Argatroban-associated adverse events: an analysis based on FDA adverse event reporting system (FAERS)

Argatroban-associated adverse events: an analysis based on FDA adverse event reporting system (FAERS) | 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 Argatroban-associated adverse events: an analysis based on FDA adverse event reporting system (FAERS) Changyu Ren, Tingting Chen, YiXuan Wang, Guimu Guo, Jintuo Zhou, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6926401/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Oct, 2025 Read the published version in Cardiovascular Toxicology → Version 1 posted 4 You are reading this latest preprint version Abstract Objective This study aims to mine and analyze adverse events (AEs) of argatroban based on the FAERS database to better understand its safety and potential risks in the real world. Methods Data from the first quarter of 2004 to the third quarter of 2024 were collected, and researchers employed various signal mining methods such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Results The study collected 54,336,884 reports of AEs, of which 2,233 were related to Argatroban. Signal mining identified 110 Preferred Terms involving 25 system organ classes. There were most reports involving adults (≥ 65 years), with a slightly higher proportion in men than women. We identified known AEs, including prolonged coagulation time, hemorrhage, abnormal hepatic function. New potential AE signals were identified, such as vascular pseudoaneurysm, retroperitoneal hematoma, gangrene, thrombotic thrombocytopenic purpura, acute cardiac failure, atrial septal defect, rhabdomyolysis. The median time to event (days): 2.00 with the majority of AEs occurring within 30 days. Conclusion Analysis of the FAERS database identified argatroban-associated AEs, including newly identified potential risks with the aim of enhancing clinicians' and pharmacists' awareness of drug-related risk signals and facilitate timely preventive and treatment interventions for patient safety. Argatroban FAERS Database Adverse events Signal mining Drug safety Figures Figure 1 Figure 2 Figure 3 1 Introduction Argatroban is a direct thrombin inhibitor administered intravenously and has the advantages of rapid onset of action, short duration of action, low bleeding tendency, and absence of immunogenicity [ 1 ] . Argatroban was first used in Japan in the early 1980s for the treatment of peripheral arterial occlusive disease, and was later approved for arterial thrombosis, acute ischemic stroke (AIS), and anticoagulation therapy for hemodialysis patients with antithrombin deficiency. In 2000, argatroban was approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of heparin-induced thrombocytopenia (HIT) in adults, including those requiring percutaneous coronary intervention (PCI). In 2005, it was approved by China's National Medical Products Administration (NMPA) for the treatment of AIS [ 2 ] . Additionally, Argatroban possesses not only anticoagulant effects but also demonstrates anti-inflammatory and antiviral pharmacological activities [ 3 ] . Among anticoagulant agents, argatroban is associated with relatively fewer reported bleeding events and has no documented cases of HIT [ 4 – 5 ] . Nevertheless, clinical experience with argatroban remains relatively limited, and its safety profile requires further investigation. For post-marketing safety surveillance of all FDA-approved drugs, the FDA Adverse Event Reporting System (FAERS) enables open, individual case reporting, which facilitates identification of potential drug-adverse event associations. This study used the FAERS database to detect argatroban-associated adverse drug event (AEs) signals with the aim of providing evidence-based references for rational clinical medication management. 2 Materials and Methods 2.1 Data source In this study, AEs reports in which argatroban served as the primary suspect drug were analyzed from the first quarter of 2004 to the third quarter of 2024. 2.2 Data standardization In this study, the preferred terms (PTs) derived from the Medical Dictionary for Regulatory Activities (MedDRA, version 27.1) were meticulously employed to code the names of adverse events documented in the FAERS database. All drug names in the database were standardized according to the WHO Drug Dictionary (March 2024 edition). Subsequently, we carried out the screening process using the standardized generic names, ensuring consistency and accuracy in the data analysis. 2.3 Data preprocessing The FAERS database relies on spontaneous reporting, which inherently contains duplicate entries and withdrawn reports. In accordance with FDA guidance documents (FDA, 2023), we rigorously applied the recommended deduplication algorithms and exclusion criteria for invalid reports during data cleaning. The data cleaning process adhered to the deduplication methods recommended by the FDA. This process utilized the fields PRIMARYID, CASEID, and FDA_DT from the DEMO table. Initially, all reports were sorted by CASEID. Subsequently, within subsets of reports sharing the same CASEID, they are sorted in descending order based on FDA_DT. Finally, among reports with both identical CASEID and FDA_DT, sorting is carried out in descending order of PRIMARYID. During this sorting procedure, for reports with the same CASEID, only the entry featuring the most recent FDA_DT is retained. In instances where both the CASEID and FDA_DT are identical across multiple reports, the report with the largest PRIMARYID is preserved. 2.4 Screening of target population In the database, each patient (represented by one report) has a unique drug designated as the "Primary Suspect (PS) Drug". When determining the population of individuals who used the target drug, only the one that served as the primary suspect for the patient was taken into consideration. In this study, we only included AEs in which argatroban was identified as the PS and presented the results based on this classification. 2.5 Disproportionate analysis This study conducted signal detection using disproportionality analysis methods including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), all based on 2×2 contingency table calculations (As shown in Supplementary Table S1 ). We identified positive signals when all the following thresholds were met: (1) a ≥ 3; (2) ROR 025 > 1; (3) PRR 025 > 1; (4) IC 025 > 0; and (5) EBGM 05 > 2(as shown in Supplementary Table S2). Higher signal values indicated stronger associations between argatroban and the corresponding AEs, thereby providing critical information about both the frequency and signal strength of AEs in this study. 2.6 Co-medication interaction analysis We conducted concomitant medication analysis by identifying cases where argatroban was used concurrently with other medications, focusing on the most frequently co-administered drugs associated with argatroban-related AEs. Drug-drug interactions were assessed using the Omega shrinkage measure (Ω) (As shown in Supplementary Table S3), which has been established as the most conservative method among various algorithms in prior research [ 6 ] . The detection threshold was set at a lower 95% confidence interval limit of Ω (Ω 025 ) > 0. 3 Results 3.1 Basic information on argatroban-associated adverse events After data cleaning, a total of 54,336,884 ADE reports were obtained from the first quarter of 2004 to the third quarter of 2024, including 2,233 argatroban-related cases (as shown in Supplementary Figure S1 ). As shown in Table 1 , the proportion of reports from males (47.55%) was slightly higher than from females (37.73%). The majority of reports involved adult population, particularly those over 65 years old. Most reports were submitted by healthcare professionals (including pharmacists and physicians), accounting for 82.87% of cases. The primary reporting countries were the United States (478 cases, 52.13%), followed by Japan and France. Regarding adverse event severity, 23.77% of cases resulted in death and 10.69% were life-threatening events. Table 1 Basic Information of Adverse Events Related to Argatroban Characteristics Case number(%) Gender Female 346(37.73) Male 436(47.55) Not Specified 135(14.72) Age < 18 17( 1.85) 18–44 111(12.10) 45–64 237(25.85) ≥ 65 333(36.31) NotSpecified 219(23.88) Reporting year 2004 9( 0.98) 2005 16( 1.74) 2006 43( 4.69) 2007 50( 5.45) 2008 33( 3.60) 2009 23( 2.51) 2010 182(19.85) 2011 66( 7.20) 2012 54( 5.89) 2013 33( 3.60) 2014 46( 5.02) 2015 40( 4.36) 2016 26( 2.84) 2017 47( 5.13) 2018 44( 4.80) 2019 62( 6.76) 2020 57( 6.22) 2021 25( 2.73) 2022 15( 1.64) 2023 26( 2.84) 2024 20( 2.18) Reported person Consumer 126(13.74) Lawyer 2( 0.22) Not Specified) 29( 3.16) Other health-professional 312(34.02) Pharmacist 263(28.68) Physician 185(20.17) Reported countries(top five) United States of America 478(52.13) Japan 262(28.57) France 54( 5.89) Germany 46( 5.02) Spain 9( 0.98) Serious report Serious 764(83.32) Non-Serious 153(16.68) Outcome Life-Threatening 98(10.69) Hospitalization - Initial or Prolonged 288(31.41) Disability 18( 1.96) Death 218(23.77) Congenital Anomaly 4( 0.44) Required Intervention to Prevent Permanent Impairment/Damage 21( 2.29) Other 400(43.62) 3.2 Comparison of SOCs involved in AEs signals Mining of AEs with argatroban as the primary suspected drug involved 25 SOCs, as detailed in Table 2 . Four SOCs met all four algorithm criteria simultaneously: investigations (ROR 025 = 4.16, PRR 025 = 3.48, IC 025 = 1.76, EBGM 05 = 3.41), vascular disorders (ROR 025 = 4.36, PRR 025 = 4.07, IC 025 = 1.98, EBGM 05 = 4.01), blood and lymphatic system disorders (ROR 025 = 3.86, PRR 025 = 3.69, IC 025 = 1.83, EBGM 05 = 3.64) and hepatobiliary disorders (ROR 025 = 2.89, PRR 025 = 2.84, IC 025 = 1.44, EBGM 05 = 2.82). Table 2 The signal intensity of ADEs at SOC level in the FAERS database System Organ Class(SOC) Case reports ROR(95% CI) PRR(95% CI) IC(IC025) EBGM(EBGM05) Investigations 516 4.59(4.16,5.06) 3.76(3.48,4.05) 1.91(1.76) 3.76(3.41) Vascular disorders 220 5.01(4.36,5.75) 4.61(4.07,5.23) 2.21(1.98) 4.61(4.01) General disorders and administration site conditions 213 0.50(0.43,0.57) 0.55(0.48,0.62) -0.87(-1.07) 0.55(0.47) Nervous system disorders 191 1.01(0.87,1.17) 1.01(0.88,1.15) 0.01(-0.21) 1.01(0.87) Injury, poisoning and procedural complications 168 0.71(0.60,0.83) 0.73(0.63,0.84) -0.46(-0.69) 0.73(0.62) Blood and lymphatic system disorders 161 4.53(3.86,5.32) 4.28(3.69,4.96) 2.10(1.83) 4.28(3.64) Gastrointestinal disorders 124 0.63(0.53,0.76) 0.65(0.55,0.77) -0.62(-0.88) 0.65(0.54) Cardiac disorders 117 2.04(1.69,2.46) 1.98(1.66,2.37) 0.99(0.70) 1.98(1.65) Respiratory, thoracic and mediastinal disorders 116 1.11(0.92,1.34) 1.10(0.92,1.32) 0.14(-0.13) 1.10(0.92) Infections and infestations 85 0.72(0.58,0.89) 0.73(0.59,0.90) -0.46(-0.77) 0.73(0.59) Hepatobiliary disorders 73 3.65(2.89,4.61) 3.56(2.84,4.47) 1.83(1.44) 3.56(2.82) Skin and subcutaneous tissue disorders 54 0.44(0.33,0.57) 0.45(0.35,0.59) -1.15(-1.53) 0.45(0.34) Renal and urinary disorders 44 1.03(0.77,1.39) 1.03(0.77,1.38) 0.05(-0.39) 1.03(0.77) Musculoskeletal and connective tissue disorders 27 0.22(0.15,0.33) 0.23(0.16,0.34) -2.10(-2.61) 0.23(0.16) Immune system disorders 25 1.02(0.69,1.51) 1.02(0.69,1.50) 0.03(-0.54) 1.02(0.69) Product issues 21 0.58(0.38,0.89) 0.58(0.38,0.89) -0.78(-1.37) 0.58(0.38) Surgical and medical procedures 19 0.63(0.40,0.99) 0.63(0.40,0.99) -0.66(-1.28) 0.63(0.40) Metabolism and nutrition disorders 15 0.30(0.18,0.51) 0.31(0.19,0.51) -1.69(-2.35) 0.31(0.19) Psychiatric disorders 11 0.08(0.05,0.15) 0.09(0.05,0.16) -3.52(-4.24) 0.09(0.05) Pregnancy, puerperium and perinatal conditions 10 1.04(0.56,1.94) 1.04(0.56,1.93) 0.06(-0.82) 1.04(0.56) Congenital, familial and genetic disorders 7 1.04(0.49,2.18) 1.04(0.50,2.17) 0.05(-0.98) 1.04(0.49) Eye disorders 6 0.13(0.06,0.30) 0.13(0.06,0.30) -2.89(-3.79) 0.14(0.06) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 4 0.07(0.02,0.18) 0.07(0.03,0.18) -3.88(-4.87) 0.07(0.03) Ear and labyrinth disorders 3 0.31(0.10,0.96) 0.31(0.10,0.96) -1.69(-2.86) 0.31(0.10) Reproductive system and breast disorders 3 0.15(0.05,0.46) 0.15(0.05,0.47) -2.73(-3.83) 0.15(0.05) Investigations 516 4.59(4.16,5.06) 3.76(3.48,4.05) 1.91(1.76) 3.76(3.41) Vascular disorders 220 5.01(4.36,5.75) 4.61(4.07,5.23) 2.21(1.98) 4.61(4.01) General disorders and administration site conditions 213 0.50(0.43,0.57) 0.55(0.48,0.62) -0.87(-1.07) 0.55(0.47) Nervous system disorders 191 1.01(0.87,1.17) 1.01(0.88,1.15) 0.01(-0.21) 1.01(0.87) Injury, poisoning