Effect of SGLT2 Inhibitor Dapagliflozin on Biomarkers of Tubular Injury in Patients with Acute Heart Failure: A Randomized Controlled Trial

Effect of SGLT2 Inhibitor Dapagliflozin on Biomarkers of Tubular Injury in Patients with Acute Heart Failure: A Randomized Controlled Trial | 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 Effect of SGLT2 Inhibitor Dapagliflozin on Biomarkers of Tubular Injury in Patients with Acute Heart Failure: A Randomized Controlled Trial Pongsathorn Gojaseni, Jananya Wattanakul, Anan Chuasuwan, Anutra Chittinandana This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3869067/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in acute heart failure (AHF) but are associated with a transient rise in serum creatinine. The aim of this study was to assess the effect of SGLT2 inhibitor on urinary biomarkers of tubular injury in patients with AHF. Patients who hospitalized for AHF were randomized to dapagliflozin added to standard of care or control group for 28 days. The primary outcome was the change of urinary [TIMP-2] x [IGFBP7] by NephroCheck ® from baseline. Out of the 32 patients who underwent randomization, 25 eligible individuals were enrolled for analysis. Compared with control group, dapagliflozin group significantly reduced urinary [TIMP-2] x [IGFBP7] after 7 days [dapagliflozin: -0.03 ± 0.11 (ng/mL) 2 /1000; control: +0.4 ± 0.14 (ng/mL) 2 /1000; P = 0.022] and continue this trend until the end of the study. In terms of clinical outcomes, dapagliflozin has demonstrated a trend towards decrease in acute kidney injury (AKI) events compared to the control group (33.3% vs 46.2%; P = 0.513). The changes in serum creatinine, and adverse events showed no differences in either group. In conclusion, initiation of SGLT2 inhibitors in patients with AHF significantly decrease the urinary AKI risk markers TIMP-2 and IGFBP7, that supported protective effect of SGLT2 inhibitor on renal tubular injury. Trial registration number: The study was registered with the Thai Clinical Trials Registry TCTR20221003002. Health sciences/Nephrology/Kidney diseases/Acute kidney injury Health sciences/Medical research/Biomarkers/Prognostic markers Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Heart failure acute heart failure acute kidney injury biomarkers of tubular injury SGLT2 inhibitor Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Acute kidney injury (AKI) in acute heart failure (AHF) or cardiorenal syndrome type 1 is common and associated with poor prognosis (1-3) . Current treatment options for AHF mainly focus on relieving symptoms and reducing fluid overload, which can have potentially harmful effects on kidney function. Consequently, there is a need for the development of novel and inventive therapies aimed at improving both cardiovascular and kidney outcomes in individuals with AHF. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a disease-modifying therapy to reduce cardiovascular events and prevent the progression of chronic kidney disease (CKD) (4-14) . The rapid growth of clinical trials on SGLT2 inhibitors has expanded the approved clinical indications for these agents. The recent clinical trials (15-18) have shown that SGLT2 inhibitor have reduced the risk of cardiovascular death in the setting of AHF. Additionally, it was observed that the occurrence of AKI within the first 3 months might be less common in the SGLT2 inhibitor group compared to the placebo group in clinically stable patients hospitalized for AHF (18) . Several hypotheses have been postulated to explain the mechanism by which SGLT2 inhibitors prevent AKI, as it cannot be attributed to a reduction in glomerular pressure. A previous animal study showed that SGLT2 inhibitors can improve renal cortical oxygen tension, which might help to improve tubular cell integrity ( 19) . Furthermore, SGLT2 inhibitors have the potential to enhance the expression of hypoxia-inducible factor 1 (HIF1) resulting in an augmentation of erythropoietin production (20) . Despite the growing evidence of benefits, physicians are still hesitant to prescribe SGLT2 inhibitors to AHF patients during their hospitalization primarily due to the transient rise in serum creatinine ( 21) . Nevertheless, there are limitations associated with employing serum creatinine as a diagnostic tool for detecting AKI in the context of AHF due to its delayed response as a marker of tubular injury (22) . Moreover, increase serum creatinine level in AKI does not always indicate renal tubular cell injury. As a result, many tubular injury biological markers have been used for the early detection of AKI in this setting. Of these, the use of tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin-like growth factor-binding protein 7 [IGFBP-7] is one of the most evidence-based (23) . Several studies demonstrated that using urinary [TIMP-2] x [IGFBP-7] can accurately predict AKI in patients hospitalized for AHF when using cut-off point more than 0.3 (ng/ml) 2 /1000 ( 24) . In this study, we investigated the protective effect of SGLT2 inhibitor on tubular injury biomarkers (urinary [TIMP-2] x [IGFBP-7]) in patients hospitalized for AHF. The primary objective of this study was to compare the change of urinary [TIMP-2] x [IGFBP-7] in SGLT2 inhibitor add on to standard of care with standard of care alone. The incident of AKI, change from baseline serum creatinine, length of stays, cumulative urine output, and adverse events were also assessed. MATERIAL AND METHODS Study design We conducted a randomized prospective open-label controlled trial of patients hospitalized for AHF in Bhumibol Adulyadej Hospital, Directorate of Medical Services, Royal Thai Air Force. The study protocol was approved by the Institutional Review Board of Bhumibol Adulyadej Hospital with approval number 46/65 and was registered in the Thai Clinical Trials Registry (TCTR) with registration number TCTR20221003002. This study was conducted in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The investigators informed patients or their surrogates concerning the study orally and written informed consent was given before entry into the study. Inclusion criteria were aged ≥ 18 years, presence of AHF requiring hospital admission as well as serum level of N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 1600 pg/ml or ≥ 2000 pg/ml in patients with atrial fibrillation regardless of ejection fraction or diabetes status. Key exclusion criteria were: patients with type 1 diabetes, history of diabetic ketoacidosis or ketosis, estimated glomerular filtration rate by the CKD Epidemiology Collaboration [eGFR (CKD-EPI)] < 30 ml/min/1.73m 2 , patients with cardiogenic shock, septic shock or systolic blood pressure < 100 mmHg, patients with intravenous vasopressor, vasodilators or inotropic drugs within 6 hours, planned for percutaneous coronary intervention therapy, acidemia (blood pH < 7.2), and liver failure. In terms of calculating the sample size, the following assumptions were considered: power 0.8, alpha 0.05, and standard deviation of urinary [TIMP-2] x [IGFBP-7] of 0.47 (ng/ml) 2 /1000. From these assumptions, a total sample size of 22 would enable the detection of a 0.6 (ng/ml) 2 /1000 difference in the change from baseline of urinary [TIMP-2] x [IGFBP-7] based on Thiele K, et al. (25) . Primary and secondary outcomes The primary outcome of this study is the change from baseline of urinary [TIMP-2] x [IGFBP-7]. Statistical analysis was based on detecting a difference in urinary [TIMP-2] x [IGFBP-7] change from baseline between the dapagliflozin group and controls. The secondary outcome is the incidence of AKI by KDIGO creatinine criteria, the change from baseline creatinine, length of stays, cumulative urine output, and adverse events. Trial procedures Patients were randomized into 2 groups using a random block of 4 allocation method to receive either dapagliflozin 10 mg on top of standard of care within 24 hours after enrollment (dapagliflozin group) or standard of care alone (control group). Baseline information including demographic data, comorbidities and current medication were recorded. Laboratory investigations were performed at baseline and 1 day, 2 days, 3 days, 