy population, possibly due to the direct effect of pre-existing cardiovascular comorbidities in cancer patients[ 25 – 27 ].Active cancer is associated with risk factors for developing AF, including advanced age, systemic inflammation, electrolyte disturbance, metabolic and endocrine abnormalities, and increased sympathetic tone caused by pain or other forms of physical or emotional stress[ 25 , 26 , 28 – 31 ].AF may also be caused by paraneoplastic disorders such as hyperparathyroidism and autoimmune reactions against atrial structures[ 32 ].Hence, some cancer patients themselves develop baseline ECG abnormalities and arrhythmias.Many anticancer drugs can cause electrical, mechanical, and structural remodeling of the atria, as well as cardiovascular toxicity, leading to hypertension, heart failure, or coronary artery disease, all of which are risk factors for AF[ 33 ].Thus, antineoplastic drugs may lead to AF in cancer patients without risk factors for AF.For example, ibrutinib-induced atrial fibrillation may be associated with off-target inhibition of cardiac Tec protein kinase and PI3K, as well as with an abnormally associated increase in autoregulation[ 34 – 36 ].In addition, the widespread use of newer antitumor drugs (e.g., axicabtagene ciloleucel, aldesleukin, etc.) poses new monitoring challenges. Notably, some antineoplastic drugs associated with DIAF do not adequately label the risk of cardiotoxicity on their drug inserts, leading to increased rates of underdiagnosis in clinical practice.Therefore, close monitoring of electrocardiograms, combined with high-sensitivity troponin testing and cardiac ultrasound for timely diagnosis is needed during oncology treatment. Optimizing antitumor treatment regimens through risk stratification strategies is expected to help reduce the incidence of atrial fibrillation in high-risk patients while maintaining the effectiveness of oncology treatment. There is also a significant proportion of metabolic and endocrine drugs present in our report, including hypoglycemic, lipid-lowering and thyroxine supplementation drugs. Among the hypoglycemic agents, the main drugs were rosiglitazone and its combinations, which is in line with the results of a previous study[ 37 ].The main adverse effect of rosiglitazone is induction of heart failure[ 3 ],which further induces atrial fibrillation.In addition to the glucose-lowering medications within this study, some glucose-lowering medications are also at risk for inducing atrial fibrillation.Previous studies have shown that the incidence of atrial fibrillation is elevated by approximately 40% in patients with type 2 diabetes mellitus compared to non-diabetic populations, and that some of the glucose-lowering medications may affect the risk of atrial fibrillation through different mechanisms[ 38 ].It is worth noting that previous studies have shown that omega-3-carboxylic acids intake can help prevent arrhythmias, but this was denied by an RCT study[ 39 ].In addition, high doses of omega-3-carboxylic acids increase the risk of atrial fibrillation[ 40 ].And omega-3-carboxylic acids also showed a potential risk of causing DIAF in the current study (ROR 8.39, 95% CI 3.09, 22.76). Therefore, drug use for drug-induced AF should focus not only on drug selection but also on dosage. Our findings are in general agreement with previous studies emphasizing the need to be vigilant for possible DIAF when using metabolic and endocrine drugs. In addition, other drug-induced AF occurrences have been reported, involving a variety of mechanisms, mostly affecting electrolytes, inducing an inflammatory response, affecting hemodynamics, and ultimately leading to alterations in cardiac electrophysiology, which in turn induces AF. DIAF still faces many diagnostic and therapeutic challenges, such as the cause of atrial fibrillation, whether it is attributable to the underlying disease or to medications, and the correct determination is important for the diagnosis of the disease and the direction of treatment.Oncology patients, cardiovascular disease patients, diabetic patients and elderly patients are at high risk of AF episodes, which may work in conjunction with medications to further increase the risk of AF. Clinicians need to be highly alert to the possibility of DIAF when new episodes of atrial fibrillation occur despite patients having received standardized anticoagulation or cardiac function improvement therapy, or when atrial fibrillation episodes are highly correlated with the time window of medication use. If primary disease activity cannot be definitively ruled out, clinicians may change medications for low AF risk as appropriate. Current bottlenecks in the treatment of DIAF are its long latency period and the lack of specific biomarkers, which make it difficult to capture changes in AF during routine ECG screening. FAERS database signal detection can break through the sample size limitation of traditional clinical trials and reveal the late-onset association between drugs and atrial fibrillation, which is conducive to the transformation of DIAF from a “passive treatment” to an “active prevention and control”. Therefore, the selection of appropriate medications by clinicians according to the situation is an important measure to further prevent the occurrence of pharmacologic atrial fibrillation. There are inherent limitations in the information on adverse reactions in drug inserts. Its limitations stem from strict subject screening criteria, which can lead to insufficient statistical validity as well as insufficient sample size in the clinical trial phase.As an important data source for post-marketing pharmacovigilance, the U.S. Food and Drug Administration's Adverse Event Reporting System effectively bridges the gap in relevant research by collecting data from spontaneous reports worldwide.However, there are still some shortcomings in the application of this database: 1. The reporting adopts a self-reporting system, and the degree of standardization of AE reporting is insufficient, and some reporters may confuse the concepts and make misreporting.2.Some records lack severity grading or laboratory validation data, which leads to significant bias in the estimation of the frequency of occurrence.3.The lack of information on patients' underlying diseases (e.g., co-medication, genetic background) makes it difficult to control confounding factors.And this makes it difficult to distinguish whether it is a direct effect of the drug or a superimposed effect of the progression of the underlying disease.4.The uneven geographical distribution of the reports is a prominent problem, such as the current report, which is mainly concentrated in the U.S.A. 5.The time lag of the databases and the phenomenon of duplicate reports further weakened the timeliness and credibility of the data. Conclusions In this study, we collected all AE reports associated with AF events in the FAERS database from the first quarter year of 2004 through the fourth quarter of 2024 and performed signal detection. We discuss the potential impact of demographic information and summarize medications that may pose a risk for inducing AF events. Our study provides a preliminary overview of potential risk factors and medications involved in real-world AF events. This information can help supervisory and regulatory agencies, medical staff, and others involved in medication management to better understand potential risks and optimize clinical treatment regimens. Reporting bias may be introduced because the data come from the FAERS database, which relies on voluntary reporting. Further in-depth studies are needed to validate these associations and establish specific and reliable causal relationships. As research progresses, events in AF can be better managed by improving understanding of disease mechanisms, optimizing drug formulations, and developing more rational dosing regimens. Declarations Author contributions JS Fu and JX Li designed the study.YX Wu drafted the manuscript.JS Fu,X Su,ZY Guo and J Wu analyzed and interpreted the data.JX Li conceived and designed the study and revised the manuscript. The authors read and approved the final manuscript. Funding This work was financially supported by the China Postdoctoral Science Foundation(2023M744100). Data availability The datasets generated during analysis in the current study are available in (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html#FOIA).Accessed May 20, 2025 Ethics approval and consent to participate This study used publicly available data from the FAERS database provided by the FDA for analysis and research. 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Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229–361. https://doi.org/10.1093/eurheartj/ehac244. Jiang L, Li L, Ruan Y, et al. Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium. Heart Rhythm. 2019;16(9):1374–82. https://doi.org/10.1016/j.hrthm.2019.04.008. McMullen JR, Boey EJH, Ooi JYY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829–30. https://doi.org/10.1182/blood-2014-10-604272. Chang PC, Wo HT, Lee HL, et al. Role of sarcoplasmic reticulum calcium in development of secondary calcium rise and early afterdepolarizations in long QT syndrome rabbit model. PLoS One. 2015;10(4):e0123868. https://doi.org/10.1371/journal.pone.0123868. Fei L, Zhao Y. Re-assessing the risk-benefit profile of thiazolidinediones: cardiovascular risks and stroke prevention through real-world data. Endocr Pract. 2025;S1530-891X(25)00118-1. https://doi.org/10.1016/j.eprac.2025.04.004. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332(7533):73–8.https://doi.org/10.1016/j.amjcard.2011.03.004 Albert CM, Cook NR, Pester J, et al. Effect of marine omega-3 fatty acid and vitamin D supplementation on incident atrial fibrillation: a randomized clinical trial. JAMA. 2021;325(11):1061–73.https://doi.org/10.1001/jama.2021.1489. Marcus GM, Link MS. Omega-3 fatty acids and arrhythmias. Circulation. 