and procedural complications 168 0.71(0.60,0.83) 0.73(0.63,0.84) -0.46(-0.69) 0.73(0.62) Blood and lymphatic system disorders 161 4.53(3.86,5.32) 4.28(3.69,4.96) 2.10(1.83) 4.28(3.64) Gastrointestinal disorders 124 0.63(0.53,0.76) 0.65(0.55,0.77) -0.62(-0.88) 0.65(0.54) Cardiac disorders 117 2.04(1.69,2.46) 1.98(1.66,2.37) 0.99(0.70) 1.98(1.65) Respiratory, thoracic and mediastinal disorders 116 1.11(0.92,1.34) 1.10(0.92,1.32) 0.14(-0.13) 1.10(0.92) Infections and infestations 85 0.72(0.58,0.89) 0.73(0.59,0.90) -0.46(-0.77) 0.73(0.59) Hepatobiliary disorders 73 3.65(2.89,4.61) 3.56(2.84,4.47) 1.83(1.44) 3.56(2.82) Skin and subcutaneous tissue disorders 54 0.44(0.33,0.57) 0.45(0.35,0.59) -1.15(-1.53) 0.45(0.34) Renal and urinary disorders 44 1.03(0.77,1.39) 1.03(0.77,1.38) 0.05(-0.39) 1.03(0.77) Musculoskeletal and connective tissue disorders 27 0.22(0.15,0.33) 0.23(0.16,0.34) -2.10(-2.61) 0.23(0.16) Immune system disorders 25 1.02(0.69,1.51) 1.02(0.69,1.50) 0.03(-0.54) 1.02(0.69) Product issues 21 0.58(0.38,0.89) 0.58(0.38,0.89) -0.78(-1.37) 0.58(0.38) Surgical and medical procedures 19 0.63(0.40,0.99) 0.63(0.40,0.99) -0.66(-1.28) 0.63(0.40) Metabolism and nutrition disorders 15 0.30(0.18,0.51) 0.31(0.19,0.51) -1.69(-2.35) 0.31(0.19) Psychiatric disorders 11 0.08(0.05,0.15) 0.09(0.05,0.16) -3.52(-4.24) 0.09(0.05) Pregnancy, puerperium and perinatal conditions 10 1.04(0.56,1.94) 1.04(0.56,1.93) 0.06(-0.82) 1.04(0.56) Congenital, familial and genetic disorders 7 1.04(0.49,2.18) 1.04(0.50,2.17) 0.05(-0.98) 1.04(0.49) Eye disorders 6 0.13(0.06,0.30) 0.13(0.06,0.30) -2.89(-3.79) 0.14(0.06) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 4 0.07(0.02,0.18) 0.07(0.03,0.18) -3.88(-4.87) 0.07(0.03) Ear and labyrinth disorders 3 0.31(0.10,0.96) 0.31(0.10,0.96) -1.69(-2.86) 0.31(0.10) Reproductive system and breast disorders 3 0.15(0.05,0.46) 0.15(0.05,0.47) -2.73(-3.83) 0.15(0.05) 3.3 Signal detects at the PT level There were a total of 110 risk signals of adverse reactions related to argatroban. When sorted by the frequency of occurrence, the top ten adverse events included international normalized ratio increased, activated partial thromboplastin time prolonged, coagulation time prolonged, hemorrhage, gastrointestinal haemorrhage, cerebral infarction, heparin-induced thrombocytopenia, thrombocytopenia, thrombosis and deep vein thrombosis. As shown in Fig. 1 , when sorted by the ROR, the top six AEs in terms of signal value were coagulation time prolonged (ROR 025 = 944.98, PRR 025 = 923.58, IC 025 = 5.62, EBGM 05 = 874.75), activated partial thromboplastin time abnormal (ROR 025 = 512.52, PRR 025 = 511.78, IC 025 = 2.37, EBGM 05 = 490.42), coagulation time abnormal (ROR 025 = 375.64, PRR 025 = 375.21, IC 025 = 2.17, EBGM 05 = 363.01), activated partial thromboplastin time shortened (ROR 025 = 254.26, PRR 025 = 253.98, IC 025 = 2.17, EBGM 05 = 248.15), hemorrhagic cerebral infarction (ROR 025 = 254.38, PRR 025 = 253.78, IC 025 = 2.85, EBGM 05 = 248.45), and Activated partial thromboplastin time prolonged (ROR 025 = 356.06, PRR 025 = 345.78, IC 025 = 5.79, EBGM 05 = 337.09), which were consistent with the drug label. In addition, although conditions such as vascular pseudoaneurysm (ROR 025 = 15.36, PRR 025 = 15.36, IC 025 = 0.47, EBGM 05 = 15.31), retroperitoneal hematoma (ROR 025 = 11.86, PRR 025 = 11.86, IC 025 = 0.44, EBGM 05 = 11.82), gangrene (ROR 025 = 9.13, PRR 025 = 9.13, IC 025 = 1.11, EBGM 05 = 9.10), thrombotic thrombocytopenic purpura (ROR 025 = 7.33, PRR 025 = 7.33, IC 025 = 0.38, EBGM 05 = 7.31), cardiac failure acute (ROR 025 = 4.14, PRR 025 = 4.14, IC 025 = 0.25, EBGM 05 = 4.13), atrial septal defect (ROR 025 = 2.97, PRR 025 = 2.97, IC 025 = 0.15, EBGM 05 = 2.96), and rhabdomyolysis (ROR 025 = 2.66, PRR 025 = 2.66, IC 025 = 0.88, EBGM 05 = 2.65) were rare, their signals were strong, which may indicate new AEs. The complete list of argatroban-associated ADR signals is provided in Supplementary Table S4. 3.3.1 Signal values associated with different group of sex The sex-stratified subgroup analysis demonstrated higher reported frequencies of hemorrhage (123 cases), abnormal hepatic function (50 cases), and coagulopathy (119 cases) in males compared to females (71, 36, and 94 cases respectively). In terms of signal strength, males showed strongest associations for prolonged coagulation time (ROR 025 = 433.96, PRR 025 = 428.71, IC 025 = 3.99, EBGM 05 = 408.22), coagulation factor V level decreased (ROR 025 = 175.51, PRR 025 = 175.50, IC 025 = 0.99, EBGM 05 = 169.68), and bronchial hemorrhage (ROR 025 = 171.58, PRR 025 = 171.57, IC 025 = 0.99, EBGM 05 = 166.00), while females exhibited the highest signals for coagulation time prolonged (ROR 025 = 1423.88, PRR 025 = 1384.74, IC 025 = 4.54, EBGM 05 = 1299.08), activated partial thromboplastin time abnormal (ROR 025 = 835.48, PRR 025 = 834.72, IC 025 = 1.36, EBGM 05 = 787.96), and hypofibrinogenemia (ROR 025 = 601.90, PRR 025 = 600.00, IC 025 = 2.18, EBGM 05 = 577.61), with detailed data available in Supplementary Table S5. 3.3.2 Signal values associated with different group of age The age-stratified analysis revealed significantly higher reported hemorrhage events in patients ≥ 65 years old (100 cases) compared to younger populations. From the value of the ROR signal, the strongest AEs signal in patients < 18 years was subarachnoid hemorrhage (ROR 025 = 197.73, PRR 025 = 198.92, IC 025 = 0.49, EBGM 05 = 184.85), while patients ≥ 65 years showed strongest associations for hemorrhagic cerebral infarction (ROR 025 = 303.16, PRR 025 = 301.27, IC 025 = 2.85, EBGM 05 = 288.00), followed by bronchial haemorrhage (ROR 025 = 134.01, PRR 025 = 134.06, IC 025 = 0.52, EBGM 05 = 129.66), with detailed data available in Supplementary Table S6. 3.4 Drug-interaction analysis Combined use of argatroban and norepinephrine was associated with adverse drug events showing enhanced signals, including leukocytosis (Ω 025 = 2.17), rhabdomyolysis (Ω 025 = 2.07), thrombocytopenia (Ω 025 = 1.65), and coagulopathy (Ω 025 = 1.16). Other significant drug interactions were identified with warfarin (Ω 025 = 1.38), aspirin (Ω 025 = 1.02), heparin (Ω 025 = 0.79), and edaravone (Ω 025 = 0.67), with complete interaction data provided in Supplementary Table S7. 3.5 Time-to-onset analysis Among 363 analyzable AEs reports with documented onset timing (after excluding spurious entries), the median time-to-onset was 2 days (interquartile range [IQR] 0–6 days) (Fig. 3 ). As illustrated in Fig. 2 , the overwhelming majority of AEs (n = 344, 94.77%) occurred within the first month of treatment initiation. 4 Discussion In earlier research, the primary focus was on the mechanism, clinical trials, and pharmacological properties of argatroban, but researchers paid limited attention to real-world evidence. This study leverages the FAERS database to mine and analyze safety signals for argatroban, aiming to explore its real-world safety and identify emerging significant argatroban-related AEs to guide safe clinical medication use. Argatroban is a univalent direct thrombin inhibitor that exerts competitive inhibition through selective and reversible binding to the catalytic site of thrombin, independent of the cofactor AT-Ⅲ [ 7 – 8 ] . Its pharmacokinetic profile remains unaffected by age, sex, or renal function, rendering it particularly suitable for patients with severe renal impairment.However, baseline information in this study revealed a slightly higher proportion of reports from male subjects than from females. The majority of reported cases were concentrated in adult populations, particularly those aged > 65 years. Sex-stratified subgroup analyses demonstrated higher reporting frequencies of hemorrhage, abnormal hepatic function, and coagulopathy among males, with particularly notable differences in hemorrhagic events. However, disproportionality analysis suggested stronger signal strength for coagulation disorders in female patients. Age-stratified analyses indicated a significantly higher incidence of hemorrhagic events in patients aged ≥ 65 years. Existing evidence suggests that age-related increases in vascular fragility and declining platelet function constitute major factors contributing to elevated bleeding risk in elderly populations [ 9 ] . Furthermore, the argatroban prescribing information notes that adverse drug reactions occur in 7.8% of elderly patients (> 65 years) during acute ischemic stroke treatment.These findings underscore the necessity for comprehensive bleeding risk assessment and development of individualized treatment regimens when administering argatroban to geriatric patients. Most AE reports originated from healthcare professionals, underscoring their key role in drug safety assessment and significantly enhancing the reliability of adverse event data. Notably, the reporting of serious AEs (e.g., death, disability, and prolonged hospitalization) highlights the need for careful patient monitoring during clinical use of argatroban. Timing analysis revealed that the peak risk period for AEs occurred within 30 days of drug initiation, particularly during the first 6 days, indicating that surveillance during early drug use should be strengthened to ensure timely detection and treatment of AEs. The study found that the high frequency of AEs induced by argatroban was mainly concentrated in the blood and lymphatic system, digestive system, cardiovascular system, and respiratory system.The analysis results showed a high consistency with the relevant descriptions in the package insert, which showed the accuracy and practicability of this study. However, AEs signals such as vascular pseudoaneurysm, retroperitoneal hematoma, gangrene, thrombotic thrombocytopenic purpura, acute cardiac failure, atrial septal defect, and rhabdomyolysis have been found in these systems, which may indicate new AEs. 4.1 Blood and lymphatic system-associated AEs Based on ROR signal strength analysis, the top six AEs were prolonged coagulation time, activated partial thromboplastin time abnormal, coagulation time abnormal, activated partial thromboplastin time shortened, and hemorrhagic cerebral infarction, which is highly consistent with the package insert. Hemorrhagic cerebral infarction was a serious adverse reaction stated in the drug label, and its incidence in the acute phase of ischemic cerebral infarction was 1.2%, with a higher incidence than expected. Therefore, when used in such patients, clinicians should closely monitor patients. The effect of argatroban on fibrinogen assay varied considerably, and the effect on factor VII or X was not as significant as that of factor IX and XI, resulting in non-specific coagulation time prolonged [ 10 , 11 ] . Many previous studies have shown that argatroban affects not only activated partial thromboplastin time (aPTT) and activated clotting time (ACT), but also INR. If combined warfarin has a greater increase in INR than warfarin alone, argatroban should be discontinued when INR exceeds 4 [ 12 , 18 ] . All these remind us that we should pay attention to the effect of argatroban on coagulation function in clinical treatment to avoid serious adverse events. Notably, argatroban is a direct thrombin inhibitor independent of AT-III and is therefore used as an alternative anticoagulant in patients with Heparin-induced thrombocytopenia (HIT). Argatroban was approved by the FDA in 2000 for the prevention and treatment of HIT in adults. However, studies have found thromboembolic events and major bleeding events in HIT patients treated with argatroban [ 13 , 15 – 16 ] . In this study, 30 cases of AEs were found to be HIT with strong signals. Although argatroban does not directly induce HIT, in some cases, patients may still have highly pathological IgG antibodies (HIT antibodies) after discontinuation of heparin, leading to continued platelet activation and the risk of blood clots. This may be attributed to either APTT confusions (HIT-related DIC causing APTT prolongation, which leads to systemic underdosing or interruption of argatroban therapy) or argatroban-mediated inhibition of thrombin-induced protein C activation [ 14 ] . Therefore, although argatroban is approved for the prevention and treatment of HIT, it may still cause or be associated with HIT-related thrombotic events under certain circumstances. 