7 days, 14 days, and 28 days following treatment initiation as shown in Figure 1 . The urine sample was collected then centrifuged and frozen at -80 °C and then urinary [TIMP-2] x [IGFBP-7] was performed by NephroCheck ® using the VITROS 5600 Integrated System (Astute Medical, San Diego, CA, USA) at baseline, on day 7, and on day 28. The outcome including length of stay, cumulative urine output, adverse events including the gastrointestinal system, urinary tract infection, electrolyte imbalance, discontinuation of treatment and date of death were collected. All patients received treatment in accordance with the ESC guidelines for the diagnosis and treatment of acute heart failure (26) . Relevant Definition Kidney disease improving global outcome (KDIGO) serum creatinine criteria were used to classify AKI status (27) . The baseline serum creatinine was the first creatinine recorded on the day of enrolment. AHF refers to heart failure that occurs suddenly or a stable condition that then becomes worse within a short period of time, according to the criteria of the European Society of Cardiology guidelines (ESC) (26) . Statistical Analysis The study used IBM SPSS Statistics Version 22 (Chicago, IL, USA) program for data analysis and data processing. The categorical data were reported as the number with a percentage. The continuous data were reported as mean ± standard deviation (SD), mean ± standard error (SE), or median (interquartile range, IQR) as appropriate. Fisher’s exact test or Chi-square test were used for categorical variable and student’s t-test or Mann Whitney U test for continuous variable. We used a P value < 0.05 as statistically significant. RESULTS Baseline characteristics The enrollment period took place from August 2022 to January 2023. Out of the initial 32 patients who underwent randomization, seven were subsequently excluded from the study due to incomplete biochemical data in the first week, comprising 5 cases discharged and 2 case died. Consequently, 25 eligible patients were enrolled for analysis (12 dapagliflozin, 13 control). The mean age was 67.1 ± 15.1 years, 48.5% were male, the mean ejection fraction was 42.1 ± 16.5% and the median NT-proBNP was 5,359 pg/ml (interquartile range 3,496 – 10,843). Other underlying diseases and medications at baseline were balanced between treatment groups as shown in Table 1 . Effect of dapagliflozin on tubular injury markers The mean ± standard error (SE) of urinary [TIMP-2] x [IGFBP-7] in the dapagliflozin and control group were 0.223 ± 0.165 vs 0.073 ± 0.048 (P = 0.340) at the enrollment. Compared with control group, dapagliflozin group significantly reduced urinary [TIMP-2] x [IGFBP7] after 7 days [dapagliflozin: -0.03 ± 0.11 (ng/mL) 2 /1000; control: +0.4 ± 0.14 (ng/mL) 2 /1000; P = 0.022]. After a 28-day follow-up period, 7 patients (3 in the dapagliflozin, 4 in the control group) were discharged home and 2 patients died (1 from each group), leaving a total of 16 patients with complete data available. The mean change in urinary [TIMP-2] x [IGFBP-7] in dapagliflozin group tended to be decreased compared to controls. [dapagliflozin: -0.09 ± 0.28 (ng/mL) 2 /1000; control: +0.67 ± 0.32 (ng/mL) 2 /1000; P = 0.096] (Figure 2) . Furthermore, we conducted additional analysis using a threshold of 0.3 (ng/ml) 2 /1000, a value that showed a strong association with AKI. We observed a trend where the number of patients with urinary [TIMP-2] x [IGFBP-7] levels exceeding 0.3 was slightly lower in the dapagliflozin group, although this difference did not reach statistically significance (25.0% vs 53.8%, P = 0.288). (Table 2) Effect of dapagliflozin on secondary outcomes Incidence of AKI by serum creatinine from KDIGO criteria in the dapagliflozin and control group was 33.3% and 46.2%, respectively (P = 0.513). All cases of AKI were KDIGO stage 1 (Table 2). Further analyses showed no difference between the dapagliflozin and control group for the change from baseline serum creatinine, length of stay, and adverse events. (Table 2 and Figure 3). The cumulative urine output during the first 3 days was not statistically different between both groups (8,587 ± 1,346 vs 8,060 ± 1,090 ml; P=0.420). (Figure 4). However, dapagliflozin group demonstrated a trend towards lower cumulative furosemide dose compared with control group. [61.94 ± 10.37 vs 104.62 ± 21.92 mg/day; P=0.100]. DISCUSSION This study demonstrated that initiation of dapagliflozin significantly decrease urine [TIMP-2] x [IGFBP7] during the first week, that supported the protective effect of SGLT2 inhibitor on renal tubular injury. The results are consistent with study from Thiele K, et al. that showed the reduction of urine [TIMP-2] x [IGFBP7] after initiation of empagliflozin in AHF patients for 3 days (25) . Thus, we may conclude that SGLT2 inhibitor can improve tubular cell injury in patients hospitalized for acute heart failure since urinary [TIMP-2] x [IGFBP-7] is the biomarker of cell cycle arrest during the early phase of tubular damage. The proximal tubule accounts for the highest oxygen consumption in the kidney because the substantial energy demand associated with the reabsorption of electrolytes and organic solutes within this tubular segment. Moreover, tubular hypoxia is a crucial factor in the pathophysiology of acute tubular necrosis (28) . It disrupts normal kidney function, triggers cellular damage and inflammation, and ultimately leads to AKI. Administration of SGLT2 inhibitors could abolish this effect. A previous studies demonstrated that SGLT2 inhibition in type 2 diabetes patents improved renal cortical oxygen tension, potentially benefiting the tubular cell integrity ( 29) . These results were collaborated by meta-analysis, which found that SGLT-2 inhibitor was associated with a reduced risk of AKI in various settings (30,31) . This study also demonstrated that SGLT2 inhibitor is safe for early administration in patients hospitalized for AHF. Although dapagliflozin initiation in AHF initially leads to a transient increase in serum creatinine, but this effect stabilizes overtime. Furthermore, dapagliflozin has demonstrated the capacity to improve renal function within the first few weeks in most patients. These findings align with sub-study of EMPA-RESPONSE-AHF (21) and EMPULSE study (18) . Furthermore, analysis from EMPULSE study showing that patients who received SGLT2 inhibitor (7.7%) had less AKI than the placebo group (12.1%) during the total study period of 3 months, although there was no statistical analysis for this outcome in EMPULSE ( 18) . In terms of secondary outcomes, both groups did not show a statistically significant in cumulative urine output, but dapagliflozin group demonstrated a tendency for reduced cumulative furosemide dose. The length of stay and adverse events such as urinary tract infection, hepatitis and electrolyte imbalance were not different in both groups. Taking all the data together, we can conclude that SGLT2 inhibitors are safe for early administration in hospitalized patients with AHF. This study also had certain limitations that should be considered. Firstly, it involved a small sample size, and some patients who had enrolled were lost to follow-up after discharge from the hospital. Thus, the power of this study must be a point of concern. Secondly, the lack of blinding among participants in this study could potentially impact the integrity of the trial protocol. Finally, our study did not possess sufficient power to detect a statistically significant difference in AKI events between the two treatment groups. Therefore, A larger prospective study should be conducted to investigate the potential benefits of this on clinical outcomes. CONCLUSION Initiation of SGLT2 inhibitors in patients with AHF significantly decrease the urinary AKI risk markers TIMP-2 and IGFBP7, that supported protective effect of SGLT2 inhibitor on renal tubular injury. References 1. Laothavorn P, Hengrussamee K, Kanjanavanit R, et al. Thai Acute Decompensated Heart Failure Registry (Thai ADHERE). Global Heart. 2010;5(3):89–95. 2. Berl T, Henrich W. 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Schanz M, Shi J, Wasser C, Alscher MD, Kimmel M. Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol. 2017;40(7):485-91. 25. Thiele K, Rau M, Hartmann NK, et al. Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure. ESC Heart Fail. 2022;9(4):2233-8. 26. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022;24(1):4-131. 27. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1-138. 28. Nourbakhsh N, Singh P. 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Declarations ACKNOWLEDGEMENT The authors would like to thank all the nurses, the cardiology team, medical and emergency physician residents, medical staffs and laboratory staffs in Bhumibol Adulyadej Hospital, Directorate of Medical Services, Royal Thai Air Force and Ms. Sasipha Tachaboon, laboratory staff in Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital. A UTHOR CONTRIBUTIONS P.G. and J.W. have contributed equally to this work. P.G. conceived the study and was in charge of overall direction and planning. All authors contributed to the trial design and protocol. J.W. was the principal investigators. P.G. analyzed the data. All authors contributed to the interpretation of the results. P.G. and J.W. prepared the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version for submission. DATA AVAILABILITY The data underlying this article will be shared on reasonable request to the corresponding author (P.G.). FUNDING This study was supported by a grant from the kidney foundation of Thailand and Bhumibol Adulyadej Hospital Research Center. COMPETING INTERESTS All authors declare that there are no competing financial or other conflicts of interest in relation to this study. ADDITIONAL INFORMATION Correspondence and requests for materials should be addressed to P.G. Tables Table 1. Baseline characteristics of study subjects Variables Dapagliflozin ( n = 12 ) Control (n = 13) P-value Age, years, mean ± SD 67.0 ± 17.4 67.2 ± 13.4 0.970 Male (%) 7 ( 58.3 ) 7 ( 53.8 ) 0.821 Cr, mg/dl, mean ± SD 1. 18 ± 0.32 1.1 6 ± 0.42 0. 886 eGFR, ml/min/1.73m 2 , mean ± SD 6 1 . 3 ± 20.7 64. 9 ± 24.4 0. 698 EF, %, mean ± SD 42.4 ± 17.0 41.8 ± 16.7 0.924 Type of AHF (%) New onset 5 ( 41.7 ) 9 ( 69.2 ) 0.238 ADHF 7 ( 58.3 ) 4 ( 30.8 ) 0.238 NT-proBNP, pg/ml (IQR) 8,048.5 (3,471, 15,760) 4,802 (3,537, 9,273) 0.550 Acute respiratory Failure ( % ) 0 ( 0 ) 2 ( 15.4 ) 0.497 Co-morbidities Type 2 Diabetes (%) 5 ( 41.7 ) 4 ( 30.8 ) 0.888 Hypertension (%) 9 ( 75.0 ) 8 ( 61.5 ) 0.471 Dyslipidemia (%) 6 ( 50.0 ) 7 ( 53.8 ) 0.848 History of Heart Failure ( % ) 3 ( 25.0 ) 3 ( 23.1 ) 1.000 History of IHD (%) 5 ( 41.7 ) 4 ( 30.8 ) 0.881 History of CVA (%) 1 ( 8.3 ) 1 ( 7.7 ) 1.000 Atrial Fibrillation ( % ) 1 ( 8.3 ) 2 ( 15.4 ) 1.000 Valvular Heart Disease ( % ) 3 ( 18.8 ) 2 ( 15.4 ) 0.920 Chronic kidney Disease ( % ) 5 ( 41.8 ) 7 ( 53.8 ) 0.858 Medications ACEIs or ARBs or ARNi (%) 3 ( 25.0 ) 7 ( 53.8 ) 0.288 Calcium channel blocker (%) 2 ( 16.7 ) 5 ( 38.5 ) 0.443 Beta blocker (%) 6 ( 50.0 ) 5 ( 38.5 ) 0.561 Furosemide ( % ) 4 ( 33.3 ) 4 ( 30.8 ) 1.000 Thiazide ( % ) 0 ( 0 ) 1 ( 7.7 ) 1.000 MRA ( % ) 2 ( 16.7 ) 2 ( 15.4 ) 1.000 Statin (%) 5 ( 41.7 ) 5 ( 38.5 ) 0.870 ADHF, acute decompensated heart failure; AHF, acute heart failure; ACEis, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; ARNi, angiotensin receptor – neprilysin inhibitor; Cr, serum creatinine; CVA, cerebrovascular disease; eGFR, estimated glomerular filtration rate; EF, ejection fraction; IHD, ischemic heart disease; NT-proBNP, Serum N-terminal pro B-type natriuretic peptide; MRA, mineralocorticoid receptor antagonist. Table 2 : Secondary outcomes and adverse events Outcomes Dapagliflozin (n = 12) Control (n = 13) P-value Acute Kidney Injury AKI by creatinine criteria (%) 4(33.3) 6(46.2) 0.513 AKI stage I 4(33.3) 6(46.2) 0.513 AKI stage II 0 0 - AKI stage III 0 0 - Predicted AKI by urinary [TIMP-2] x [IGFBP-7] criteria* (%) 3(25) 7(53.8) 0.288 Mean Urine Output (first 3 days), ml, mean ± SE 2,237.0 ± 876.1 1,855.9 ± 473.5 0.184 Length of stay, days, median (IQR) 4(3-4) 5(3-11) 0.141 28-day mortality (%) 1(8.3) 1(7.7) 1.0 Revisit in 28-day (%) 1(8.3) 1(7.7) 1.0 Adverse Events (%) Urinary Tract Infection 1(8.3) 2(15.4) 1.0 Hypokalemia 8(66.7) 8(53.8) 0.839 Hypomagnesemia 6(50.0) 4(30.8) 0.622 Hypotension 0 1(7.7) 1.0 Hepatitis 2(16.7) 2(15.4) 0.656 *Predicted AKI by urinary [TIMP-2] x [IGFBP-7] criteria using a threshold of 0.3 (ng/ml) 2 /100 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3869067","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":270489010,"identity":"e1e1f67c-a9c0-47dd-aac7-ad4cd237abc7","order_by":0,"name":"Pongsathorn Gojaseni","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYBCDBBiDnx/MLSCowyABplNyZgOINiBFy4YDYAHcas3Zew+//FHzJ49f+uwB5sofdhLG51cnfnhgwCDPL3YAqxbLnnNp1jzHDIol+/ISGM8kJEuY3Xi7WQLoMMOZsxOwu+hGjpkxA5tB4oYzPAaMDQnMdWY3zm4AaUkwuI1bi+GPf3At9RLGM85u/kFAi/ED3ja4lsMSBvy92/DaYtlzxoyZt884cWYPj8HBhrTjEhI3eLdZJBhI4PSLOXuP8ccf3+QS+3l4DB822FRL8Pef3XzzR4WNPL80DocxMLBJwDgHwKQEWKUEVuVQLcwfUIX4D+BUPQpGwSgYBSMTAAAoYV66SfOySQAAAABJRU5ErkJggg==","orcid":"","institution":"Bhumibol Adulyadej Hospital","correspondingAuthor":true,"prefix":"","firstName":"Pongsathorn","middleName":"","lastName":"Gojaseni","suffix":""},{"id":285523553,"identity":"7b189076-b717-4589-8886-c99dfeef42ae","order_by":1,"name":"Jananya Wattanakul","email":"","orcid":"","institution":"Bhumibol Adulyadej Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jananya","middleName":"","lastName":"Wattanakul","suffix":""},{"id":285523554,"identity":"2a06d293-7ce4-481c-8351-a69536ff2da2","order_by":2,"name":"Anan Chuasuwan","email":"","orcid":"","institution":"Bhumibol Adulyadej Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anan","middleName":"","lastName":"Chuasuwan","suffix":""},{"id":285523555,"identity":"92f69601-0a4c-4fe3-a67d-862fc9b3a4cc","order_by":3,"name":"Anutra Chittinandana","email":"","orcid":"","institution":"Bhumibol Adulyadej Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anutra","middleName":"","lastName":"Chittinandana","suffix":""}],"badges":[],"createdAt":"2024-01-16 07:15:59","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-3869067/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-3869067/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53895047,"identity":"35b01d24-d7bc-4f14-a8cd-3e2749a5e579","added_by":"auto","created_at":"2024-04-02 00:23:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35769,"visible":true,"origin":"","legend":"\u003cp\u003eProtocol and timeline of the study\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3869067/v2/f5ce25db68448c4713f9be2f.png"},{"id":53894923,"identity":"2033efe9-7ffd-44c8-bc1b-4d19e7482455","added_by":"auto","created_at":"2024-04-02 00:15:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":49628,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of dapagliflozin on urinary [TIMP-2] x [IGFBP-7] in patients with acute heart failure treated with dapagliflozin (n = 12, orange line) or control (n = 13, blue line). Data are shown as mean urinary [TIMP-2] x [IGFBP-7] at baseline, after 7, and 28 days. p-value compared changes from baseline between both groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3869067/v2/392acdb97d02760a63530356.png"},{"id":53894921,"identity":"7d60cd73-eaad-4c7f-ade8-a143eaf9bcda","added_by":"auto","created_at":"2024-04-02 00:15:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":45327,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of dapagliflozin on serum creatinine in patients with acute heart failure treated with dapagliflozin (n = 12, orange line) or control (n = 13, blue line). Data are shown as mean serum creatinine at baseline, after 1, 2, 3, 7, 14, and 28 days. p-value compared changes from baseline between both groups.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3869067/v2/776035da42fc0886b18ea4f5.png"},{"id":53894919,"identity":"dfbe752e-93b7-4e14-9365-09b5d1e04aa9","added_by":"auto","created_at":"2024-04-02 00:15:41","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":14196,"visible":true,"origin":"","legend":"\u003cp\u003eThe mean of cumulative urine output during the first 3 days in patients with acute heart failure treated with dapagliflozin (n = 12, orange line) or control (n = 13, blue line). p-value compared the cumulative urine output at day 3.