2024;150(6):488–503. https://doi.org/10.1161/CIRCULATIONAHA.123.065769. Tables Tables 1 and 5 are available in the Supplementary Files section Table 2. Characteristic table Characteristics AER numbers Gender female 36170(45.05) male 37079(46.18) unknown 7040( 8.77) Age 70.00(62.00,77.00) =65 38561(48.03) unknow 23976(29.86) Reporter consumer 26404(32.89) physician 25020(31.16) pharmacist 12201(15.20) other health-professional 10891(13.56) lawyer 1049( 1.31) registered Nurse 53( 0.07) unknown 4671( 5.82) Reported countries United States 34514(42.99) other 28448(35.43) Germany 3905( 4.86) Canada 3591( 4.47) United Kingdom 2827( 3.52) France 2245( 2.80) Japan 2009( 2.50) Italy 1731( 2.16) Australia 1019( 1.27) Outcomes other serious 50396(42.60) hospitalization 49011(41.43) death 9404( 7.95) life threatening 6308( 5.33) disability 2422( 2.05) required intervention to prevent permanent impairment/damage 716( 0.61) congenital anomaly 51( 0.04) Table 3. Top 50 drugs in terms of number Drug Case Reports ROR(95% CI) PRR(95% CI) chisq IC(IC025) ibrutinib 2906 10.73(10.33, 11.14) 10.3(9.9, 10.71) 23627.16 3.32(3.26) rosiglitazone 2015 5.38(5.14, 5.62) 5.28(5.08, 5.49) 6837.71 2.37(2.31) sacubitril/valsartan 1712 3.85(3.67, 4.04) 3.8(3.65, 3.95) 3477.35 1.9(1.83) digoxin 1121 27.75(26.07, 29.54) 24.87(23.45, 26.38) 25433.14 4.62(4.53) dronedarone 1050 53.09(49.62, 56.8) 43.3(40.83, 45.92) 43014.22 5.42(5.32) amiodarone 771 9.1(8.46, 9.78) 8.79(8.13, 9.51) 5292.87 3.12(3.02) metoprolol 758 6.72(6.25, 7.23) 6.56(6.07, 7.1) 3554.74 2.7(2.6) bosentan 671 3.77(3.49, 4.07) 3.73(3.45, 4.03) 1332.85 1.89(1.78) dofetilide* 668 23.57(21.76, 25.54) 21.46(19.84, 23.21) 12980.65 4.41(4.3) macitentan 612 3.75(3.46, 4.06) 3.71(3.43, 4.01) 1205.33 1.88(1.77) alendronate sodium 587 3.79(3.49, 4.12) 3.75(3.47, 4.06) 1178.86 1.9(1.78) bisoprolol 545 11.74(10.76, 12.79) 11.21(10.36, 12.12) 5055.78 3.48(3.35) clopidogrel 535 3.13(2.87, 3.41) 3.1(2.87, 3.35) 758.56 1.62(1.5) diltiazem* 363 8.9(8.01, 9.88) 8.6(7.8, 9.49) 2437.17 3.1(2.95) furosemide 340 3.42(3.07, 3.8) 3.38(3.06, 3.73) 570.31 1.75(1.6) tafamidis 332 7.19(6.45, 8.02) 7(6.35, 7.72) 1708.27 2.8(2.64) valsartan 324 3.03(2.71, 3.38) 3(2.67, 3.37) 432.72 1.58(1.42) propafenone 287 32.87(29.04, 37.21) 28.84(25.64, 32.44) 7720.54 4.85(4.67) carvedilol 202 4.06(3.53, 4.67) 4.01(3.5, 4.6) 456.42 2(1.8) daratumumab* 197 3.29(2.85, 3.78) 3.25(2.83, 3.73) 308.16 1.7(1.5) carfilzomib* 195 3.29(2.86, 3.79) 3.26(2.84, 3.74) 305.7 1.7(1.5) selexipag 186 3.9(3.37, 4.51) 3.85(3.36, 4.42) 392.95 1.94(1.73) agalsidase β 177 5.11(4.4, 5.93) 5.02(4.38, 5.76) 571.1 2.33(2.11) flecainide 171 18.31(15.67, 21.4) 17.02(14.84, 19.52) 2584.09 4.09(3.86) mavacamten 165 18.71(15.96, 21.93) 17.36(15.13, 19.91) 2549.87 4.11(3.89) sotalol 164 19.13(16.31, 22.44) 17.72(15.15, 20.73) 2593.56 4.14(3.92) obinutuzumab* 164 4.87(4.17, 5.69) 4.79(4.09, 5.6) 492.82 2.26(2.03) acalabrutinib* 163 5.1(4.37, 5.96) 5.01(4.28, 5.86) 524.24 2.32(2.1) Atenolol* 155 3.81(3.25, 4.47) 3.77(3.22, 4.41) 315.95 1.91(1.68) bendamustine* 151 3.65(3.11, 4.29) 3.61(3.09, 4.22) 285.29 1.85(1.62) verapamil hydrochloride 136 4.15(3.5, 4.91) 4.09(3.43, 4.88) 318.44 2.03(1.79) ponatinib 133 3.35(2.82, 3.98) 3.32(2.78, 3.96) 215.79 1.73(1.48) dobutamine 125 25.74(21.39, 30.97) 23.22(19.85, 27.16) 2665 4.53(4.27) aliskiren 105 4.32(3.56, 5.25) 4.26(3.5, 5.18) 263.01 2.09(1.81) melphalan 94 3.35(2.73, 4.11) 3.32(2.73, 4.04) 152.71 1.73(1.44) bamlanivimab 86 3.68(2.97, 4.56) 3.64(2.93, 4.52) 165.13 1.86(1.56) spironolactone* 85 3.24(2.62, 4.02) 3.21(2.59, 3.98) 129.84 1.68(1.37) perindopril 84 7(5.64, 8.7) 6.82(5.5, 8.46) 418.84 2.77(2.46) ivabradine* 81 6.46(5.18, 8.06) 6.31(5.09, 7.83) 363.27 2.66(2.34) ethyl icosapentate* 80 5.37(4.31, 6.71) 5.27(4.25, 6.54) 277.97 2.4(2.08) pamidronate disodium 79 4.73(3.78, 5.91) 4.65(3.75, 5.77) 227.2 2.22(1.9) sevoflurane* 77 4.82(3.84, 6.04) 4.74(3.82, 5.88) 227.94 2.24(1.92) idelalisib 77 3.09(2.47, 3.87) 3.06(2.47, 3.8) 107.1 1.61(1.29) clofarabine 73 7.25(5.74, 9.16) 7.06(5.58, 8.93) 380.99 2.82(2.48) theophylline 72 12.68(10, 16.08) 12.07(9.73, 14.97) 733.26 3.59(3.25) sipuleucel 71 3.1(2.45, 3.92) 3.07(2.43, 3.88) 99.51 1.62(1.28) metformin hydrochloride/rosiglita-zone maleate 68 4.9(3.85, 6.23) 4.82(3.81, 6.1) 206.45 2.27(1.92) nebivolol 68 3.81(3, 4.85) 3.77(2.98, 4.77) 138.71 1.91(1.57) doxazosin 59 3.09(2.39, 3.99) 3.06(2.37, 3.95) 82.07 1.61(1.24) efgartigimod alfa 58 4.25(3.28, 5.52) 4.19(3.25, 5.41) 141.57 2.07(1.7) * the package insert suggest risk for AF Table4. Top 50 drugs in terms of ROR Drug Case Reports ROR(95% CI) PRR(95% CI) chisq IC(IC025) dronedarone 1050 53.09(49.62, 56.8) 43.3(40.83, 45.92) 43014.22 5.42(5.32) eplontersen 3 42.48(12.38, 145.79) 35.93(12.71, 101.53) 102.32 5.17(3.62) propafenone 287 32.87(29.04, 37.21) 28.84(25.64, 32.44) 7720.54 4.85(4.67) digoxin 1121 27.75(26.07, 29.54) 24.87(23.45, 26.38) 25433.14 4.62(4.53) dobutamine 125 25.74(21.39, 30.97) 23.22(19.85, 27.16) 2665 4.53(4.27) dofetilide* 668 23.57(21.76, 25.54) 21.46(19.84, 23.21) 12980.65 4.41(4.3) recombinant human interleukin-11* 5 19.87(7.97, 49.58) 18.35(7.9, 42.62) 82.39 4.2(2.99) sotalol 164 19.13(16.31, 22.44) 17.72(15.15, 20.73) 2593.56 4.14(3.92) mavacamten 165 18.71(15.96, 21.93) 17.36(15.13, 19.91) 2549.87 4.11(3.89) flecainide 171 18.31(15.67, 21.4) 17.02(14.84, 19.52) 2584.09 4.09(3.86) aldesleukin 42 16.33(11.94, 22.34) 15.3(11.4, 20.53) 563.49 3.93(3.49) isoproterenol 10 16.18(8.52, 30.74) 15.17(8.26, 27.85) 132.95 3.92(3.04) theophylline 72 12.68(10, 16.08) 12.07(9.73, 14.97) 733.26 3.59(3.25) clevidipine* 15 12.68(7.54, 21.33) 12.06(7.39, 19.69) 152.83 3.59(2.87) disopyramide 31 12.55(8.74, 18.01) 11.94(8.56, 16.66) 311.99 3.58(3.06) gadoversetamide 19 12.2(7.69, 19.35) 11.62(7.55, 17.88) 185.28 3.54(2.89) bisoprolol 545 11.74(10.76, 12.79) 11.21(10.36, 12.12) 5055.78 3.48(3.35) reteplase 25 11.42(7.64, 17.07) 10.92(7.38, 16.16) 226.27 3.45(2.88) ibrutinib* 2906 10.73(10.33, 11.14) 10.3(9.9, 10.71) 23627.16 3.32(3.26) levothyroxine/liothyro -nine* 28 10.14(6.94, 14.8) 9.75(6.85, 13.87) 220.64 3.28(2.75) amiodarone 771 9.1(8.46, 9.78) 8.79(8.13, 9.51) 5292.87 3.12(3.02) diltiazem* 363 8.9(8.01, 9.88) 8.6(7.8, 9.49) 2437.17 3.1(2.95) bendroflumethiazide* 3 8.71(2.75, 27.61) 8.43(2.76, 25.76) 19.73 3.08(1.63) omega-3-carboxylic acids 4 8.39(3.09, 22.76) 8.13(3.11, 21.24) 25.11 3.02(1.73) romidepsin 40 8.35(6.09, 11.45) 8.09(5.91, 11.07) 249.4 3.01(2.57) belumosudil mesylate 7 8.22(3.87, 17.47) 7.96(3.85, 16.44) 42.82 2.99(1.97) thyroid tab 36 8.11(5.82, 11.31) 7.86(5.74, 10.76) 216.56 2.97(2.5) omaveloxolone 28 8.01(5.5, 11.68) 7.77(5.35, 11.28) 165.9 2.96(2.42) migalastat 14 7.95(4.67, 13.55) 7.71(4.63, 12.83) 82.17 2.95(2.2) trandolapril 20 7.91(5.06, 12.35) 7.68(4.99, 11.82) 116.61 2.94(2.31) denileukin diftitox 6 7.86(3.48, 17.73) 7.63(3.48, 16.71) 34.7 2.93(1.84) etoricoxib* 10 7.36(3.92, 13.81) 7.16(3.9, 13.15) 53.19 2.84(1.97) clofarabine 73 7.25(5.74, 9.16) 7.06(5.58, 8.93) 380.99 2.82(2.48) porfimer sodium* 10 7.24(3.86, 13.59) 7.05(3.84, 12.94) 52.1 2.82(1.95) tafamidis 332 7.19(6.45, 8.02) 7(6.35, 7.72) 1708.27 2.8(2.64) perindopril 84 7(5.64, 8.7) 6.82(5.5, 8.46) 418.84 2.77(2.46) metoprolol 758 6.72(6.25, 7.23) 6.56(6.07, 7.1) 3554.74 2.7(2.6) ioxilan* 4 6.47(2.4, 17.49) 6.32(2.42, 16.51) 18 2.66(1.37) ivabradine* 81 6.46(5.18, 8.06) 6.31(5.09, 7.83) 363.27 2.66(2.34) pentostatin 10 6.21(3.31, 11.64) 6.07(3.31, 11.14) 42.52 2.6(1.74) glimepiride/rosiglitazone 13 6.15(3.54, 10.67) 6.01(3.54, 10.2) 54.57 2.59(1.82) alvimopan 6 6.07(2.7, 13.65) 5.94(2.71, 13.01) 24.74 2.57(1.48) ferric hydroxide 6 5.99(2.66, 13.47) 5.86(2.68, 12.83) 24.29 2.55(1.47) atenolol/chlorthalidone 8 5.96(2.95, 12.03) 5.84(2.94, 11.6) 32.19 2.54(1.59) daunorubicin 30 5.88(4.09, 8.45) 5.76(4.05, 8.2) 118.42 2.53(2.01) zanubrutinib* 39 5.65(4.11, 7.76) 5.53(4.04, 7.57) 145.48 2.47(2.02) mosunetuzumab-axgb 11 5.45(3, 9.92) 5.35(2.97, 9.63) 39.06 2.42(1.59) milrinone 9 5.39(2.79, 10.45) 5.29(2.77, 10.1) 31.47 2.4(1.5) rosiglitazone 2015 5.38(5.14, 5.62) 5.28(5.08, 5.49) 6837.71 2.37(2.31) ethyl icosapentate* 80 5.37(4.31, 6.71) 5.27(4.25, 6.54) 277.97 2.4(2.08) * the package insert suggest risk for A Additional Declarations No competing interests reported. Supplementary Files Table1Dataminingmethodsandspecificformulas.xlsx Table5Listoftop50drugsbynumberandRORstrengthbyindication.xlsx 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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2","display":"","copyAsset":false,"role":"figure","size":119820,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of reported cases of drug-induced hypoglycemia from 2004 to 2024\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/17ac13034ec307454d432e50.png"},{"id":84529020,"identity":"c1434392-a7de-4065-bddf-b0ca6be5800e","added_by":"auto","created_at":"2025-06-13 05:51:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":72201,"visible":true,"origin":"","legend":"\u003cp\u003eIndications for medications related to DIAF\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/6dcd2a7e5e20dfe0a9582aa6.png"},{"id":84530599,"identity":"ffe4ab53-361b-4a37-8d8f-d1a3709321dd","added_by":"auto","created_at":"2025-06-13 06:07:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":204083,"visible":true,"origin":"","legend":"\u003cp\u003eTop 50 drugs in terms of number\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/6073a84f759b221efccc7beb.png"},{"id":84529011,"identity":"518cc7a3-e17b-42f0-b7bc-68002b7cda12","added_by":"auto","created_at":"2025-06-13 05:51:14","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":239170,"visible":true,"origin":"","legend":"\u003cp\u003eTop 50 drugs in terms of ROR\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/d8a441e40f104c4b7e073c40.png"},{"id":95227581,"identity":"9e91a464-de03-466a-bb3b-ccf21a17ba2f","added_by":"auto","created_at":"2025-11-05 16:32:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1581945,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/fec4b1ae-7bb9-4c10-866e-77030827566e.pdf"},{"id":84530265,"identity":"a34d3de9-b045-43dc-8fb6-424b6a4cf90e","added_by":"auto","created_at":"2025-06-13 05:59:14","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":255840,"visible":true,"origin":"","legend":"","description":"","filename":"Table1Dataminingmethodsandspecificformulas.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/5dc1185a8d34a12fa84aecf5.xlsx"},{"id":84530266,"identity":"e8e08871-b3fb-4b80-97ef-1f185150cc30","added_by":"auto","created_at":"2025-06-13 05:59:14","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11923,"visible":true,"origin":"","legend":"","description":"","filename":"Table5Listoftop50drugsbynumberandRORstrengthbyindication.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6622422/v1/446b4038be0173ba018484ea.