4.2 Other SOCs-associated AEs Analysis of the adverse event reports identified robust safety signals for hemorrhagic cerebral infarction, cerebral hemorrhage, gastrointestinal hemorrhage, anaphylactic shock (all of which are classified as "serious adverse reactions" in the Package Insert). Concomitantly, argatroban is contraindicated in patients with or suspected of having cerebral infarction [ 19 ] . Thrombosis-related AEs encompass aortic thrombosis, arterial embolism, vascular stent thrombosis, thrombosis in devices, cardiac ventricular thrombosis, vena cava thrombosis, limb venous thrombosis, peripheral artery thrombosis, superficial vein thrombosis, deep vein thrombosis. Based on the above-mentioned findings, argatroban demonstrates robust signal strength for thrombosis-related events, indicating a significant risk profile in this regard. Some studies have suggested that this may be related to fluctuations in anticoagulant intensity during the conversion from heparin to argatroban, which may lead to thrombotic events, and improper dose adjustment, resulting in poor anticoagulant effect and increased thrombosis risk [ 14 , 17 ] . Hepatobiliary system-related AEs include: ischemic hepatitis, hepatic failure, increased aspartate aminotransferase, abnormal liver function tests, increased blood alkaline phosphatase, hepatocellular injury, and liver disorder. Current evidence indicates that patients with abnormal liver function tests have reduced clearance rates, resulting in elevated plasma argatroban concentrations and more pronounced anticoagulant responses, as measured by aPTT and ACT. Research indicates that in all patients with suspected liver dysfunction due to the recent elevation of liver transaminase levels and concurrent renal failure, a decrease in the initial dosage of argatroban and careful titration of the infusion are mandatory [ 20 , 21 ] . Concomitantly, argatroban should be used with extreme caution in patients with severe hepatic impairment [ 19 ] . Gastrointestinal system-related AEs include: intestinal ischemia, gastrointestinal hemorrhage, and rectal hemorrhage. Notably, intestinal ischemia is not mentioned in the package insert. Concurrently, we identified unexpected safety signals including rhabdomyolysis, a potentially life-threatening condition characterized by skeletal muscle cell damage and the subsequent release of intracellular contents into the systemic circulation [ 22 ] . However, the causal relationship between rhabdomyolysis and argatroban remains unclear. In age-stratified subgroup analysis, rhabdomyolysis was found to occur between 45 and 64 years of age, and interaction results showed that the interaction between argatroban and norepinephrine resulted in an increased risk signal for rhabdomyolysis. Analysis of interactions suggests that the combination of argatroban with norepinephrine, warfarin, heparin and aspirin may increase the risk of bleeding, thrombosis and other adverse reactions. Some studies have found that the combination of argatroban and edaravone is ineffective and can lead to AEs such as cerebral infarction [ 23 ] , suggesting that drug interactions need to be carefully assessed during clinical practice and monitored and intervened accordingly. However, it is important to acknowledge the limitations inherent in this study design. As with any large registry-based study, there is a significant risk of bias due to the high volume of missing data. The significant amount of missing or anomalous data (60.41%) may affect the reliability of the results and could lead to skewed interpretations of the adverse event frequencies and severities. This is a common limitation of spontaneous reporting systems like the FAERS. Consequently, some events may not have been included in the database, leading to potential underestimation of certain AEs. Additionally, due to the lack of detailed individual patient information in the database, such as baseline health conditions, comorbidities, and concurrent medications, our understanding of the mechanisms behind AEs is limited. Future studies should aim to address these data gaps to provide a more accurate assessment of argatroban’s safety profile. 5 Conclusion This study confirmed several known AEs of argatroban, such as prolonged coagulation time, various sites hemorrhage, and abnormal hepatic function. It also revealed several new potential AEs, including pseudoaneurysm, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, atrial septal defect, rhabdomyolysis. These findings provide clinicians and pharmacists with an opportunity to deepen their understanding of argatroban and offer important guidance for the clinical use of argatroban. Future research should focus on exploring the specific mechanisms of these potential AEs and finding ways to minimize adverse reactions while ensuring therapeutic efficacy, thus providing safer and more effective therapeutic options for patients using argatroban. Declarations Funding This work was supported by Health Commission of Sichuan Province (No. 21PJ149) . Author contribution CYR conceived the project and supervised the project and drafted the muniscript. TTC were involved in the design of the study, took responsibility for the collection, integrity, and analysis of the data. YXW summed up the literature. GMG, JTZ and PGN provided the code of analysis and contributed to the collection and assembly of the data. JHZ were involved in the conception and design of the study. All authors have reviewed the manuscript and approved the final version. Data availability statement The data underlying this article will be shared upon reasonable request to the corresponding author. Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethical Approval Not applicable. Consent to Participate Not applicable. Consent for Publication Not applicable. References Ikoma, H. (2002). Development of argatroban as an anticoagulant and antithrombin agent in Japan[J]. Pathophysiology Of Haemostasis And Thrombosis , :(32 Suppl)3:23 – 8. David, A., Garcia,Trevor, P., Baglin, J. I., Weitz, et al. (2012). Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis,9th ed:American College of Chest Physicians evidence-based clinical practice guidelines[J]. Chest , 141 (2 Suppl), e24S–e43S. Kholoud, F., Aliter, Rami, A., & Al-Horani (2021). Thrombin inhibition by argatroban: potential therapeutic benefits in COVID-19[J]. Cardiovascular Drugs And Therapy , 35 (2), 195–203. LaMonte, M. P., Nash, M. L., Wang, D. Z., et al. (2004). Argatroban anticoagulation in patients with acute ischemic stroke(ARGIS-1): a randomized, placebo-controlled safety study[J]. Stroke , 35 (7), 1677–1682. Wada, T., Yasunage, H., Horiguchi, H., et al. (2016). Outcomes of argatroban treatment in patients with atherothrombotic stroke: observational nationwide study in Japan[J]. Stroke , 47 (2), 471–476. Noguchi, Y., Tachi, T., & Teramachi, H. (2020). Comparison of Signal Detection Algorithms Based on Frequency Statistical Model for Drug-Drug Interaction Using Spontaneous Reporting Systems[J]. Pharm Re , 37 (5), 86. Swan, S. K., & Hursting, M. J. (2000). The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction [. J] Pharmacotherapy , 20 (3), 318–329. Argatroban package insert[Internet]Available from: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/PrescribingInformating/Argatroban/pdf/ARGATROBAN . PDF. Accessed 18 Dec 2016. Kwaan, H. C., McMahon, B. J., Hylek, E. M., et al. (2014). Age-related changes in thrombosis and hemostasis[J]. Seminars In Thrombosis And Hemostasis , 40 (6), 619–620. Arsenault, K. A., Hirsh, J., Whitlock, R. P., et al. (2012). Direct thrombin inhibitors in cardiovascular disease[J]. Nature Reviews. Cardiology , 9 (7), 402–414. Siegmund, R., Boer, K., Poeschel, K., et al. (2008). Influence of direct thrombin inhibitor argatroban on coagulation assays in healthy individuals, patients under oral anticoagulation therapy and patients with liver dysfunction[J]. Blood Coagulation & Fibrinolysis , 19 (4), 288–293. Bartholomew, J. R., & Hursting, M. J. (2005). Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR)[J]. Journal of thrombosis and thrombolysis , 19 (3), 183–183. Lewis, B. E., Wallis, D. E., Berkowitz, S. D., et al. (2001). Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia[J]. Circulation , 103 (14), 1838–1843. Warkentin, T. E. (2023). Autoimmune Heparin-Induced Thrombocytopenia[J]. Journal of clinical medicine , 12 (21), 6921. Warkentin, T. E. (2022). How to dose and monitor argatroban for treatment of HIT[J]. British journal of haematology , 197 (6), 653–655. Tardy-Poncet, B., Nguyen, P., Thiranos, J. C. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial[J]. Critical care (London, England), 2015(19),:396. Ma, H., Zhang, Q., Gu, Y., et al. (2023). Argatroban Resistance and Successful Adjunctive Anticoagulation for Cerebral Venous Sinus Thrombosis With SERPINC1 Mutation: A Case Report[J]. Neurol Clin Pract , 13 (2), e200122. Xu jun tang (2007). Advances in the clinical use of argatroban[J]. Thrombosis and hemostasis , (04):180–182. Pharmaceutical Administration Committee of Chongqing Hospital Association. (2023). Expert consensus on prescription review rules of anticoagulants[J]. China Pharmacy , 34 (24), 2951–2967. Swan, S. K., & Hursting, M. J. (2000). The pharmacokinetics and pharmacodynamics of argatroban: effects of age, sex, and hepatic or renal dysfunction[J]. Pharmacotherapy , 20 (3), 318–329. Williamson, D. R., Boulanger, I., Tardif, M., et al. (2004). Argatroban dosing in intensive care patients with acute renal failure and liver dysfunction[J]. Pharmacotherapy , 24 (3), 409–414. Stahl, K., Rastelli, E., & Schoser, B. (2020). A systematic review on the definition of rhabdomyolysis[J]. Jounal of neuroloy , 267 (4), 877–882. Oguro, H., Mitaki, S., Takayoshi, H., et al. (2018). Retrospective Analysis of Argatroban in 353 Patients with Acute Noncardioembolic Stroke[J]. Jounal of stroke and cerebrovascular diseases , 27 (8), 2175–2181. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 17 Oct, 2025 Read the published version in Cardiovascular Toxicology → Version 1 posted Editorial decision: Revision requested 26 Jun, 2025 Editor assigned by journal 26 Jun, 2025 Submission checks completed at journal 20 Jun, 2025 First submitted to journal 18 Jun, 2025 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6926401","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":477121990,"identity":"ca6edbb7-aa58-4f5a-a275-743fdf0fbd86","order_by":0,"name":"Changyu Ren","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Changyu","middleName":"","lastName":"Ren","suffix":""},{"id":477121991,"identity":"512e686b-7e51-4502-b4ef-5c489472f716","order_by":1,"name":"Tingting Chen","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Chen","suffix":""},{"id":477121992,"identity":"85d5cec9-6a63-420e-b193-3c73448ddc60","order_by":2,"name":"YiXuan Wang","email":"","orcid":"","institution":"Chengdu Fifth People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"YiXuan","middleName":"","lastName":"Wang","suffix":""},{"id":477121993,"identity":"720fa001-8d1e-440f-a2e3-c1ed24ac6435","order_by":3,"name":"Guimu Guo","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guimu","middleName":"","lastName":"Guo","suffix":""},{"id":477121994,"identity":"3f42511b-e37b-464e-9118-9ebc8911fe64","order_by":4,"name":"Jintuo Zhou","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jintuo","middleName":"","lastName":"Zhou","suffix":""},{"id":477121995,"identity":"09851f65-475f-40be-b198-ace7a5bb5976","order_by":5,"name":"Peiguang Niu","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Peiguang","middleName":"","lastName":"Niu","suffix":""},{"id":477121996,"identity":"e5279bda-d618-42c9-a377-6a825b426d73","order_by":6,"name":"Jinhua Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYFAC5sYDDAwHQIwDBxIqbHj42RsIaWFsgGphS3zw4UyajGTPAaK18Bgbzmw5bGNwwwG/BnP2xobDPH/uyJvzLzCT5m04z8Nwg4Hxw8cc3Fosew4CtfA8M9w540GaNO+O2zyMsxuYJWduw63F4EYiUIvEYcYNNw4ck+Y9c5uHWeYAGzMvQS0Gh+033DjYJs3bdo6HTSKBGC0JhxM3nG9mNpzZdoCHh5AWkF8OzjlwOHnDDTZGYCAn80jwHGzG6xdz9uaDD978OWy74fz5D8CotLO3P9588MNHfA4DYiYeEEsiASbG2IBbPVQL4w8Qi/8AXoWjYBSMglEwggEAoSNjZcVYQu0AAAAASUVORK5CYII=","orcid":"","institution":"Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jinhua","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-06-19 00:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6926401/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6926401/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12012-025-10066-8","type":"published","date":"2025-10-17T15:57:45+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89656389,"identity":"1276627f-18b2-4af2-acf0-ed69629d8142","added_by":"auto","created_at":"2025-08-22 10:28:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":446876,"visible":true,"origin":"","legend":"\u003cp\u003eThe top 50 adverse event signal intensities sorted by ROR.