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3869067/v2/e18a2733c19c6368a210139c.png"},{"id":53895290,"identity":"6ea9099e-9357-4d2e-9f35-fbe0cdef6d2b","added_by":"auto","created_at":"2024-04-02 00:31:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":496245,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3869067/v2/8797e98a-3dfa-4594-969b-2554b2fc815b.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eEffect of SGLT2 Inhibitor Dapagliflozin on Biomarkers of Tubular Injury in Patients with Acute Heart Failure: A Randomized Controlled Trial\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAcute kidney injury (AKI) in acute heart failure (AHF) or cardiorenal syndrome type 1 is common and associated with poor prognosis \u003csup\u003e(1-3)\u003c/sup\u003e.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eCurrent treatment options for AHF mainly focus on relieving symptoms and reducing fluid overload, which can have potentially harmful effects on kidney function. Consequently, there is a need for the development of novel and inventive therapies aimed at improving both cardiovascular and kidney outcomes in individuals with AHF.\u003c/p\u003e\n\u003cp\u003eSodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a disease-modifying therapy to reduce cardiovascular events and prevent the progression of chronic kidney disease (CKD)\u003csup\u003e\u0026nbsp;(4-14)\u003c/sup\u003e. The rapid growth of clinical trials on SGLT2 inhibitors has expanded the approved clinical indications for these agents. The recent clinical trials \u003csup\u003e(15-18)\u003c/sup\u003e have shown that SGLT2 inhibitor have reduced the risk of cardiovascular death in the setting of AHF. Additionally, it was observed that the occurrence of AKI within the first 3 months might be less common in the SGLT2 inhibitor group compared to the placebo group in clinically stable patients hospitalized for AHF \u003csup\u003e(18)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral hypotheses have been postulated to explain the mechanism by which SGLT2 inhibitors prevent AKI, as it cannot be attributed to a reduction in glomerular pressure.\u0026nbsp;A previous animal study showed that\u0026nbsp;SGLT2 inhibitors can improve renal cortical oxygen tension,\u0026nbsp;which might help to improve tubular cell integrity \u003csup\u003e(\u003c/sup\u003e\u003csup\u003e19)\u003c/sup\u003e. Furthermore, SGLT2 inhibitors have the potential to enhance the expression of \u003cem\u003ehypoxia-inducible factor 1\u003c/em\u003e (HIF1) resulting in an augmentation of erythropoietin production \u003csup\u003e(20)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite the growing evidence of benefits, physicians are still hesitant to prescribe SGLT2\u0026nbsp;inhibitors\u0026nbsp;to AHF patients during their hospitalization primarily due to the transient rise in serum creatinine \u003csup\u003e(\u003c/sup\u003e\u003csup\u003e21)\u003c/sup\u003e.\u0026nbsp;Nevertheless, there are limitations associated with employing serum creatinine as a diagnostic tool for detecting AKI in the context of AHF due to its delayed\u0026nbsp;response as a marker of tubular injury \u003csup\u003e(22)\u003c/sup\u003e. Moreover, increase serum creatinine level in AKI does not always indicate renal tubular cell injury. As a result, many tubular injury biological markers have been used for the early detection of AKI in this setting. Of these, the use of tissue inhibitor of metalloproteinases-2 [TIMP-2] and\u0026nbsp;insulin-like growth factor-binding protein\u0026nbsp;7\u0026nbsp;[IGFBP-7]\u0026nbsp;is one of the most evidence-based \u003csup\u003e(23)\u003c/sup\u003e. Several studies demonstrated that using urinary [TIMP-2] x [IGFBP-7] can accurately predict AKI in patients hospitalized for AHF when using cut-off point more than 0.3 (ng/ml)\u003csup\u003e2\u003c/sup\u003e/1000 \u003csup\u003e(\u003c/sup\u003e\u003csup\u003e24)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn this study, we investigated the protective effect of SGLT2 inhibitor on tubular injury biomarkers (urinary [TIMP-2] x [IGFBP-7]) in patients hospitalized for AHF.\u0026nbsp;The primary objective of this study was to\u003csup\u003e\u0026nbsp;\u003c/sup\u003ecompare the change\u0026nbsp;of urinary [TIMP-2] x [IGFBP-7] in\u0026nbsp;SGLT2 inhibitor add on to standard of care with standard of care alone.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eThe incident of AKI, change from baseline serum creatinine, length of stays, cumulative urine output, and adverse events were also assessed.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a randomized prospective open-label \u003cem\u003econtrolled trial\u003c/em\u003e of patients hospitalized for AHF in Bhumibol Adulyadej Hospital, Directorate of Medical Services, Royal Thai Air Force. The study protocol\u0026nbsp;was approved by the Institutional Review Board of Bhumibol Adulyadej Hospital with approval number 46/65 and was registered in the Thai Clinical Trials Registry (TCTR) with registration number TCTR20221003002. This study was conducted in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The investigators informed patients or their surrogates concerning the study orally and written informed consent was given before entry into the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Inclusion criteria were aged \u0026ge; 18 years, presence of AHF requiring hospital admission as well as serum level of N-terminal pro-brain natriuretic peptide (NT-proBNP) \u0026ge; 1600 pg/ml\u003c/p\u003e\n\u003cp\u003eor \u0026ge; 2000 pg/ml in patients with atrial fibrillation regardless of ejection fraction or diabetes status. Key exclusion criteria were: patients with type 1 diabetes, history of diabetic ketoacidosis or ketosis, estimated glomerular filtration rate by the\u0026nbsp;CKD Epidemiology Collaboration [eGFR\u0026nbsp;(CKD-EPI)] \u0026lt; 30 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e, patients with cardiogenic shock, septic shock or systolic blood pressure \u0026lt; 100 mmHg, patients with intravenous vasopressor, vasodilators or inotropic drugs within 6 hours, planned for percutaneous coronary intervention therapy, acidemia (blood pH \u0026lt; 7.2), and liver failure. In terms of calculating the sample size, the following assumptions were considered: power 0.8, alpha 0.05, and standard deviation of urinary [TIMP-2] x [IGFBP-7] of 0.47 (ng/ml)\u003csup\u003e2\u003c/sup\u003e/1000. From these assumptions, a total sample size of 22 would enable the detection of a 0.6 (ng/ml)\u003csup\u003e2\u003c/sup\u003e/1000 difference in the change from baseline of urinary [TIMP-2] x [IGFBP-7]\u0026nbsp;based on Thiele K, et al. \u003csup\u003e(25)\u003c/sup\u003e.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary and secondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The primary outcome of this study is the change from baseline of urinary [TIMP-2] x [IGFBP-7].\u0026nbsp;Statistical analysis was based on detecting a difference in urinary [TIMP-2] x [IGFBP-7] change from baseline\u0026nbsp;between the dapagliflozin group and controls.\u0026nbsp;The secondary outcome is the incidence of AKI by KDIGO creatinine criteria, the change from baseline creatinine, length of stays, cumulative urine output, and adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Patients were randomized\u0026nbsp;into 2 groups using a random block of 4 allocation method\u0026nbsp;to receive either dapagliflozin 10 mg on top of standard of care within 24 hours after enrollment (dapagliflozin group) or standard of care alone (control group). Baseline information including demographic data, comorbidities and current medication were recorded. Laboratory investigations were performed at baseline and 1\u003csup\u003e\u0026nbsp;\u003c/sup\u003eday, 2\u003csup\u003e\u0026nbsp;\u003c/sup\u003edays, 3\u003csup\u003e\u0026nbsp;\u003c/sup\u003edays, 7\u003csup\u003e\u0026nbsp;\u003c/sup\u003edays, 14\u003csup\u003e\u0026nbsp;\u003c/sup\u003edays, and 28\u003csup\u003e\u0026nbsp;\u003c/sup\u003edays\u003csup\u003e\u0026nbsp;\u003c/sup\u003efollowing treatment initiation as shown in \u003cstrong\u003eFigure 1\u003c/strong\u003e. The urine sample was collected then centrifuged and frozen at -80\u0026nbsp;\u0026deg;C and then urinary [TIMP-2] x [IGFBP-7] was performed by NephroCheck\u003csup\u003e\u0026reg;\u0026nbsp;\u003c/sup\u003eusing\u0026nbsp;the VITROS 5600\u0026nbsp;Integrated System (Astute Medical, San Diego, CA, USA)\u0026nbsp;at baseline, on day 7, and on day 28. The outcome including length of stay, cumulative urine output, adverse events including the gastrointestinal system, urinary tract infection, electrolyte imbalance, discontinuation of treatment and date of death were collected.