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Drug-induced atrial fibrillation: A real-world pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System database","fulltext":[{"header":"Background","content":"\u003cp\u003eAtrial fibrillation (AF) is a type of cardiac arrhythmia and the main clinical symptoms include palpitations, chest tightness, and shortness of breath. AF can lead to serious complications such as death, stroke, and peripheral embolism, and is one of the leading causes of cardiac hospitalization and death worldwide. It is estimated that by 2030, the number of AF patients in the United States will increase from 5.2\u0026nbsp;million in 2010 to 12.1\u0026nbsp;million [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].The pathogenesis of AF is not fully elucidated at present, and it is mainly an electrophysiological alteration of the heart, involving many factors such as changes in neural tone, myocardial injury, and oxidative stress. Meanwhile, genetic factors, unhealthy lifestyle and dietary habits are positively associated with the occurrence of AF [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].Notably, many widely used medications may cause or exacerbate atrial fibrillation, which we call drug-induced atrial fibrillation (DIAF). Similarly, there is no clear cause or pathogenesis of DIAF. Most DIAF is paroxysmal, but sometimes the disease persists. Since most cases of DIAF are short-lived, doctors and patients do not take this occurrence seriously. However, DIAF is a matter of concern because the occurrence of this phenomenon increases the risk of malignant events in the elderly and in patients with associated comorbidities. Therefore, it is crucial to identify medications that may be associated with DIAF.A large-scale retrospective study based on the years 2004 to 2019 analyzed drug-induced arrhythmias but was limited in its analysis of drug-induced atrial fibrillation[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The number of reported cases of drug-induced atrial fibrillation has increased substantially in the last 5 years, and there is a need to update and improve studies on drug-induced atrial fibrillation.A review[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]systematically summarized drug studies and mechanisms related to pharmacological atrial fibrillation according to drug class, but did not provide a comprehensive quantitative analysis from the perspective of active mining.Therefore, a systematic analysis is necessary to address the extent of the effects of various drugs.Big data analytics have promising applications in the prevention and treatment of drug-induced diseases. The U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) is the largest public drug safety database for spontaneous reporting of adverse events, and is the primary source for post-marketing safety monitoring and evaluation of chemical drugs and therapeutic biologics.Therefore, in this study, we reviewed reports related to the occurrence of AF in the FAERS database and detected the ADR signals of AF-related drugs using disproportionality analysis, aiming to comprehensively uncover drugs that may induce AF from a pharmacovigilance point of view and to provide a reference for clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eData source\u003c/p\u003e \u003cp\u003eThis retrospective pharmacovigilance study was conducted based on the FAERS database.FAERS is an is an open database where healthcare professionals, consumers, and drug manufacturers from around the world can report adverse drug information to FAERS.It collects information on adverse events and medication errors, including DEMO (patient demographics and management information), DRUG (drug/biologic information), REAC (all coded terms for adverse events), OUTC (patient outcomes), RPSR (reporting source), THER (date of initiation and end of drug therapy), and INDI (all coded terms for indications)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].This study retrospectively analyzed adverse event information in the FAERS system from January 2004 to December 2024, yielding a total of 21,890,177 reports. Removal of duplicate information resulted in 18,282,801 actual reports.(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eData cleaning\u003c/p\u003e \u003cp\u003eAdverse reports (AEs) in the REAC file were coded by the Preferred Term (PT) in the Medical Dictionary of Regulatory Activities (MedDRA) nomenclature, and we searched the PT column for \u0026ldquo;atrial fibrillation\u0026rdquo; (MedDRA code: 10003658) to find medications that may induce atrial fibrillation[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].Role codes for AEs were assigned by the reporter and included primary suspect (PS), secondary suspect drug (SS), concomitant (C), and interaction (I).We screened the primary suspect drugs (PS) for analysis.All reports on AF were subsequently downloaded and analyzed using the drug's generic name as a unique identifier for statistical analysis. For some FAERS database reports of drugs with trade names, we converted them to generic names based on their active ingredient composition and drug name.In addition, some reporters may have confused the concepts of adverse reactions and indications, reporting indications for some drugs as adverse reactions.Therefore, we deleted some drugs (DOAC, warfarin and heparin) based on previous studies to exclude the influence of related drugs on the results.\u003c/p\u003e \u003cp\u003eData mining and statistical analysis\u003c/p\u003e \u003cp\u003eWe performed a descriptive evaluation of all AE characteristics and outcome indicators associated with AF. Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as medians and interquartile spacing.The analytical approach uses disproportionality analysis to detect potential signals of drug-induced adverse events in AF.Higher values are usually obtained when the target drug is more likely to trigger a specific adverse event than all other drugs. We prioritized the use of two frequency methods, reporting ratio of ratios (ROR)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and proportional reporting rate (PRR)[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], to rapidly identify potential signals. We also verified the signal reliability by combining Bayesian methods (BCPNN and EBGM)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].The formulas of the four disproportionality algorithms and their corresponding criteria are listed in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;1.\u003c/b\u003e Data mining methods and specific formulas(Table\u0026nbsp;1 is provided as a supplementary file)\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBasic information for AE reports\u003c/p\u003e\n\u003cp\u003eFrom the first quarter of 2004 through the fourth quarter of 2024, we conducted a narrow search using \u0026ldquo;AF\u0026rdquo; and retrieved a total of 118,074 AE reports related to AF in the FAERS database.We set medications as the \u0026ldquo;primary suspected medications\u0026rdquo; causing DIAF and excluded anticoagulants used for AF (e.g., rivaroxaban, dabigatran, heparin, etc.), resulting in 80,289 targeted AE reports.\u003c/p\u003e\n\u003cp\u003eThe annual distribution of AE reports related to DIAF is shown, with the highest number of reports received in 2024(Fig.2). In terms of source and type of report, the top three were consumers, physicians, and pharmacists, with AE reports coming primarily from the United States.In terms of patients, the prevalence was higher in men than in women, with 65 years of age or older being the age group with the highest number of cases. In terms of patient outcomes, hospitalization for AF events accounted for 41.43% of cases and death accounted for 7.95% of cases.(Table 2)In terms of drug indications, the highest percentage of drugs were indicated for chronic lymphocytic leukaemia, followed by pulmonary arterial hypertension, rheumatoid arthritis, atrial fibrillation, plasma cell myeloma, diabetes mellitus, and so on.(Fig.3)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Characteristic table（Table2 is located at the end of the file）\u003c/p\u003e\n\u003cp\u003eDisproportionality analysis\u003c/p\u003e\n\u003cp\u003eFrom the 80,289 targeted AE reports collected, we identified 156 drugs associated with the occurrence of DIAF, and a total of 22,255 adverse reaction reports were eligible for screening after setting the signaling detection conditions (ROR \u0026ge; 3,PRR \u0026ge; 2,IC025 \u0026gt; 0,EBGM05 \u0026gt; 2). For AE reports associated with specific PTs and their contained drugs, we ranked the top 50 drugs by number of cases and signal intensity respectively.\u003c/p\u003e\n\u003cp\u003eThe top fifty drugs in order of the number of adverse reaction reports are shown in Fig.4 and Table 3.The top ten drugs are as follows:ibrutinib(2906),rosiglitazone(2015),\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;3.\u003c/strong\u003eTop 50 drugs in terms of number (Table 3 is located at the end of the file)\u003c/p\u003e\n\u003cp\u003esacubitril/valsartan(1712),digoxin(1121),dronedarone(1050),amiodarone(771),metoprolol(758),bosentan(671),and dofetilide(668).The top 50 drugs mainly contained cardiovascular system drugs, antineoplastic drugs, metabolic and endocrine drugs, respiratory system drugs, anti-infective and immunomodulatory drugs, with cardiovascular system drugs being the most reported(26/50).\u003c/p\u003e\n\u003cp\u003eBased on the magnitude of ROR values, we ranked the top 50 drugs in terms of ROR values as shown in Fig.5 and Table 4.Among them, the top 10 drugs were as follows:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003eTop 50 drugs in terms of ROR (Table 4 is located at the end of the file)\u003c/p\u003e\n\u003cp\u003edronedarone(ROR53.09,95%CI49.62,56.8),eplontersen(ROR42.48,95%CI12.38,145.79), propafenone(ROR32.87,95%CI29.04,37.21),digoxin(ROR27.75,95%CI26.07,29.54),dobutamine(ROR25.74,95%CI21.39,30.97),dofetilide(ROR23.57,95%CI21.76,25.54),recombinant human-interleukin-11(ROR19.87,95%CI7.97,49.58),sotalol(ROR19.13,95%CI16.31,22.44),mavacamten(ROR18.71,95%CI15.96,21.93),flecainide(ROR18.31,95%CI15.67,21.4).We ranked them according to PRR values and the results were consistent with the order of drugs by ROR.The top fifty drugs mainly contain cardiovascular system drugs, antineoplastic drugs,metabolic and endocrine drugs,respiratory drugs,anti-infective and immunomodulatory drugs,with the most reported being cardiovascular system drugs(22/50).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDIAF has a significant impact on the health and quality of life of patients and requires attention in the clinical setting, and it can lead to serious consequences such as sudden cardiac death. This study comprehensively evaluated real-world AE reports of DIAF based on the FAERS database. We described the basic features of AE reports of DIAF and summarized a list of drugs that can cause AF and are potential culprits for AF. Also, based on this list of drugs, we counted the proportion of reports for different drugs and drug classes, and integrated ADR signal detection and signal distribution for each drug.\u003c/p\u003e \u003cp\u003eFrom 2004 to 2024, the number of DIAF reports shows an upward trend. The reasons for this situation may be multifactorial. First, the public and the pharmaceutical industry are becoming more aware of medication safety, leading to a greater focus on adverse events. The source of reports shows that the proportion of consumer reports is higher than that of physicians and is the most frequent source of all reporters, which may be related to the fact that DIAFs tend to be paroxysmal and transient in nature.