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6926401/v1/891c42bce844bfc1b45f1d77.png"},{"id":89656387,"identity":"88347b77-c256-42f3-92fa-57026454c5d5","added_by":"auto","created_at":"2025-08-22 10:28:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61822,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution Map of the Onset Time of Adverse Reactions. The figure illustrates the distribution of AEs by time to event onset, categorized into specific time intervals. The left panel (blue bars) depicts the absolute number of cases for each time interval, while the right panel (red bars) represents the proportion of cases as a percentage of the total.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6926401/v1/a3463fd66a40b559ab95253b.png"},{"id":89657729,"identity":"dbfbcd0c-35ab-4ac4-8c26-2b12ef65f5b4","added_by":"auto","created_at":"2025-08-22 10:36:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":55037,"visible":true,"origin":"","legend":"\u003cp\u003eThe cumulative incidence rate of adverse events.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6926401/v1/b2a353b9e0e6dca80dbcb439.png"},{"id":93956136,"identity":"cf3a2a79-d6f6-4494-879b-96f607225cf4","added_by":"auto","created_at":"2025-10-20 16:11:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1692918,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6926401/v1/96572859-7809-43fe-bf93-9f687e2d68b6.pdf"},{"id":89656390,"identity":"4e7b354a-3547-4ecd-bb85-8d6492b27d62","added_by":"auto","created_at":"2025-08-22 10:28:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":277439,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6926401/v1/4c5629fb17bb33bdf2bc93ad.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Argatroban-associated adverse events: an analysis based on FDA adverse event reporting system (FAERS)","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eArgatroban is a direct thrombin inhibitor administered intravenously and has the advantages of rapid onset of action, short duration of action, low bleeding tendency, and absence of immunogenicity\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Argatroban was first used in Japan in the early 1980s for the treatment of peripheral arterial occlusive disease, and was later approved for arterial thrombosis, acute ischemic stroke (AIS), and anticoagulation therapy for hemodialysis patients with antithrombin deficiency. In 2000, argatroban was approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of heparin-induced thrombocytopenia (HIT) in adults, including those requiring percutaneous coronary intervention (PCI). In 2005, it was approved by China's National Medical Products Administration (NMPA) for the treatment of AIS\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Additionally, Argatroban possesses not only anticoagulant effects but also demonstrates anti-inflammatory and antiviral pharmacological activities\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Among anticoagulant agents, argatroban is associated with relatively fewer reported bleeding events and has no documented cases of HIT\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNevertheless, clinical experience with argatroban remains relatively limited, and its safety profile requires further investigation. For post-marketing safety surveillance of all FDA-approved drugs, the FDA Adverse Event Reporting System (FAERS) enables open, individual case reporting, which facilitates identification of potential drug-adverse event associations. This study used the FAERS database to detect argatroban-associated adverse drug event (AEs) signals with the aim of providing evidence-based references for rational clinical medication management.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data source\u003c/h2\u003e\u003cp\u003eIn this study, AEs reports in which argatroban served as the primary suspect drug were analyzed from the first quarter of 2004 to the third quarter of 2024.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data standardization\u003c/h2\u003e\u003cp\u003eIn this study, the preferred terms (PTs) derived from the Medical Dictionary for Regulatory Activities (MedDRA, version 27.1) were meticulously employed to code the names of adverse events documented in the FAERS database. All drug names in the database were standardized according to the WHO Drug Dictionary (March 2024 edition). Subsequently, we carried out the screening process using the standardized generic names, ensuring consistency and accuracy in the data analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Data preprocessing\u003c/h2\u003e\u003cp\u003eThe FAERS database relies on spontaneous reporting, which inherently contains duplicate entries and withdrawn reports. In accordance with FDA guidance documents (FDA, 2023), we rigorously applied the recommended deduplication algorithms and exclusion criteria for invalid reports during data cleaning.\u003c/p\u003e\u003cp\u003eThe data cleaning process adhered to the deduplication methods recommended by the FDA. This process utilized the fields PRIMARYID, CASEID, and FDA_DT from the DEMO table. Initially, all reports were sorted by CASEID. Subsequently, within subsets of reports sharing the same CASEID, they are sorted in descending order based on FDA_DT. Finally, among reports with both identical CASEID and FDA_DT, sorting is carried out in descending order of PRIMARYID. During this sorting procedure, for reports with the same CASEID, only the entry featuring the most recent FDA_DT is retained. In instances where both the CASEID and FDA_DT are identical across multiple reports, the report with the largest PRIMARYID is preserved.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Screening of target population\u003c/h2\u003e\u003cp\u003eIn the database, each patient (represented by one report) has a unique drug designated as the \"Primary Suspect (PS) Drug\". When determining the population of individuals who used the target drug, only the one that served as the primary suspect for the patient was taken into consideration. In this study, we only included AEs in which argatroban was identified as the PS and presented the results based on this classification.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Disproportionate analysis\u003c/h2\u003e\u003cp\u003eThis study conducted signal detection using disproportionality analysis methods including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), all based on 2\u0026times;2 contingency table calculations (As shown in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). We identified positive signals when all the following thresholds were met: (1) a\u0026thinsp;\u0026ge;\u0026thinsp;3; (2) ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;1; (3) PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;1; (4) IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0; and (5) EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;2(as shown in Supplementary Table S2). Higher signal values indicated stronger associations between argatroban and the corresponding AEs, thereby providing critical information about both the frequency and signal strength of AEs in this study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Co-medication interaction analysis\u003c/h2\u003e\u003cp\u003eWe conducted concomitant medication analysis by identifying cases where argatroban was used concurrently with other medications, focusing on the most frequently co-administered drugs associated with argatroban-related AEs. Drug-drug interactions were assessed using the Omega shrinkage measure (Ω) (As shown in Supplementary Table S3), which has been established as the most conservative method among various algorithms in prior research\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. The detection threshold was set at a lower 95% confidence interval limit of Ω (Ω\u003csub\u003e025\u003c/sub\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;0.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Basic information on argatroban-associated adverse events\u003c/h2\u003e\u003cp\u003eAfter data cleaning, a total of 54,336,884 ADE reports were obtained from the first quarter of 2004 to the third quarter of 2024, including 2,233 argatroban-related cases (as shown in Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the proportion of reports from males (47.55%) was slightly higher than from females (37.73%). The majority of reports involved adult population, particularly those over 65 years old. Most reports were submitted by healthcare professionals (including pharmacists and physicians), accounting for 82.87% of cases. The primary reporting countries were the United States (478 cases, 52.13%), followed by Japan and France. Regarding adverse event severity, 23.77% of cases resulted in death and 10.69% were life-threatening events.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBasic Information of Adverse Events Related to Argatroban\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase number(%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e346(37.73)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e436(47.55)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot Specified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e135(14.72)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e17( 1.85)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u0026ndash;44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e111(12.10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e45\u0026ndash;64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e237(25.85)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e333(36.31)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNotSpecified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e219(23.88)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporting year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9( 0.98)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16( 1.74)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43( 4.69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e50( 5.45)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33( 3.60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e23( 2.51)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e182(19.85)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e66( 7.20)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e54( 5.89)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33( 3.60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e46( 5.02)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40( 4.36)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e26( 2.84)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e47( 5.13)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e44( 4.80)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e62( 6.76)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57( 6.22)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25( 2.73)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15( 1.64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e26( 2.84)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20( 2.18)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReported person\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConsumer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e126(13.74)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLawyer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2( 0.22)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot Specified)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e29( 3.16)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther health-professional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e312(34.02)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePharmacist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e263(28.68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhysician\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e185(20.17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReported countries(top five)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited States of America\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e478(52.13)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e262(28.57)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFrance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e54( 5.89)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e46( 