\u0026nbsp;All patients received treatment in accordance with the\u0026nbsp;ESC guidelines for the diagnosis and treatment of acute heart failure\u003csup\u003e\u0026nbsp;(26)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant Definition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKidney disease improving global outcome (KDIGO) serum creatinine criteria were used to classify AKI status \u003csup\u003e(27)\u003c/sup\u003e.\u0026nbsp;The baseline serum creatinine was the first creatinine recorded on the day of enrolment. AHF refers to heart failure that occurs suddenly or a stable condition that then becomes worse within a short period of time, according to the criteria of the European Society of Cardiology guidelines (ESC) \u003csup\u003e(26)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The study used\u0026nbsp;IBM SPSS Statistics Version 22 (Chicago, IL, USA)\u0026nbsp;program for data analysis and data processing. The categorical data were reported as the number with a percentage. The continuous data were reported as mean\u0026nbsp;\u0026plusmn;\u0026nbsp;standard\u0026nbsp;deviation (SD),\u0026nbsp;mean\u0026nbsp;\u0026plusmn;\u0026nbsp;standard error\u0026nbsp;(SE), or median (interquartile range, IQR) as appropriate.\u0026nbsp;Fisher\u0026rsquo;s exact test or Chi-square test were used for categorical variable and student\u0026rsquo;s\u003cem\u003e\u0026nbsp;t-test\u003c/em\u003e or Mann Whitney U test for continuous variable. We used a P value \u0026lt; 0.05 as statistically significant. \u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe enrollment period took place from August 2022 to January 2023. Out of the initial 32 patients who underwent randomization, seven were subsequently excluded from the study due to incomplete biochemical data in the first week, comprising\u0026nbsp;5\u0026nbsp;cases discharged and 2 case died.\u0026nbsp;Consequently, 25 eligible patients were enrolled for analysis (12 dapagliflozin, 13 control).\u0026nbsp;The mean age was 67.1\u0026nbsp;\u0026plusmn;\u0026nbsp;15.1 years, 48.5% were male, the mean ejection fraction was 42.1\u0026nbsp;\u0026plusmn;\u0026nbsp;16.5% and the median NT-proBNP was 5,359 pg/ml\u0026nbsp;(interquartile range 3,496 \u0026ndash;\u0026nbsp;10,843). Other underlying diseases and medications at baseline were balanced between treatment groups as shown in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of dapagliflozin on tubular injury markers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean\u0026nbsp;\u0026plusmn;\u0026nbsp;standard error (SE) of\u0026nbsp;urinary [TIMP-2] x [IGFBP-7] in the\u0026nbsp;dapagliflozin and control group were 0.223\u0026nbsp;\u0026plusmn;\u0026nbsp;0.165 vs 0.073\u0026nbsp;\u0026plusmn;\u0026nbsp;0.048 (P = 0.340)\u0026nbsp;at the enrollment. Compared with control group, dapagliflozin group significantly reduced\u0026nbsp;urinary [TIMP-2] x [IGFBP7] after 7 days [dapagliflozin: -0.03\u0026nbsp;\u0026plusmn;\u0026nbsp;0.11 (ng/mL)\u003csup\u003e2\u003c/sup\u003e/1000; control: +0.4\u0026nbsp;\u0026plusmn;\u0026nbsp;0.14 (ng/mL)\u003csup\u003e2\u003c/sup\u003e/1000; P = 0.022]. After a\u0026nbsp;28-day follow-up period, 7 patients (3 in the dapagliflozin, 4 in the control group) were discharged\u0026nbsp;home and 2 patients died (1 from each group), leaving a total of\u0026nbsp;16 patients with complete data available.\u0026nbsp;The mean change in urinary [TIMP-2] x [IGFBP-7] in dapagliflozin group tended to be decreased compared to controls. [dapagliflozin: -0.09\u0026nbsp;\u0026plusmn;\u0026nbsp;0.28 (ng/mL)\u003csup\u003e2\u003c/sup\u003e/1000; control: +0.67\u0026nbsp;\u0026plusmn;\u0026nbsp;0.32 (ng/mL)\u003csup\u003e2\u003c/sup\u003e/1000; P = 0.096] \u003cstrong\u003e(Figure 2)\u003c/strong\u003e. Furthermore, we conducted additional analysis using a threshold of\u0026nbsp;0.3\u0026nbsp;(ng/ml)\u003csup\u003e2\u003c/sup\u003e/1000, a value that showed a strong association with AKI. We observed a trend where the number of patients with\u0026nbsp;urinary [TIMP-2] x [IGFBP-7] levels exceeding\u0026nbsp;0.3\u0026nbsp;was slightly lower in the dapagliflozin group, although this difference did not reach statistically significance (25.0% vs 53.8%, P = 0.288). \u003cstrong\u003e(Table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEffect of dapagliflozin on secondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIncidence of\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAKI by serum creatinine from KDIGO criteria in the dapagliflozin and control group was 33.3% and 46.2%, respectively\u0026nbsp;(P = 0.513). All cases of AKI were KDIGO stage 1\u0026nbsp;\u003cstrong\u003e(Table 2).\u003c/strong\u003e Further analyses showed no difference between the dapagliflozin and control group for the change from baseline serum creatinine, length of stay, and adverse events.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(Table 2 and Figure 3).\u0026nbsp;\u003c/strong\u003eThe cumulative urine output during the first 3 days was not statistically different between both groups (8,587\u0026nbsp;\u0026plusmn;\u0026nbsp;1,346 vs 8,060\u0026nbsp;\u0026plusmn;\u0026nbsp;1,090 ml; P=0.420).\u0026nbsp;\u003cstrong\u003e(Figure 4).\u003c/strong\u003e However, dapagliflozin group demonstrated a trend towards lower cumulative furosemide dose compared with control group. [61.94 \u0026plusmn; 10.37 vs 104.62 \u0026plusmn; 21.92 mg/day; P=0.100].\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study demonstrated that initiation of dapagliflozin significantly decrease urine [TIMP-2] x [IGFBP7] during the first week, that supported the protective effect of SGLT2 inhibitor on renal tubular injury.\u0026nbsp;The results are consistent with study from Thiele K, et al.\u0026nbsp;that showed the reduction of urine [TIMP-2] x [IGFBP7] after initiation of empagliflozin in AHF patients for 3 days \u003csup\u003e(25)\u003c/sup\u003e.\u0026nbsp;Thus, we may conclude that SGLT2 inhibitor can improve tubular cell injury in patients hospitalized for acute heart failure since\u0026nbsp;urinary [TIMP-2] x [IGFBP-7] is the biomarker of cell cycle arrest during the early phase of tubular damage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe proximal tubule accounts for the highest oxygen consumption in the kidney because the substantial energy demand associated with the reabsorption of electrolytes and organic solutes within this tubular segment. Moreover, tubular hypoxia is a crucial factor in the pathophysiology of acute tubular necrosis \u003csup\u003e(28)\u003c/sup\u003e. It disrupts normal kidney function, triggers cellular damage and inflammation, and ultimately leads to AKI.\u0026nbsp;Administration of SGLT2 inhibitors could abolish this effect. A previous studies demonstrated that SGLT2 inhibition in type 2 diabetes patents improved renal cortical oxygen tension, potentially benefiting the tubular cell integrity \u003csup\u003e(\u003c/sup\u003e\u003csup\u003e29)\u003c/sup\u003e.