\u003c/p\u003e \u003cp\u003eAtrial fibrillation involves a number of pathogenetic mechanisms that are fundamentally dependent on electrophysiological abnormalities[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], involving electrophysiological changes in the atria (increased atrial arrhythmia, ectopic activity of the pulmonary veins, slow intra-atrial conduction, decrease in the ratio of duration of the action potential to the effective response time, changes in the regulation of ion channels, and intracellular changes in calcium ions, etc.), changes in cardiac autonomic tone (increased vagal tone, increased sympathetic tone, etc.), myocardial damage (myocardial ischemia, cardiac fibrosis, myocarditis, etc.),In addition, DIAF involves mechanisms such as increased oxidative stress, mitochondrial damage, hyperthyroidism, increased sympathetic tone, myocardial injury (e.g., myocardial ischemia, cardiac fibrosis, myocarditis, etc.) and inhibition of cardiac signaling pathways. All of these factors affect the normal electrophysiologic activity of the heart, ultimately leading to atrial fibrillation.\u003c/p\u003e \u003cp\u003eDuring the study period, we observed a correlation between DIAF cases submitted to the FDA and age and gender. From the data, 48.03% of DIAF reports were aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years, and men reported more frequently than women. Smoking is an important risk factor for AF patients, and men have more smoking preference than women, which may explain the higher frequency of reporting in men[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].The number of DIAF increases with age, which may be related to several factors. Elderly people usually have altered atrial structure, in which oxidative stress is thought to be the central pathological mechanism triggering the process of atrial electrical remodeling and fibrosis.With age, the body's antioxidant defense system exhibits a significant decline, manifested as a decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), leading to ROS scavenging ability is weakened.Excessive ROS can disrupt the oxidative-antioxidant homeostasis of atrial myocytes, inducing apoptosis and fibrosis through activation of calcium overload, mitochondrial dysfunction and other pathways, leading to the development of atrial fibrillation[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].At the same time, the activity of drug metabolizing enzyme systems (e.g., CYP450 family) is reduced in the elderly population, which delays the clearance of some drugs and their active metabolites and aggravates the accumulation of toxicity in atrial tissues[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It is worth noting that the anti-inflammatory response and repair mechanisms in elderly individuals present dual obstacles: on the one hand, inflammatory signaling pathways such as NF-κB are abnormally activated, and pro-inflammatory factors (e.g., TNF-α, IL-6) are persistently released; on the other hand, the diminished ability of atrial stem cells to proliferate and differentiate, and the imbalance of extracellular matrix repair, accelerate the irreversible development of the fibrotic lesions[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition, underlying diseases in the elderly are an important cause of DIAF, and their effects are more complex. For example, in hypertensive patients, elevated levels of angiotensin II can activate NADPH oxidase, leading to overproduction of ROS[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].In patients with chronic kidney disease, impaired drug excretion may allow toxic metabolites (e.g. anthracycline chemotherapeutic agents) to accumulate in atrial tissues and then trigger DIAF[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].Epidemiological data show that the incidence of AF in the elderly has increased exponentially during the global aging process, and its high lethality and treatment complexity pose a serious challenge to the public health system. The current study showed that death accounted for 7.95% of the prognosis of drug-induced atrial fibrillation, suggesting that DIAF has a serious adverse prognosis and requires great attention from clinicians and patients[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the number of reported cases and signal strength, we categorized the respective top 50 drugs by indication, as shown in Table\u0026nbsp;5.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;5.\u003c/b\u003eList of top 50 drugs by number and ROR strength by indication(Table\u0026nbsp;5 is provided as a supplementary file)\u003c/p\u003e \u003cp\u003eAmong the top 50 drugs ordered according to the number of ROR and adverse reaction reports, cardiovascular-related drugs occupy a major portion of the list, including blood pressure control drugs,rhythm regulators, antiplatelet drugs, and some anticoagulants(There is no evidence in previous studies that direct oral anticoagulants (DOAC), warfarin, and heparin can cause arrhythmias, and these medications were excluded from the study to exclude any confounding of adverse reactions and indications that might have affected the accuracy of the results by those completing the adverse reaction reports.), which affect cardiac electrophysiology through a series of changes such as altering hemodynamics and direct modulation of the heart's electrical activity to ultimately induce atrial fibrillation.For example, when the heart is ischemic, the atrial electrical conduction velocity decreases and the duration of AF increases. And the use of antihypertensive drugs may lead to inadequate cardiac perfusion, which in turn induces AF[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].Another example is the hypertensive state that decreases atrial conduction velocity and wavelength and increases the dispersion of conduction velocity[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e],especially in enlarged or fibrotic atria[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], which can promote atrial fibrillation. And some medications used to treat heart failure may elevate blood pressure and induce atrial fibrillation.These seemingly contradictory results suggest that the occurrence of AF may be associated with hemodynamics that are different from the usual state, and therefore it is important to maintain stable hemodynamics in the treatment of cardiovascular disease. Therefore, in the clinic, we need to select clinical medications based on the patient's specific situation and conduct intensive monitoring to minimize the risk.\u003c/p\u003e \u003cp\u003eIt is noteworthy that antineoplastic drugs also occupied a major portion of this study, which was especially dominated by the types used for the treatment of lymphoma. There have been previous studies of antineoplastic drugs for AF based on the faers database, but most were single-drug taps, such as studies of ponatinib causing arrhythmias[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].Cancer patients have a higher incidence of AF than the healthy population, possibly due to the direct effect of pre-existing cardiovascular comorbidities in cancer patients[\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].Active cancer is associated with risk factors for developing AF, including advanced age, systemic inflammation, electrolyte disturbance, metabolic and endocrine abnormalities, and increased sympathetic tone caused by pain or other forms of physical or emotional stress[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].AF may also be caused by paraneoplastic disorders such as hyperparathyroidism and autoimmune reactions against atrial structures[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].Hence, some cancer patients themselves develop baseline ECG abnormalities and arrhythmias.Many anticancer drugs can cause electrical, mechanical, and structural remodeling of the atria, as well as cardiovascular toxicity, leading to hypertension, heart failure, or coronary artery disease, all of which are risk factors for AF[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].Thus, antineoplastic drugs may lead to AF in cancer patients without risk factors for AF.For example, ibrutinib-induced atrial fibrillation may be associated with off-target inhibition of cardiac Tec protein kinase and PI3K, as well as with an abnormally associated increase in autoregulation[\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].In addition, the widespread use of newer antitumor drugs (e.g., axicabtagene ciloleucel, aldesleukin, etc.) poses new monitoring challenges. Notably, some antineoplastic drugs associated with DIAF do not adequately label the risk of cardiotoxicity on their drug inserts, leading to increased rates of underdiagnosis in clinical practice.Therefore, close monitoring of electrocardiograms, combined with high-sensitivity troponin testing and cardiac ultrasound for timely diagnosis is needed during oncology treatment. Optimizing antitumor treatment regimens through risk stratification strategies is expected to help reduce the incidence of atrial fibrillation in high-risk patients while maintaining the effectiveness of oncology treatment.\u003c/p\u003e \u003cp\u003eThere is also a significant proportion of metabolic and endocrine drugs present in our report, including hypoglycemic, lipid-lowering and thyroxine supplementation drugs. Among the hypoglycemic agents, the main drugs were rosiglitazone and its combinations, which is in line with the results of a previous study[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].The main adverse effect of rosiglitazone is induction of heart failure[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e],which further induces atrial fibrillation.In addition to the glucose-lowering medications within this study, some glucose-lowering medications are also at risk for inducing atrial fibrillation.Previous studies have shown that the incidence of atrial fibrillation is elevated by approximately 40% in patients with type 2 diabetes mellitus compared to non-diabetic populations, and that some of the glucose-lowering medications may affect the risk of atrial fibrillation through different mechanisms[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].It is worth noting that previous studies have shown that omega-3-carboxylic acids intake can help prevent arrhythmias, but this was denied by an RCT study[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].In addition, high doses of omega-3-carboxylic acids increase the risk of atrial fibrillation[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].And omega-3-carboxylic acids also showed a potential risk of causing DIAF in the current study (ROR 8.39, 95% CI 3.09, 22.76). Therefore, drug use for drug-induced AF should focus not only on drug selection but also on dosage. Our findings are in general agreement with previous studies emphasizing the need to be vigilant for possible DIAF when using metabolic and endocrine drugs.