5.02)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9( 0.98)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerious report\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerious\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e764(83.32)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-Serious\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e153(16.68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLife-Threatening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e98(10.69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization - Initial or Prolonged\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e288(31.41)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18( 1.96)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e218(23.77)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongenital Anomaly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4( 0.44)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRequired Intervention to Prevent Permanent Impairment/Damage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21( 2.29)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e400(43.62)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Comparison of SOCs involved in AEs signals\u003c/h2\u003e\u003cp\u003eMining of AEs with argatroban as the primary suspected drug involved 25 SOCs, as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Four SOCs met all four algorithm criteria simultaneously: investigations (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.16, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.48, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.76, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.41), vascular disorders (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.36, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.07, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.98, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.01), blood and lymphatic system disorders (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.86, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.69, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.83, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.64) and hepatobiliary disorders (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.89, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.84, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.44, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.82).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe signal intensity of ADEs at SOC level in the FAERS database\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystem Organ Class(SOC)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase reports\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eROR(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRR(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIC(IC025)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eEBGM(EBGM05)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInvestigations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e516\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.59(4.16,5.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.76(3.48,4.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.91(1.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.76(3.41)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVascular disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.01(4.36,5.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.61(4.07,5.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.21(1.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.61(4.01)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e213\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.50(0.43,0.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.55(0.48,0.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.87(-1.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.55(0.47)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.01(0.87,1.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.01(0.88,1.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.01(-0.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.01(0.87)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e168\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.71(0.60,0.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.73(0.63,0.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.46(-0.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.73(0.62)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.53(3.86,5.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.28(3.69,4.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.10(1.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.28(3.64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.63(0.53,0.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.65(0.55,0.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.62(-0.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.65(0.54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e117\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.04(1.69,2.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.98(1.66,2.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.99(0.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.98(1.65)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e116\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.11(0.92,1.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.10(0.92,1.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.14(-0.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.10(0.92)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfections and infestations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.72(0.58,0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.73(0.59,0.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.46(-0.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.73(0.59)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatobiliary disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.65(2.89,4.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.56(2.84,4.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.83(1.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.56(2.82)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.44(0.33,0.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.45(0.35,0.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.15(-1.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.45(0.34)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal and urinary disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.03(0.77,1.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.03(0.77,1.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.05(-0.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.03(0.77)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.22(0.15,0.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.23(0.16,0.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-2.10(-2.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.23(0.16)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmune system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.02(0.69,1.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.02(0.69,1.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.03(-0.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.02(0.69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProduct issues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.58(0.38,0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.58(0.38,0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.78(-1.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.58(0.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical and medical procedures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.63(0.40,0.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.63(0.40,0.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.66(-1.28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.63(0.40)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.30(0.18,0.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.31(0.19,0.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.69(-2.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.31(0.19)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.08(0.05,0.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.09(0.05,0.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-3.52(-4.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.09(0.05)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePregnancy, puerperium and perinatal conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.04(0.56,1.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.04(0.56,1.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.06(-0.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.04(0.56)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongenital, familial and genetic disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.04(0.49,2.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.04(0.50,2.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.05(-0.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.04(0.49)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEye disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.13(0.06,0.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.13(0.06,0.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-2.89(-3.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.14(0.06)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.07(0.02,0.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.07(0.03,0.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-3.88(-4.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.07(0.03)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEar and labyrinth disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.31(0.10,0.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.31(0.10,0.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.69(-2.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.31(0.10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReproductive system and breast disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.15(0.05,0.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.15(0.05,0.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-2.73(-3.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.15(0.05)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInvestigations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e516\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.59(4.16,5.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.76(3.48,4.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.91(1.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.76(3.41)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVascular disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.01(4.36,5.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.61(4.07,5.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.21(1.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.61(4.01)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e213\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.50(0.43,0.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.55(0.48,0.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.87(-1.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.55(0.47)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.01(0.87,1.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.01(0.88,1.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.01(-0.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.01(0.87)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e168\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.71(0.60,0.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.73(0.63,0.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.46(-0.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.73(0.62)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.53(3.86,5.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.28(3.69,4.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.10(1.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.28(3.64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.63(0.53,0.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.65(0.55,0.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.62(-0.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.65(0.54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e117\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.04(1.69,2.