\u0026nbsp;These\u0026nbsp;results were collaborated by meta-analysis, which found that SGLT-2 inhibitor was associated with a reduced risk of AKI\u0026nbsp;in various settings \u003csup\u003e(30,31)\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThis study also demonstrated that SGLT2 inhibitor is safe for early administration in patients hospitalized for AHF. Although\u0026nbsp;dapagliflozin initiation in AHF initially leads to a transient increase in serum creatinine, but this effect stabilizes overtime. Furthermore, dapagliflozin has demonstrated the capacity to improve renal function within the first few weeks in most patients. These findings align with\u0026nbsp;sub-study of EMPA-RESPONSE-AHF \u003csup\u003e(21)\u003c/sup\u003e and\u0026nbsp;EMPULSE study \u003csup\u003e(18)\u003c/sup\u003e. Furthermore, analysis from EMPULSE study showing that patients who received SGLT2 inhibitor (7.7%) had less AKI than the placebo group (12.1%) during the total study period of 3 months, although there was no statistical analysis for this outcome in EMPULSE \u003csup\u003e(\u003c/sup\u003e\u003csup\u003e18)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn terms of secondary outcomes, both groups did not show a statistically significant in cumulative urine output, but dapagliflozin group\u0026nbsp;demonstrated a tendency for reduced cumulative furosemide dose. The length of stay and adverse events such as urinary tract infection, hepatitis and electrolyte imbalance were not different in both groups. Taking all the data together, we can conclude that SGLT2 inhibitors are safe for early administration in hospitalized patients with AHF.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study also had certain limitations that should be considered. Firstly, it involved a small sample size, and some patients who had enrolled were lost to follow-up after discharge from the hospital. Thus, the power of this study must be a point of concern. Secondly, the lack of blinding among participants in this study could potentially impact the integrity of the trial protocol.\u0026nbsp;Finally, our\u0026nbsp;\u003cem\u003estudy did not possess sufficient\u0026nbsp;\u003c/em\u003epower to detect\u0026nbsp;a\u0026nbsp;\u003cem\u003estatistically significant difference\u003c/em\u003e in\u0026nbsp;\u003cem\u003eAKI\u003c/em\u003e events\u0026nbsp;between the two treatment groups. Therefore, A larger prospective\u0026nbsp;\u003cem\u003estudy\u003c/em\u003e should be conducted to investigate the potential benefits of this on clinical outcomes.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Initiation of SGLT2 inhibitors in patients with AHF significantly decrease the urinary AKI risk markers TIMP-2 and IGFBP7, that supported protective effect of SGLT2 inhibitor on renal tubular injury.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Laothavorn P, Hengrussamee K, Kanjanavanit R, et al. Thai Acute Decompensated Heart Failure Registry (Thai ADHERE). Global Heart. 2010;5(3):89\u0026ndash;95.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Berl T, Henrich W. Kidney-Heart Interactions: Epidemiology, Pathogenesis, and Treatment. CJASN 2006;1(1):8\u0026ndash;18.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Pickering JW, Blunt IRH, Than MP. Acute kidney injury and mortality prognosis in acute coronary syndrome patients: a meta-analysis. Nephrol 2018;23:237\u0026ndash;46.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28.\u003c/p\u003e\n\u003cp\u003e6.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380:347-57.\u003c/p\u003e\n\u003cp\u003e7.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.\u003c/p\u003e\n\u003cp\u003e8.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-24.\u003c/p\u003e\n\u003cp\u003e9.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-61.\u003c/p\u003e\n\u003cp\u003e10.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-29.\u003c/p\u003e\n\u003cp\u003e11.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun;380(24):2295-306.\u003c/p\u003e\n\u003cp\u003e12.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Heerspink HJL, Stef\u0026aacute;nsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.\u003c/p\u003e\n\u003cp\u003e13.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in Patients with Chronic Kidney Disease N Engl J Med. 2023;388(2):117-127.\u003c/p\u003e\n\u003cp\u003e14.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists\u0026apos; Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788-1801.\u003c/p\u003e\n\u003cp\u003e15.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020;22(4):713-22.\u003c/p\u003e\n\u003cp\u003e16.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Bhatt DL, Szarek M, Steg PG, et al. Sotagiflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384:117-28.\u003c/p\u003e\n\u003cp\u003e17.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ul Amin N, Sabir F, Amin T, et al. SGLT2 Inhibitors in Acute Heart Failure: A Meta-Analysis of Randomized Controlled Trials. Healthcare (Basel). 2022;10(12):2356.\u003c/p\u003e\n\u003cp\u003e18.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022:568\u0026ndash;74.\u003c/p\u003e\n\u003cp\u003e19.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Chu C, Lu YP, Yin L, Hocher B. The SGLT2 Inhibitor Empagliflozin Might Be a New Approach for the Prevention of Acute Kidney Injury. Kidney Blood Press Res. 2019;44:149-57.\u003c/p\u003e\n\u003cp\u003e20.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Packer M. Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors. Eur Heart J. 2023:ehad235.\u003c/p\u003e\n\u003cp\u003e21.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Boorsma EM, Beusekamp JC, Ter Maaten JM, et al. Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure. Eur J Heart Fail. 2021;23(1):68-78.\u003c/p\u003e\n\u003cp\u003e22.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ngam PK, Chandra A. Positive and negative false estimate of serum creatinine. Interv Cardiol. 2017;9(4):163-7.\u003c/p\u003e\n\u003cp\u003e23.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Fan W, Ankawi G, Zhang J, et al. Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice. Clin Chem Lab Med. 2019;57(5):567-76.\u003c/p\u003e\n\u003cp\u003e24.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Schanz M, Shi J, Wasser C, Alscher MD, Kimmel M. Urinary [TIMP-2]\u0026thinsp;\u0026times;\u0026thinsp;[IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure. Clin Cardiol. 2017;40(7):485-91.\u003c/p\u003e\n\u003cp\u003e25.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Thiele K, Rau M, Hartmann NK, et al. Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure. ESC Heart Fail. 2022;9(4):2233-8.\u003c/p\u003e\n\u003cp\u003e26.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022;24(1):4-131.\u003c/p\u003e\n\u003cp\u003e27.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1-138.\u003c/p\u003e\n\u003cp\u003e28.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nourbakhsh N, Singh P. Role of renal oxygenation and mitochondrial function in the pathophysiology of acute kidney injury. Nephron Clin Pract. 2014;127(1-4):149-52.\u003c/p\u003e\n\u003cp\u003e29.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Zhou S, Zhang Y, Wang T, et al. Canagliflozin could improve the levels of renal oxygenation in newly diagnosed type 2 diabetes patients with normal renal function. Diabetes Metab. 2021;47(5):101274.\u003c/p\u003e\n\u003cp\u003e30.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systemic review and meta-analysis. PLoS Med. 2019;16(12):e1002983.\u003c/p\u003e\n\u003cp\u003e31. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Zhuo M, Paik JM, Wexler DJ, Bonventre JV, Kim SC, Patorno E. SGLT2 Inhibitors and the Risk of Acute Kidney Injury in Older Adults With Type 2 Diabetes. Am J Kidney Dis. 2022 Jun;79(6):858-867.e1.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all the nurses, the cardiology team, medical and emergency physician residents, medical staffs and laboratory staffs in Bhumibol Adulyadej Hospital, Directorate of Medical Services, Royal Thai Air Force and Ms. Sasipha Tachaboon, laboratory staff in Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003cstrong\u003eUTHOR\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCONTRIBUTIONS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP.G. and J.W. have contributed equally to this work. P.G. conceived the study and was in charge of overall direction and planning. All authors contributed to the trial design and protocol. J.W. was the principal investigators. P.G. analyzed the data. All authors contributed to the interpretation of the results. P.G. and J.W. prepared the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version for submission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data underlying this article will be shared on reasonable request to the corresponding author (P.G.