\u003c/p\u003e \u003cp\u003eIn addition, other drug-induced AF occurrences have been reported, involving a variety of mechanisms, mostly affecting electrolytes, inducing an inflammatory response, affecting hemodynamics, and ultimately leading to alterations in cardiac electrophysiology, which in turn induces AF. DIAF still faces many diagnostic and therapeutic challenges, such as the cause of atrial fibrillation, whether it is attributable to the underlying disease or to medications, and the correct determination is important for the diagnosis of the disease and the direction of treatment.Oncology patients, cardiovascular disease patients, diabetic patients and elderly patients are at high risk of AF episodes, which may work in conjunction with medications to further increase the risk of AF. Clinicians need to be highly alert to the possibility of DIAF when new episodes of atrial fibrillation occur despite patients having received standardized anticoagulation or cardiac function improvement therapy, or when atrial fibrillation episodes are highly correlated with the time window of medication use. If primary disease activity cannot be definitively ruled out, clinicians may change medications for low AF risk as appropriate. Current bottlenecks in the treatment of DIAF are its long latency period and the lack of specific biomarkers, which make it difficult to capture changes in AF during routine ECG screening. FAERS database signal detection can break through the sample size limitation of traditional clinical trials and reveal the late-onset association between drugs and atrial fibrillation, which is conducive to the transformation of DIAF from a \u0026ldquo;passive treatment\u0026rdquo; to an \u0026ldquo;active prevention and control\u0026rdquo;. Therefore, the selection of appropriate medications by clinicians according to the situation is an important measure to further prevent the occurrence of pharmacologic atrial fibrillation.\u003c/p\u003e \u003cp\u003eThere are inherent limitations in the information on adverse reactions in drug inserts. Its limitations stem from strict subject screening criteria, which can lead to insufficient statistical validity as well as insufficient sample size in the clinical trial phase.As an important data source for post-marketing pharmacovigilance, the U.S. Food and Drug Administration's Adverse Event Reporting System effectively bridges the gap in relevant research by collecting data from spontaneous reports worldwide.However, there are still some shortcomings in the application of this database: 1. The reporting adopts a self-reporting system, and the degree of standardization of AE reporting is insufficient, and some reporters may confuse the concepts and make misreporting.2.Some records lack severity grading or laboratory validation data, which leads to significant bias in the estimation of the frequency of occurrence.3.The lack of information on patients' underlying diseases (e.g., co-medication, genetic background) makes it difficult to control confounding factors.And this makes it difficult to distinguish whether it is a direct effect of the drug or a superimposed effect of the progression of the underlying disease.4.The uneven geographical distribution of the reports is a prominent problem, such as the current report, which is mainly concentrated in the U.S.A. 5.The time lag of the databases and the phenomenon of duplicate reports further weakened the timeliness and credibility of the data.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this study, we collected all AE reports associated with AF events in the FAERS database from the first quarter year of 2004 through the fourth quarter of 2024 and performed signal detection. We discuss the potential impact of demographic information and summarize medications that may pose a risk for inducing AF events. Our study provides a preliminary overview of potential risk factors and medications involved in real-world AF events. This information can help supervisory and regulatory agencies, medical staff, and others involved in medication management to better understand potential risks and optimize clinical treatment regimens. Reporting bias may be introduced because the data come from the FAERS database, which relies on voluntary reporting. Further in-depth studies are needed to validate these associations and establish specific and reliable causal relationships. As research progresses, events in AF can be better managed by improving understanding of disease mechanisms, optimizing drug formulations, and developing more rational dosing regimens.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eJS Fu and JX Li designed the study.YX Wu drafted the manuscript.JS Fu,X Su,ZY Guo and J Wu analyzed and interpreted the data.JX Li conceived and designed the study and revised the manuscript. The authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was financially supported by the China Postdoctoral Science Foundation(2023M744100).\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe datasets generated during analysis in the current study are available in (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html#FOIA).Accessed May 20, 2025\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study used publicly available data from the FAERS database provided by the FDA for analysis and research. All studies were conducted in accordance with the Helsinki Declaration and approved by the Institutional Ethics Committee, therefore no additional ethical approval is required.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eThe manuscript is approved by all authors for publication.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eClinical trial number:\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eColilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the US adult population. Am J Cardiol. 2013;112(8):1142\u0026ndash;7. https://doi.org/10.1016/j.amjcard.2013.05.063.\u003c/li\u003e\n\u003cli\u003eBrundel BJJM, Ai X, Hills MT, Kuipers MF, Lip GYH, de Groot NMS. Atrial fibrillation. 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Front Cardiovasc Med. 2020;7:96. https://doi.org/10.3389/fcvm.2020.00096.\u003c/li\u003e\n\u003cli\u003eHimmelreich JC, Veelers L, Lucassen WA, et al. Prediction models for atrial fibrillation applicable in the community: a systematic review and meta-analysis. Europace. 2020;22(5):684\u0026ndash;94. https://doi.org/10.1093/europace/euaa005.\u003c/li\u003e\n\u003cli\u003eWorkman AJ, et al. Mechanisms of termination and prevention of atrial fibrillation by drug therapy. Pharmacol Ther. 2011;131(2):221\u0026ndash;41. doi:10.1016/j.pharmthera.2011.02.002\u003c/li\u003e\n\u003cli\u003eLau DH, Mackenzie L, Kelly DJ, et al. Short-term hypertension is associated with the development of atrial fibrillation substrate: a study in an ovine hypertensive model. Heart Rhythm. 2010;7(3):396\u0026ndash;404. https://doi.org/10.1016/j.hrthm.2009.11.031.\u003c/li\u003e\n\u003cli\u003eKistler PM, Sanders P, Dodic M, et al. Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation. Eur Heart J. 2006;27(24):3045\u0026ndash;56. https://doi.org/10.1093/eurheartj/ehl360.\u003c/li\u003e\n\u003cli\u003eYe JZ, Hansen FB, Mills RW, Lundby A. Oncotherapeutic protein kinase inhibitors associated with pro-arrhythmic liability. JACC CardioOncol. 2021;3(1):88\u0026ndash;97.https://doi.org/10.1016/j.jaccao.2021.01.009.\u003c/li\u003e\n\u003cli\u003eTamargo J, Caballero R, Delp\u0026oacute;n E. Cancer chemotherapy and cardiac arrhythmias: a review. Drug Saf. 2015;38(2):129\u0026ndash;52.https://doi.org/10.1007/s40264-014-0258-4.\u003c/li\u003e\n\u003cli\u003eFarmakis D, Parissis J, Filippatos G. Insights into onco-cardiology: atrial fibrillation in cancer. J Am Coll Cardiol. 2014;63(10):945\u0026ndash;53.https://doi.org/10.1016/j.jacc.2013.11.026.\u003c/li\u003e\n\u003cli\u003eFradley MG, Beckie TM, Brown SA, et al. Recognition, prevention, and management of arrhythmias and autonomic disorders in cardio-oncology: a scientific statement from the American Heart Association. Circulation. 2021;144(3):e41\u0026ndash;55. https://doi.org/10.1161/CIR.0000000000000986.\u003c/li\u003e\n\u003cli\u003eLainscak M, Dagres N, Filippatos GS, et al. Atrial fibrillation in chronic non-cardiac disease: where do we stand? Int J Cardiol. 2008;128(3):311\u0026ndash;5.https://doi.org/10.1016/j.ijcard.2007.12.078.\u003c/li\u003e\n\u003cli\u003eGuzzetti S, Costantino G, Fundar\u0026ograve; C. Systemic inflammation, atrial fibrillation, and cancer. Circulation. 2002;106(9):e40.https://doi.org/10.1161/01.cir.0000028399.42411.13.\u003c/li\u003e\n\u003cli\u003eFradley MG, Gliksman M, Emole J, et al. 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Pharmacol Ther. 2018;189:89\u0026ndash;103. https://doi.org/10.1016/j.pharmthera.2018.04.009.\u003c/li\u003e\n\u003cli\u003eLyon AR, L\u0026oacute;pez-Fern\u0026aacute;ndez T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229\u0026ndash;361. https://doi.org/10.1093/eurheartj/ehac244.\u003c/li\u003e\n\u003cli\u003eJiang L, Li L, Ruan Y, et al. Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium. Heart Rhythm. 2019;16(9):1374\u0026ndash;82. https://doi.org/10.1016/j.hrthm.2019.04.008.\u003c/li\u003e\n\u003cli\u003eMcMullen JR, Boey EJH, Ooi JYY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829\u0026ndash;30. https://doi.org/10.1182/blood-2014-10-604272.\u003c/li\u003e\n\u003cli\u003eChang PC, Wo HT, Lee HL, et al. Role of sarcoplasmic reticulum calcium in development of secondary calcium rise and early afterdepolarizations in long QT syndrome rabbit model. PLoS One. 2015;10(4):e0123868. https://doi.org/10.1371/journal.pone.0123868.\u003c/li\u003e\n\u003cli\u003eFei L, Zhao Y. Re-assessing the risk-benefit profile of thiazolidinediones: cardiovascular risks and stroke prevention through real-world data. Endocr Pract. 2025;S1530-891X(25)00118-1. https://doi.org/10.1016/j.eprac.2025.04.004.\u003c/li\u003e\n\u003cli\u003eHuxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332(7533):73\u0026ndash;8.https://doi.org/10.1016/j.amjcard.2011.03.004\u003c/li\u003e\n\u003cli\u003eAlbert CM, Cook NR, Pester J, et al. Effect of marine omega-3 fatty acid and vitamin D supplementation on incident atrial fibrillation: a randomized clinical trial. JAMA. 2021;325(11):1061\u0026ndash;73.https://doi.org/10.1001/jama.2021.1489.\u003c/li\u003e\n\u003cli\u003eMarcus GM, Link MS. Omega-3 fatty acids and arrhythmias. Circulation. 