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.98(1.66,2.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.99(0.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.98(1.65)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e116\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.11(0.92,1.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.10(0.92,1.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.14(-0.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.10(0.92)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfections and infestations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.72(0.58,0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.73(0.59,0.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.46(-0.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.73(0.59)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatobiliary disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.65(2.89,4.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.56(2.84,4.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.83(1.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.56(2.82)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.44(0.33,0.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.45(0.35,0.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.15(-1.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.45(0.34)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal and urinary disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.03(0.77,1.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.03(0.77,1.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.05(-0.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.03(0.77)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.22(0.15,0.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.23(0.16,0.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-2.10(-2.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.23(0.16)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmune system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.02(0.69,1.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.02(0.69,1.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.03(-0.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.02(0.69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProduct issues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.58(0.38,0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.58(0.38,0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.78(-1.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.58(0.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical and medical procedures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.63(0.40,0.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.63(0.40,0.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-0.66(-1.28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.63(0.40)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.30(0.18,0.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.31(0.19,0.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.69(-2.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.31(0.19)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.08(0.05,0.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.09(0.05,0.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-3.52(-4.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.09(0.05)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePregnancy, puerperium and perinatal conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.04(0.56,1.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.04(0.56,1.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.06(-0.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.04(0.56)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongenital, familial and genetic disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.04(0.49,2.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.04(0.50,2.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.05(-0.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.04(0.49)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEye disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.13(0.06,0.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.13(0.06,0.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-2.89(-3.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.14(0.06)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.07(0.02,0.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.07(0.03,0.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-3.88(-4.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.07(0.03)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEar and labyrinth disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.31(0.10,0.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.31(0.10,0.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-1.69(-2.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.31(0.10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReproductive system and breast disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.15(0.05,0.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.15(0.05,0.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e-2.73(-3.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.15(0.05)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Signal detects at the PT level\u003c/h2\u003e\u003cp\u003eThere were a total of 110 risk signals of adverse reactions related to argatroban. When sorted by the frequency of occurrence, the top ten adverse events included international normalized ratio increased, activated partial thromboplastin time prolonged, coagulation time prolonged, hemorrhage, gastrointestinal haemorrhage, cerebral infarction, heparin-induced thrombocytopenia, thrombocytopenia, thrombosis and deep vein thrombosis. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, when sorted by the ROR, the top six AEs in terms of signal value were coagulation time prolonged (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;944.98, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;923.58, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;5.62, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;874.75), activated partial thromboplastin time abnormal (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;512.52, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;511.78, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.37, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;490.42), coagulation time abnormal (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;375.64, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;375.21, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.17, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;363.01), activated partial thromboplastin time shortened (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;254.26, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;253.98, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.17, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;248.15), hemorrhagic cerebral infarction (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;254.38, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;253.78, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.85, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;248.45), and Activated partial thromboplastin time prolonged (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;356.06, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;345.78, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;5.79, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;337.09), which were consistent with the drug label. In addition, although conditions such as vascular pseudoaneurysm (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;15.36, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;15.36, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.47, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;15.31), retroperitoneal hematoma (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;11.86, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;11.86, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.44, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;11.82), gangrene (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;9.13, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;9.13, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.11, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;9.10), thrombotic thrombocytopenic purpura (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;7.33, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;7.33, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.38, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;7.31), cardiac failure acute (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.14, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.14, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.25, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.13), atrial septal defect (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.97, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.97, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.15, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.96), and rhabdomyolysis (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.66, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.66, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.88, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.65) were rare, their signals were strong, which may indicate new AEs. The complete list of argatroban-associated ADR signals is provided in Supplementary Table S4.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e3.3.1 Signal values associated with different group of sex\u003c/h2\u003e\u003cp\u003eThe sex-stratified subgroup analysis demonstrated higher reported frequencies of hemorrhage (123 cases), abnormal hepatic function (50 cases), and coagulopathy (119 cases) in males compared to females (71, 36, and 94 cases respectively). In terms of signal strength, males showed strongest associations for prolonged coagulation time (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;433.96, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;428.71, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.99, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;408.22), coagulation factor V level decreased (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;175.51, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;175.50, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.99, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;169.68), and bronchial hemorrhage (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;171.58, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;171.57, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.99, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;166.00), while females exhibited the highest signals for coagulation time prolonged (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1423.88, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1384.74, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.54, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1299.08), activated partial thromboplastin time abnormal (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;835.48, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;834.72, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.36, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;787.96), and hypofibrinogenemia (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;601.90, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;600.00, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.18, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;577.61), with detailed data available in Supplementary Table S5.