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by a grant from\u0026nbsp;the kidney foundation of Thailand\u0026nbsp;and Bhumibol Adulyadej Hospital Research Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that there are no competing financial or other conflicts of interest in relation to this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADDITIONAL INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand requests for materials should be addressed to P.G.\u0026nbsp;\u003c/p\u003e"},{"header":"Tables","content":"\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Baseline characteristics of study subjects\u003c/p\u003e\n\u003ctable style=\"border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eVariables\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eDapagliflozin\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003en = 12\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eControl\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;(n = 13)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eP-value\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eAge, years, mean\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e67.0\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;17.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e67.2\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;13.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.970\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eMale (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e58.3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e53.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.821\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eCr, mg/dl, mean\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e18\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height: 150%;\"\u003e\u0026nbsp;0.32\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e6\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height: 150%;\"\u003e\u0026nbsp;0.42\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e886\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eeGFR, ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e, mean\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e6\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e.\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e3\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height: 150%;\"\u003e\u0026nbsp;20.7\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e64.\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e9\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height: 150%;\"\u003e\u0026nbsp;24.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e698\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eEF, %, mean\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;SD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e42.4\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;17.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e41.8\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;16.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.924\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eType of AHF (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp; New onset\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e41.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e9\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e69.2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.238\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp; ADHF\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e58.3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e30.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.238\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eNT-proBNP, pg/ml (IQR)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e8,048.5\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(3,471, 15,760)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e4,802\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(3,537, 9,273)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.550\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eAcute respiratory Failure\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e15.4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.497\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eCo-morbidities\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eType 2 Diabetes (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e41.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e30.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.888\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eHypertension (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e9\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e75.0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e61.5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.471\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eDyslipidemia (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e6\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e50.0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e53.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.848\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eHistory of Heart Failure\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e25.0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e23.1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eHistory of IHD (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e41.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e30.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.881\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eHistory of CVA (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e8.3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eAtrial Fibrillation\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e8.3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e15.4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eValvular Heart Disease\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e18.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e15.4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.920\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eChronic kidney Disease\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e41.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e53.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.858\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eMedications\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eACEIs or ARBs or ARNi (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e25.0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e53.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.288\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eCalcium channel blocker (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e16.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e38.5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.443\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eBeta blocker (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e6\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e50.0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e38.5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.561\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eFurosemide\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e33.3\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e30.8\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eThiazide\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e7.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eMRA\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e%\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e16.