2024;150(6):488\u0026ndash;503. https://doi.org/10.1161/CIRCULATIONAHA.123.065769.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 5 are available in the Supplementary Files section\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eCharacteristic table\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAER numbers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e36170(45.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e37079(46.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eunknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e7040( 8.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e70.00(62.00,77.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e151( 0.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e18-40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e1467( 1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e40-65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e16134(20.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026gt;=65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e38561(48.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eunknow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e23976(29.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReporter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003econsumer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e26404(32.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003ephysician\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e25020(31.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003epharmacist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e12201(15.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eother health-professional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e10891(13.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003elawyer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e1049( 1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eregistered Nurse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e53( 0.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eunknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e4671( 5.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReported countries\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eUnited States\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e34514(42.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e28448(35.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eGermany\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e3905( 4.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e3591( 4.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e2827( 3.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eFrance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e2245( 2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e2009( 2.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eItaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e1731( 2.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e1019( 1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003eother serious\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e50396(42.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003ehospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e49011(41.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003edeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e9404( 7.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003elife threatening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e6308( 5.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003edisability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e2422( 2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003erequired intervention to prevent permanent impairment/damage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 284px;\"\u003e\n \u003cp\u003e716( 0.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003econgenital anomaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 284px;\"\u003e\n \u003cp\u003e51( 0.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 3.\u003c/strong\u003eTop 50 drugs in terms of number\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCase Reports\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROR(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRR(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003echisq\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIC(IC025)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eibrutinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e2906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e10.73(10.33, 11.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e10.3(9.9, 10.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e23627.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.32(3.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003erosiglitazone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.38(5.14, 5.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.28(5.08, 5.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e6837.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.37(2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003esacubitril/valsartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e1712\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.85(3.67, 4.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.8(3.65, 3.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3477.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.9(1.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003edigoxin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e1121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e27.75(26.07, 29.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e24.87(23.45, 26.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e25433.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.62(4.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003edronedarone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e1050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e53.09(49.62, 56.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e43.3(40.83, 45.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e43014.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5.42(5.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eamiodarone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e9.1(8.46, 9.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.79(8.13, 9.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5292.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.12(3.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003emetoprolol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e758\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e6.72(6.25, 7.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e6.56(6.07, 7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3554.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.7(2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003ebosentan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.77(3.49, 4.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.73(3.45, 4.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1332.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.89(1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003edofetilide*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e668\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e23.57(21.76, 25.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e21.46(19.84, 23.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e12980.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.41(4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003emacitentan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.75(3.46, 4.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.71(3.43, 4.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1205.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.88(1.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003ealendronate sodium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.79(3.49, 4.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.75(3.47, 4.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1178.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.9(1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n 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82px;\"\u003e\n \u003cp\u003e2.8(2.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003evalsartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.03(2.71, 3.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3(2.67, 3.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e432.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.58(1.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003epropafenone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e32.87(29.04, 37.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e28.84(25.64, 32.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7720.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.85(4.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003ecarvedilol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.06(3.53, 4.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.01(3.5, 4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e456.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2(1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n 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3.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e305.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.7(1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eselexipag\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.9(3.37, 4.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.85(3.36, 4.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e392.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.94(1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eagalsidase \u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n 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\u003cp\u003e2584.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.09(3.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003emavacamten\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e18.71(15.96, 21.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e17.36(15.13, 19.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2549.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.11(3.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003esotalol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e164\u003c/p\u003e\n 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\u003cp\u003e2.26(2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eacalabrutinib*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.1(4.37, 5.