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.3.2 Signal values associated with different group of age\u003c/h2\u003e\u003cp\u003eThe age-stratified analysis revealed significantly higher reported hemorrhage events in patients\u0026thinsp;\u0026ge;\u0026thinsp;65 years old (100 cases) compared to younger populations. From the value of the ROR signal, the strongest AEs signal in patients\u0026thinsp;\u0026lt;\u0026thinsp;18 years was subarachnoid hemorrhage (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;197.73, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;198.92, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.49, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;184.85), while patients\u0026thinsp;\u0026ge;\u0026thinsp;65 years showed strongest associations for hemorrhagic cerebral infarction (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;303.16, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;301.27, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.85, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;288.00), followed by bronchial haemorrhage (ROR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;134.01, PRR\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;134.06, IC\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.52, EBGM\u003csub\u003e05\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;129.66), with detailed data available in Supplementary Table S6.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Drug-interaction analysis\u003c/h2\u003e\u003cp\u003eCombined use of argatroban and norepinephrine was associated with adverse drug events showing enhanced signals, including leukocytosis (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.17), rhabdomyolysis (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.07), thrombocytopenia (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.65), and coagulopathy (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.16). Other significant drug interactions were identified with warfarin (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.38), aspirin (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.02), heparin (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.79), and edaravone (Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.67), with complete interaction data provided in Supplementary Table S7.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Time-to-onset analysis\u003c/h2\u003e\u003cp\u003eAmong 363 analyzable AEs reports with documented onset timing (after excluding spurious entries), the median time-to-onset was 2 days (interquartile range [IQR] 0\u0026ndash;6 days) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the overwhelming majority of AEs (n\u0026thinsp;=\u0026thinsp;344, 94.77%) occurred within the first month of treatment initiation.\u003c/p\u003e\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn earlier research, the primary focus was on the mechanism, clinical trials, and pharmacological properties of argatroban, but researchers paid limited attention to real-world evidence. This study leverages the FAERS database to mine and analyze safety signals for argatroban, aiming to explore its real-world safety and identify emerging significant argatroban-related AEs to guide safe clinical medication use.\u003c/p\u003e\n\u003cp\u003eArgatroban is a univalent direct thrombin inhibitor that exerts competitive inhibition through selective and reversible binding to the catalytic site of thrombin, independent of the cofactor AT-Ⅲ\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Its pharmacokinetic profile remains unaffected by age, sex, or renal function, rendering it particularly suitable for patients with severe renal impairment.However, baseline information in this study revealed a slightly higher proportion of reports from male subjects than from females. The majority of reported cases were concentrated in adult populations, particularly those aged\u0026thinsp;\u0026gt;\u0026thinsp;65 years. Sex-stratified subgroup analyses demonstrated higher reporting frequencies of hemorrhage, abnormal hepatic function, and coagulopathy among males, with particularly notable differences in hemorrhagic events. However, disproportionality analysis suggested stronger signal strength for coagulation disorders in female patients. Age-stratified analyses indicated a significantly higher incidence of hemorrhagic events in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years. Existing evidence suggests that age-related increases in vascular fragility and declining platelet function constitute major factors contributing to elevated bleeding risk in elderly populations\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Furthermore, the argatroban prescribing information notes that adverse drug reactions occur in 7.8% of elderly patients (\u0026gt;\u0026thinsp;65 years) during acute ischemic stroke treatment.These findings underscore the necessity for comprehensive bleeding risk assessment and development of individualized treatment regimens when administering argatroban to geriatric patients.\u003c/p\u003e\n\u003cp\u003eMost AE reports originated from healthcare professionals, underscoring their key role in drug safety assessment and significantly enhancing the reliability of adverse event data. Notably, the reporting of serious AEs (e.g., death, disability, and prolonged hospitalization) highlights the need for careful patient monitoring during clinical use of argatroban. Timing analysis revealed that the peak risk period for AEs occurred within 30 days of drug initiation, particularly during the first 6 days, indicating that surveillance during early drug use should be strengthened to ensure timely detection and treatment of AEs.\u003c/p\u003e\n\u003cp\u003eThe study found that the high frequency of AEs induced by argatroban was mainly concentrated in the blood and lymphatic system, digestive system, cardiovascular system, and respiratory system.The analysis results showed a high consistency with the relevant descriptions in the package insert, which showed the accuracy and practicability of this study. However, AEs signals such as vascular pseudoaneurysm, retroperitoneal hematoma, gangrene, thrombotic thrombocytopenic purpura, acute cardiac failure, atrial septal defect, and rhabdomyolysis have been found in these systems, which may indicate new AEs.\u003c/p\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003e4.1 Blood and lymphatic system-associated AEs\u003c/h2\u003e\n \u003cp\u003eBased on ROR signal strength analysis, the top six AEs were prolonged coagulation time, activated partial thromboplastin time abnormal, coagulation time abnormal, activated partial thromboplastin time shortened, and hemorrhagic cerebral infarction, which is highly consistent with the package insert. Hemorrhagic cerebral infarction was a serious adverse reaction stated in the drug label, and its incidence in the acute phase of ischemic cerebral infarction was 1.2%, with a higher incidence than expected. Therefore, when used in such patients, clinicians should closely monitor patients. The effect of argatroban on fibrinogen assay varied considerably, and the effect on factor VII or X was not as significant as that of factor IX and XI, resulting in non-specific coagulation time prolonged\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Many previous studies have shown that argatroban affects not only activated partial thromboplastin time (aPTT) and activated clotting time (ACT), but also INR. If combined warfarin has a greater increase in INR than warfarin alone, argatroban should be discontinued when INR exceeds 4\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. All these remind us that we should pay attention to the effect of argatroban on coagulation function in clinical treatment to avoid serious adverse events.\u003c/p\u003e\n \u003cp\u003eNotably, argatroban is a direct thrombin inhibitor independent of AT-III and is therefore used as an alternative anticoagulant in patients with Heparin-induced thrombocytopenia (HIT). Argatroban was approved by the FDA in 2000 for the prevention and treatment of HIT in adults. However, studies have found thromboembolic events and major bleeding events in HIT patients treated with argatroban\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. In this study, 30 cases of AEs were found to be HIT with strong signals. Although argatroban does not directly induce HIT, in some cases, patients may still have highly pathological IgG antibodies (HIT antibodies) after discontinuation of heparin, leading to continued platelet activation and the risk of blood clots. This may be attributed to either APTT confusions (HIT-related DIC causing APTT prolongation, which leads to systemic underdosing or interruption of argatroban therapy) or argatroban-mediated inhibition of thrombin-induced protein C activation\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Therefore, although argatroban is approved for the prevention and treatment of HIT, it may still cause or be associated with HIT-related thrombotic events under certain circumstances.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003e4.2 Other SOCs-associated AEs\u003c/h2\u003e\n \u003cp\u003eAnalysis of the adverse event reports identified robust safety signals for hemorrhagic cerebral infarction, cerebral hemorrhage, gastrointestinal hemorrhage, anaphylactic shock (all of which are classified as \u0026quot;serious adverse reactions\u0026quot; in the Package Insert). Concomitantly, argatroban is contraindicated in patients with or suspected of having cerebral infarction\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Thrombosis-related AEs encompass aortic thrombosis, arterial embolism, vascular stent thrombosis, thrombosis in devices, cardiac ventricular thrombosis, vena cava thrombosis, limb venous thrombosis, peripheral artery thrombosis, superficial vein thrombosis, deep vein thrombosis. Based on the above-mentioned findings, argatroban demonstrates robust signal strength for thrombosis-related events, indicating a significant risk profile in this regard. Some studies have suggested that this may be related to fluctuations in anticoagulant intensity during the conversion from heparin to argatroban, which may lead to thrombotic events, and improper dose adjustment, resulting in poor anticoagulant effect and increased thrombosis risk\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eHepatobiliary system-related AEs include: ischemic hepatitis, hepatic failure, increased aspartate aminotransferase, abnormal liver function tests, increased blood alkaline phosphatase, hepatocellular injury, and liver disorder. Current evidence indicates that patients with abnormal liver function tests have reduced clearance rates, resulting in elevated plasma argatroban concentrations and more pronounced anticoagulant responses, as measured by aPTT and ACT. Research indicates that in all patients with suspected liver dysfunction due to the recent elevation of liver transaminase levels and concurrent renal failure, a decrease in the initial dosage of argatroban and careful titration of the infusion are mandatory\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Concomitantly, argatroban should be used with extreme caution in patients with severe hepatic impairment\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Gastrointestinal system-related AEs include: intestinal ischemia, gastrointestinal hemorrhage, and rectal hemorrhage. Notably, intestinal ischemia is not mentioned in the package insert.\u003c/p\u003e\n \u003cp\u003eConcurrently, we identified unexpected safety signals including rhabdomyolysis, a potentially life-threatening condition characterized by skeletal muscle cell damage and the subsequent release of intracellular contents into the systemic circulation\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. However, the causal relationship between rhabdomyolysis and argatroban remains unclear. In age-stratified subgroup analysis, rhabdomyolysis was found to occur between 45 and 64 years of age, and interaction results showed that the interaction between argatroban and norepinephrine resulted in an increased risk signal for rhabdomyolysis.\u003c/p\u003e\n \u003cp\u003eAnalysis of interactions suggests that the combination of argatroban with norepinephrine, warfarin, heparin and aspirin may increase the risk of bleeding, thrombosis and other adverse reactions. Some studies have found that the combination of argatroban and edaravone is ineffective and can lead to AEs such as cerebral infarction\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, suggesting that drug interactions need to be carefully assessed during clinical practice and monitored and intervened accordingly.