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e2\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e15.4\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e1.000\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003eStatin (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e41.7\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e(\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e38.5\u003c/span\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54.15pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cspan style=\"font-size:15px;line-height:150%;\"\u003e0.870\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size:13px;\"\u003eADHF, acute decompensated heart failure; AHF, acute heart failure; ACEis, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; ARNi, angiotensin receptor \u0026ndash; neprilysin inhibitor; Cr, serum creatinine; CVA, cerebrovascular disease; eGFR, estimated glomerular filtration rate; EF, ejection fraction; IHD, ischemic heart disease; NT-proBNP, Serum N-terminal pro B-type natriuretic peptide; MRA, mineralocorticoid receptor antagonist.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;'\u003e\u003cstrong\u003e\u003cspan style='font-size:21px;font-family:\"TH SarabunPSK\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e: Secondary outcomes and adverse events\u003c/p\u003e\n\u003ctable style=\"width:460.45pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003eDapagliflozin\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e(n = 12)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003eControl\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e(n = 13)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;line-height:150%;'\u003e\u003cstrong\u003eAcute Kidney Injury\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003eAKI by creatinine criteria (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e4(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e6(46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.513\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;AKI stage I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e4(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e6(46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.513\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;AKI stage II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;AKI stage III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003ePredicted AKI by urinary \u003cspan style=\"color:black;\"\u003e[TIMP-2] x [IGFBP-7] criteria* (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e3(25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e7(53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.288\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u003cstrong\u003eMean Urine Output (first 3 days), ml, mean\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e SE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e2,237.0\u0026nbsp;\u003cspan style=\"font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e 876.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1,855.9\u0026nbsp;\u003cspan style=\"font-family:Symbol;\"\u003e\u0026plusmn;\u003c/span\u003e 473.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;line-height:150%;'\u003e\u003cstrong\u003eLength of stay, days, median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e4(3-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e5(3-11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;line-height:150%;'\u003e\u003cstrong\u003e28-day mortality (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1(7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;line-height:150%;'\u003e\u003cstrong\u003eRevisit in 28-day (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1(7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;line-height:150%;'\u003e\u003cstrong\u003eAdverse Events\u003c/strong\u003e \u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;Urinary Tract Infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1(8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e2(15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;Hypokalemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e8(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e8(53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.839\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;Hypomagnesemia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e6(50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e4(30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.622\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;Hypotension\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1(7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;line-height:150%;'\u003e\u0026nbsp; \u0026nbsp;Hepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e2(16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e2(15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1in;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;'\u003e0.656\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:justify;'\u003e\u003cspan style=\"font-size:15px;\"\u003e*Predicted AKI by urinary \u003cspan style=\"color:black;\"\u003e[TIMP-2] x [IGFBP-7] criteria using a threshold of\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003cspan style=\"font-size:15px;color:black;\"\u003e0.3\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size:15px;color:black;\"\u003e(ng/ml)\u003csup\u003e2\u003c/sup\u003e/100\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style='font-size:19px;font-family:\"TH SarabunPSK\",sans-serif;color:black;'\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute heart failure, acute kidney injury, biomarkers of tubular injury, SGLT2 inhibitor","lastPublishedDoi":"10.21203/rs.3.rs-3869067/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3869067/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in acute heart failure (AHF) but are associated with a transient rise in serum creatinine. The aim of this study was to assess the effect of SGLT2 inhibitor on urinary biomarkers of tubular injury in patients with AHF. Patients who hospitalized for AHF were randomized to dapagliflozin added to standard of care or control group for 28 days. The primary outcome was the change of urinary [TIMP-2] x [IGFBP7] by NephroCheck\u003csup\u003e®\u003c/sup\u003e from baseline. Out of the 32 patients who underwent randomization, 25 eligible individuals were enrolled for analysis. Compared with control group, dapagliflozin group significantly reduced urinary [TIMP-2] x [IGFBP7] after 7 days [dapagliflozin: -0.03 ± 0.11 (ng/mL)\u003csup\u003e2\u003c/sup\u003e/1000; control: +0.4 ± 0.14 (ng/mL)\u003csup\u003e2\u003c/sup\u003e/1000; P = 0.022] and continue this trend until the end of the study. In terms of clinical outcomes, dapagliflozin has demonstrated a trend towards decrease in acute kidney injury (AKI) events compared to the control group (33.3% vs 46.2%; P = 0.513). The changes in serum creatinine, and adverse events showed no differences in either group. In conclusion, initiation of SGLT2 inhibitors in patients with AHF significantly decrease the urinary AKI risk markers TIMP-2 and IGFBP7, that supported protective effect of SGLT2 inhibitor on renal tubular injury.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number:\u003c/strong\u003e The study was registered with the Thai Clinical Trials Registry\u0026nbsp;TCTR20221003002.\u003c/p\u003e","manuscriptTitle":"Effect of SGLT2 Inhibitor Dapagliflozin on Biomarkers of Tubular Injury in Patients with Acute Heart Failure: A Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2024-04-02 00:15:36","doi":"10.21203/rs.3.rs-3869067/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2024-02-01 15:54:14","doi":"10.21203/rs.3.rs-3869067/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5169c85-d734-4f4e-b985-84bf32dac60c","owner":[],"postedDate":"April 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30060300,"name":"Health sciences/Nephrology/Kidney diseases/Acute kidney injury"},{"id":30060301,"name":"Health sciences/Medical research/Biomarkers/Prognostic markers"},{"id":30060302,"name":"Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Heart failure"}],"tags":[],"updatedAt":"2024-02-28T14:37:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-02 00:15:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-3869067","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3869067","identity":"rs-3869067","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}