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.01(4.28, 5.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e524.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.32(2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eAtenolol*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.81(3.25, 4.47)\u003c/p\u003e\n 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style=\"width: 144px;\"\u003e\n \u003cp\u003everapamil hydrochloride\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.15(3.5, 4.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.09(3.43, 4.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e318.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.03(1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eponatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.35(2.82, 3.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.32(2.78, 3.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e215.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.73(1.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003edobutamine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e25.74(21.39, 30.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e23.22(19.85, 27.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.53(4.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003ealiskiren\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.32(3.56, 5.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.26(3.5, 5.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e263.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.09(1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003emelphalan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.35(2.73, 4.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.32(2.73, 4.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e152.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.73(1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003ebamlanivimab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.68(2.97, 4.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.64(2.93, 4.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e165.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.86(1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003espironolactone*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.24(2.62, 4.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.21(2.59, 3.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e129.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.68(1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eperindopril\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7(5.64, 8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e6.82(5.5, 8.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e418.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.77(2.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eivabradine*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e6.46(5.18, 8.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e6.31(5.09, 7.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e363.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.66(2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eethyl icosapentate*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.37(4.31, 6.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.27(4.25, 6.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e277.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.4(2.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003epamidronate disodium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.73(3.78, 5.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.65(3.75, 5.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e227.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.22(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003esevoflurane*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.82(3.84, 6.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.74(3.82, 5.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e227.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.24(1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eidelalisib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.09(2.47, 3.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.06(2.47, 3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e107.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.61(1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eclofarabine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.25(5.74, 9.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.06(5.58, 8.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e380.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.82(2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003etheophylline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.68(10, 16.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.07(9.73, 14.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e733.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.59(3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003esipuleucel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.1(2.45, 3.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.07(2.43, 3.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e99.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.62(1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003emetformin hydrochloride/rosiglita-zone maleate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.9(3.85, 6.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.82(3.81, 6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e206.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.27(1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003enebivolol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.81(3, 4.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.77(2.98, 4.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e138.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.91(1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003edoxazosin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.09(2.39, 3.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3.06(2.37, 3.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e82.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e1.61(1.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003eefgartigimod alfa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.25(3.28, 5.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e4.19(3.25, 5.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e141.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.07(1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* the package insert suggest risk for AF\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable4.\u003c/strong\u003eTop 50 drugs in terms of ROR\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCase Reports\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROR(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRR(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003echisq\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIC(IC025)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003edronedarone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e53.09(49.62, 56.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e43.3(40.83, 45.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e43014.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5.42(5.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eeplontersen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e42.48(12.38, 145.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e35.93(12.71, 101.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e102.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5.17(3.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003epropafenone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e32.87(29.04, 37.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e28.84(25.64, 32.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e7720.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.85(4.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003edigoxin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e27.75(26.07, 29.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e24.87(23.45, 26.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e25433.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.62(4.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003edobutamine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e25.74(21.39, 30.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e23.22(19.85, 27.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.53(4.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003edofetilide*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e668\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e23.57(21.76, 25.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e21.46(19.84, 23.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e12980.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.41(4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003erecombinant human interleukin-11*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e19.87(7.97, 49.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e18.35(7.9, 42.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e82.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.2(2.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003esotalol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e19.13(16.31, 22.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e17.72(15.15, 20.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2593.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.14(3.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003emavacamten\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e18.71(15.96, 21.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e17.36(15.13, 19.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2549.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.11(3.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eflecainide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e18.31(15.67, 21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e17.02(14.84, 19.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2584.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e4.09(3.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ealdesleukin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e16.33(11.94, 22.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e15.3(11.4, 20.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e563.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.93(3.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eisoproterenol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e16.18(8.52, 30.