\u003c/p\u003e\n \u003cp\u003eHowever, it is important to acknowledge the limitations inherent in this study design. As with any large registry-based study, there is a significant risk of bias due to the high volume of missing data. The significant amount of missing or anomalous data (60.41%) may affect the reliability of the results and could lead to skewed interpretations of the adverse event frequencies and severities. This is a common limitation of spontaneous reporting systems like the FAERS. Consequently, some events may not have been included in the database, leading to potential underestimation of certain AEs. Additionally, due to the lack of detailed individual patient information in the database, such as baseline health conditions, comorbidities, and concurrent medications, our understanding of the mechanisms behind AEs is limited. Future studies should aim to address these data gaps to provide a more accurate assessment of argatroban\u0026rsquo;s safety profile.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThis study confirmed several known AEs of argatroban, such as prolonged coagulation time, various sites hemorrhage, and abnormal hepatic function. It also revealed several new potential AEs, including pseudoaneurysm, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, atrial septal defect, rhabdomyolysis. These findings provide clinicians and pharmacists with an opportunity to deepen their understanding of argatroban and offer important guidance for the clinical use of argatroban. Future research should focus on exploring the specific mechanisms of these potential AEs and finding ways to minimize adverse reactions while ensuring therapeutic efficacy, thus providing safer and more effective therapeutic options for patients using argatroban.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Health Commission of Sichuan Province (No. 21PJ149) .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCYR conceived the project and supervised the project and drafted the muniscript. TTC were involved in the design of the study, took responsibility for the collection, integrity, and analysis of the data. YXW summed up the literature. GMG, JTZ and PGN provided the code of analysis and contributed to the collection and assembly of the data. JHZ were involved in the conception and design of the study. All authors have reviewed the manuscript and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data underlying this article will be shared upon reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIkoma, H. (2002). Development of argatroban as an anticoagulant and antithrombin agent in Japan[J]. \u003cem\u003ePathophysiology Of Haemostasis And Thrombosis\u003c/em\u003e, :(32 Suppl)3:23\u0026thinsp;\u0026ndash;\u0026thinsp;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavid, A., Garcia,Trevor, P., Baglin, J. I., Weitz, et al. (2012). Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis,9th ed:American College of Chest Physicians evidence-based clinical practice guidelines[J]. \u003cem\u003eChest\u003c/em\u003e, \u003cem\u003e141\u003c/em\u003e(2 Suppl), e24S\u0026ndash;e43S.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKholoud, F., Aliter, Rami, A., \u0026amp; Al-Horani (2021). Thrombin inhibition by argatroban: potential therapeutic benefits in COVID-19[J]. \u003cem\u003eCardiovascular Drugs And Therapy\u003c/em\u003e, \u003cem\u003e35\u003c/em\u003e(2), 195\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaMonte, M. P., Nash, M. L., Wang, D. Z., et al. (2004). Argatroban anticoagulation in patients with acute ischemic stroke(ARGIS-1): a randomized, placebo-controlled safety study[J]. \u003cem\u003eStroke\u003c/em\u003e, \u003cem\u003e35\u003c/em\u003e(7), 1677\u0026ndash;1682.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWada, T., Yasunage, H., Horiguchi, H., et al. (2016). Outcomes of argatroban treatment in patients with atherothrombotic stroke: observational nationwide study in Japan[J]. \u003cem\u003eStroke\u003c/em\u003e, \u003cem\u003e47\u003c/em\u003e(2), 471\u0026ndash;476.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNoguchi, Y., Tachi, T., \u0026amp; Teramachi, H. (2020). Comparison of Signal Detection Algorithms Based on Frequency Statistical Model for Drug-Drug Interaction Using Spontaneous Reporting Systems[J]. \u003cem\u003ePharm Re\u003c/em\u003e, \u003cem\u003e37\u003c/em\u003e(5), 86.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSwan, S. K., \u0026amp; Hursting, M. J. (2000). The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction [. \u003cem\u003eJ] Pharmacotherapy\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e(3), 318\u0026ndash;329.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArgatroban package insert[Internet]Available from:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/PrescribingInformating/Argatroban/pdf/ARGATROBAN\u003c/span\u003e\u003cspan address=\"https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/PrescribingInformating/Argatroban/pdf/ARGATROBAN\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PDF. Accessed 18 Dec 2016.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKwaan, H. C., McMahon, B. J., Hylek, E. M., et al. (2014). Age-related changes in thrombosis and hemostasis[J]. \u003cem\u003eSeminars In Thrombosis And Hemostasis\u003c/em\u003e, \u003cem\u003e40\u003c/em\u003e(6), 619\u0026ndash;620.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArsenault, K. A., Hirsh, J., Whitlock, R. P., et al. (2012). Direct thrombin inhibitors in cardiovascular disease[J]. \u003cem\u003eNature Reviews. Cardiology\u003c/em\u003e, \u003cem\u003e9\u003c/em\u003e(7), 402\u0026ndash;414.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSiegmund, R., Boer, K., Poeschel, K., et al. (2008). Influence of direct thrombin inhibitor argatroban on coagulation assays in healthy individuals, patients under oral anticoagulation therapy and patients with liver dysfunction[J]. \u003cem\u003eBlood Coagulation \u0026amp; Fibrinolysis\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(4), 288\u0026ndash;293.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBartholomew, J. R., \u0026amp; Hursting, M. J. (2005). Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR)[J]. \u003cem\u003eJournal of thrombosis and thrombolysis\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(3), 183\u0026ndash;183.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLewis, B. E., Wallis, D. E., Berkowitz, S. D., et al. (2001). Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia[J]. \u003cem\u003eCirculation\u003c/em\u003e, \u003cem\u003e103\u003c/em\u003e(14), 1838\u0026ndash;1843.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWarkentin, T. E. (2023). Autoimmune Heparin-Induced Thrombocytopenia[J]. \u003cem\u003eJournal of clinical medicine\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(21), 6921.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWarkentin, T. E. (2022). How to dose and monitor argatroban for treatment of HIT[J]. \u003cem\u003eBritish journal of haematology\u003c/em\u003e, \u003cem\u003e197\u003c/em\u003e(6), 653\u0026ndash;655.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTardy-Poncet, B., Nguyen, P., Thiranos, J. C. Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial[J]. Critical care (London, England), 2015(19),:396.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMa, H., Zhang, Q., Gu, Y., et al. (2023). Argatroban Resistance and Successful Adjunctive Anticoagulation for Cerebral Venous Sinus Thrombosis With SERPINC1 Mutation: A Case Report[J]. \u003cem\u003eNeurol Clin Pract\u003c/em\u003e, \u003cem\u003e13\u003c/em\u003e(2), e200122.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXu jun tang (2007). Advances in the clinical use of argatroban[J]. \u003cem\u003eThrombosis and hemostasis\u003c/em\u003e, (04):180\u0026ndash;182.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePharmaceutical Administration Committee of Chongqing Hospital Association. (2023). Expert consensus on prescription review rules of anticoagulants[J]. \u003cem\u003eChina Pharmacy\u003c/em\u003e, \u003cem\u003e34\u003c/em\u003e(24), 2951\u0026ndash;2967.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSwan, S. K., \u0026amp; Hursting, M. J. (2000). The pharmacokinetics and pharmacodynamics of argatroban: effects of age, sex, and hepatic or renal dysfunction[J]. \u003cem\u003ePharmacotherapy\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e(3), 318\u0026ndash;329.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWilliamson, D. R., Boulanger, I., Tardif, M., et al. (2004). Argatroban dosing in intensive care patients with acute renal failure and liver dysfunction[J]. \u003cem\u003ePharmacotherapy\u003c/em\u003e, \u003cem\u003e24\u003c/em\u003e(3), 409\u0026ndash;414.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStahl, K., Rastelli, E., \u0026amp; Schoser, B. (2020). A systematic review on the definition of rhabdomyolysis[J]. \u003cem\u003eJounal of neuroloy\u003c/em\u003e, \u003cem\u003e267\u003c/em\u003e(4), 877\u0026ndash;882.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOguro, H., Mitaki, S., Takayoshi, H., et al. (2018). Retrospective Analysis of Argatroban in 353 Patients with Acute Noncardioembolic Stroke[J]. \u003cem\u003eJounal of stroke and cerebrovascular diseases\u003c/em\u003e, \u003cem\u003e27\u003c/em\u003e(8), 2175\u0026ndash;2181.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cato","sideBox":"Learn more about [Cardiovascular Toxicology](http://link.springer.com/journal/12012)","snPcode":"12012","submissionUrl":"https://submission.nature.com/new-submission/12012/3","title":"Cardiovascular Toxicology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Argatroban, FAERS Database, Adverse events, Signal mining, Drug safety","lastPublishedDoi":"10.21203/rs.3.rs-6926401/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6926401/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study aims to mine and analyze adverse events (AEs) of argatroban based on the FAERS database to better understand its safety and potential risks in the real world.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eData from the first quarter of 2004 to the third quarter of 2024 were collected, and researchers employed various signal mining methods such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe study collected 54,336,884 reports of AEs, of which 2,233 were related to Argatroban. Signal mining identified 110 Preferred Terms involving 25 system organ classes. There were most reports involving adults (\u0026ge;\u0026thinsp;65 years), with a slightly higher proportion in men than women. We identified known AEs, including prolonged coagulation time, hemorrhage, abnormal hepatic function. New potential AE signals were identified, such as vascular pseudoaneurysm, retroperitoneal hematoma, gangrene, thrombotic thrombocytopenic purpura, acute cardiac failure, atrial septal defect, rhabdomyolysis. The median time to event (days): 2.00 with the majority of AEs occurring within 30 days.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAnalysis of the FAERS database identified argatroban-associated AEs, including newly identified potential risks with the aim of enhancing clinicians' and pharmacists' awareness of drug-related risk signals and facilitate timely preventive and treatment interventions for patient safety.\u003c/p\u003e","manuscriptTitle":"Argatroban-associated adverse events: an analysis based on FDA adverse event reporting system (FAERS)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 10:28:51","doi":"10.21203/rs.3.rs-6926401/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-27T02:09:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-27T01:48:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-20T13:51:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Toxicology","date":"2025-06-19T00:46:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cato","sideBox":"Learn more about [Cardiovascular Toxicology](http://link.springer.com/journal/12012)","snPcode":"12012","submissionUrl":"https://submission.nature.com/new-submission/12012/3","title":"Cardiovascular Toxicology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"51f34c16-8218-4b6e-a9d3-b2e8e6c399e5","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:06:37+00:00","versionOfRecord":{"articleIdentity":"rs-6926401","link":"https://doi.org/10.1007/s12012-025-10066-8","journal":{"identity":"cardiovascular-toxicology","isVorOnly":false,"title":"Cardiovascular Toxicology"},"publishedOn":"2025-10-17 15:57:45","publishedOnDateReadable":"October 17th, 2025"},"versionCreatedAt":"2025-08-22 10:28:51","video":"","vorDoi":"10.1007/s12012-025-10066-8","vorDoiUrl":"https://doi.org/10.1007/s12012-025-10066-8","workflowStages":[]},"version":"v1","identity":"rs-6926401","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6926401","identity":"rs-6926401","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}