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e15.17(8.26, 27.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e132.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.92(3.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003etheophylline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.68(10, 16.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.07(9.73, 14.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e733.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.59(3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eclevidipine*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.68(7.54, 21.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.06(7.39, 19.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e152.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.59(2.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003edisopyramide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.55(8.74, 18.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e11.94(8.56, 16.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e311.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.58(3.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003egadoversetamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12.2(7.69, 19.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e11.62(7.55, 17.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e185.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.54(2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ebisoprolol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e545\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e11.74(10.76, 12.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e11.21(10.36, 12.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5055.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.48(3.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ereteplase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e11.42(7.64, 17.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e10.92(7.38, 16.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e226.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.45(2.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eibrutinib*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e2906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e10.73(10.33, 11.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e10.3(9.9, 10.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e23627.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.32(3.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003elevothyroxine/liothyro\u003c/p\u003e\n \u003cp\u003e-nine*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e10.14(6.94, 14.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e9.75(6.85, 13.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e220.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.28(2.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eamiodarone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e771\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e9.1(8.46, 9.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.79(8.13, 9.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e5292.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.12(3.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ediltiazem*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.9(8.01, 9.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.6(7.8, 9.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2437.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.1(2.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ebendroflumethiazide*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.71(2.75, 27.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.43(2.76, 25.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e19.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.08(1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eomega-3-carboxylic acids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.39(3.09, 22.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.13(3.11, 21.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e25.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.02(1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eromidepsin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.35(6.09, 11.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.09(5.91, 11.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e249.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e3.01(2.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ebelumosudil mesylate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.22(3.87, 17.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.96(3.85, 16.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e42.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.99(1.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003ethyroid tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.11(5.82, 11.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.86(5.74, 10.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e216.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.97(2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eomaveloxolone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8.01(5.5, 11.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.77(5.35, 11.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e165.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.96(2.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003emigalastat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.95(4.67, 13.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.71(4.63, 12.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e82.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.95(2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003etrandolapril\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.91(5.06, 12.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.68(4.99, 11.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e116.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.94(2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003edenileukin diftitox\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.86(3.48, 17.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.63(3.48, 16.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e34.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.93(1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eetoricoxib*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.36(3.92, 13.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.16(3.9, 13.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e53.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.84(1.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eclofarabine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.25(5.74, 9.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e7.06(5.58, 8.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e380.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.82(2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eporfimer sodium*\u003c/p\u003e\n \u003c/td\u003e\n 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\u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 153px;\"\u003e\n \u003cp\u003eethyl icosapentate*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.37(4.31, 6.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e5.27(4.25, 6.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e277.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\n \u003cp\u003e2.4(2.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* the package insert suggest risk for A\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":"atrial fibrillation, drug-induced atrial fibrillation, FAERS, disproportionality analyses","lastPublishedDoi":"10.21203/rs.3.rs-6622422/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6622422/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction\u003c/p\u003e\n\u003cp\u003eDrug-induced atrial fibrillation is a serious adverse drug reaction (ADR) that occurs during the use of certain medications. The results of ADR signal detection derived from the analysis of a large number of reports, can help understand the safety profile of drugs and optimize clinical practice.Currently, there is a lack of comprehensive quantitative analysis of the major drugs that contribute to atrial fibrillation.\u003c/p\u003e\n\u003cp\u003eObjective\u003c/p\u003e\n\u003cp\u003eTo identify the primary drugs associated with atrial fibrillation and provide information for clinical practice.\u003c/p\u003e\n\u003cp\u003eMethod\u003c/p\u003e\n\u003cp\u003eWe used disproportionality analyses to assess the association between medications and AF adverse events.Data were extracted from the U.S. Food and Drug Administration Adverse Event Reporting System database from January 2004 through December 2024. This study analyzed the distribution of drug types and related drug indications associated with drug-induced AF.\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eFrom the first quarter of 2004 to the fourth quarter of 2024, there were a total of 118,074 adverse reaction reports on AF in the FAERS database. After setting screening criteria, we ultimately screened 80,289 AF-related reports and identified 156 medications associated with pharmacologic AF episodes.A wide range of drugs were reported, with cardiovascular system drugs, antineoplastic drugs and metabolic and endocrine drugs being the most common.Based on the number of reported cases,ibrutinib was the most commonly reported drug followed by rosiglitazone,sacubitril/valsartan,digoxin,dronedarone.Based on the ROR signal intensity,the highest signal intensity was dronedarone followed by eplantersen, propafenone,digoxin,dobutamine.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eOur study provides a real-world overview of drug-induced AF and a list of potential culprit drugs. We examined ADR signals, and the results of ADR signal detection and ADR signal distribution characteristics help to understand the safety profile of a drug and optimize clinical practice.\u003c/p\u003e","manuscriptTitle":"Drug-induced atrial fibrillation: A real-world pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-13 05:51:09","doi":"10.21203/rs.3.rs-6622422/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":"fdff4b22-8bb7-4e63-8f6a-1dc3abf064c2","owner":[],"postedDate":"June 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-05T09:09:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-13 05:51:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6622422","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6622422","identity":"rs-6622422","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}