{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:18:45Z","timestamp":1784931525153,"version":"3.55.0"},"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"japan society for the promotion of science","doi-asserted-by":"publisher","award":["JP19K17514"],"award-info":[{"award-number":["JP19K17514"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Esaxerenone, a mineralocorticoid receptor blocker (MRB), is a new antihypertensive agent. However, esaxerenone-related data with respect to hypertension with heart failure are limited. We investigated the safety and efficacy of esaxerenone in hypertensive patients with heart failure with reduced ejection fraction (HFrEF). Hypertensive patients with HFrEF treated with esaxerenone were retrospectively analyzed at two timepoints (short-term: 35\u00b115 days; mid-term: 167\u00b145 days). Adverse events including hyperkalemia (K<jats:sup>+<\/jats:sup> &gt;5.5 mEq\/L), worsening renal function (WRF; estimated glomerular filtration rate (eGFR) reduction by \u226520%), and hypotension (systolic blood pressure &lt;90 mmHg) were evaluated. eGFR and K<jats:sup>+<\/jats:sup>, serum creatinine, and brain natriuretic peptide (BNP) levels at baseline, short-term, and mid-term assessments were compared. Patients administered esaxerenone as their first MRB (first-MRB cohort) and those who converted from another MRB (conversion cohort) were separately analyzed. There were 50 (56\u00b110 years old, 26% female) patients. At the short-term assessment, hyperkalemia or hypotension was not observed at a dose of 2.0\u00b10.9 mg\/day. Seven patients (14%) showed WRF. K<jats:sup>+<\/jats:sup> was slightly elevated (4.12\u00b10.41 to 4.25\u00b10.39 mmol\/L, <jats:italic>p<\/jats:italic> = 0.07) and eGFR was significantly reduced (66.9\u00b119.6 mL\/min\/1.73 m<jats:sup>2<\/jats:sup> to 62.4\u00b119.7 mL\/min\/1.73 m<jats:sup>2<\/jats:sup>, <jats:italic>p<\/jats:italic> = 0.006). In the conversion cohort, significant changes in K<jats:sup>+<\/jats:sup> and eGFR from baseline were not observed at the short-term assessment. BNP levels were consistently improved regardless of the cohorts (first-MRB cohort, 310 [110\u2013370] pg\/mL to 137 [47\u2013152] pg\/mL, <jats:italic>p<\/jats:italic> = 0.001; conversion cohort, 181 [30\u2013203] pg\/mL to 108 [26\u2013146] pg\/mL, <jats:italic>p<\/jats:italic> = 0.028). At the mid-term assessment, there were no significant changes in K<jats:sup>+<\/jats:sup> and eGFR compared with the short-term assessment. In conclusion, esaxerenone was safe for hypertensive patients with HFrEF. Hyperkalemia and hypotension were rarely noted, while eGFR was marginally reduced. Moreover, esaxerenone might be beneficial for HFrEF in terms of BNP level reduction.<\/jats:p>","DOI":"10.1371\/journal.pone.0259485","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T18:28:01Z","timestamp":1636396081000},"page":"e0259485","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Safety and efficacy of esaxerenone in Japanese hypertensive patients with heart failure with reduced ejection fraction: A retrospective study"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5821-0110","authenticated-orcid":true,"given":"Togo","family":"Iwahana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotoshi","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryohei","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"issue":"9932","key":"pone.0259485.ref001","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1016\/S0140-6736(14)60685-1","article-title":"Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1\u00b725 million people","volume":"383","author":"E Rapsomaniki","year":"2014","journal-title":"The Lancet"},{"issue":"5","key":"pone.0259485.ref002","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/ajh.2011.245","article-title":"Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension","volume":"25","author":"H Shibata","year":"2012","journal-title":"Am J Hypertens"},{"issue":"5","key":"pone.0259485.ref003","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.1161\/HYP.0000000000000084","article-title":"Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association","volume":"72","author":"RM Carey","year":"2018","journal-title":"Hypertension"},{"issue":"10","key":"pone.0259485.ref004","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators","volume":"341","author":"B Pitt","year":"1999","journal-title":"N Engl J Med"},{"issue":"14","key":"pone.0259485.ref005","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1056\/NEJMoa030207","article-title":"Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction","volume":"348","author":"B Pitt","year":"2003","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0259485.ref006","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1009492","article-title":"Eplerenone in patients with systolic heart failure and mild symptoms","volume":"364","author":"F Zannad","year":"2011","journal-title":"N Engl J Med"},{"issue":"27","key":"pone.0259485.ref007","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"P Ponikowski","year":"2016","journal-title":"Eur Heart J"},{"issue":"6","key":"pone.0259485.ref008","doi-asserted-by":"crossref","first-page":"e137","DOI":"10.1161\/CIR.0000000000000509","article-title":"2017 ACC\/AHA\/HFSA Focused Update of the 2013 ACCF\/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America","volume":"136","author":"CW Yancy","year":"2017","journal-title":"Circulation"},{"issue":"23","key":"pone.0259485.ref009","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1056\/NEJMoa2025845","article-title":"Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 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Rakugi","year":"2020","journal-title":"Hypertens Res"},{"issue":"12","key":"pone.0259485.ref019","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1038\/s41440-019-0320-9","article-title":"Does the temporary decrease in the estimated glomerular filtration rate (eGFR) after initiation of mineralocorticoid receptor (MR) antagonist treatment lead to a long-term renal protective effect?","volume":"42","author":"A Sato","year":"2019","journal-title":"Hypertens Res"},{"issue":"2","key":"pone.0259485.ref020","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1093\/ehjcvp\/pvu023","article-title":"Cardiorenal protection during chronic renin-angiotensin-aldosterone system suppression: evidences and caveats","volume":"1","author":"G Ruiz-Hurtado","year":"2015","journal-title":"Eur Heart J Cardiovasc Pharmacother"},{"issue":"7","key":"pone.0259485.ref021","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.jchf.2018.02.007","article-title":"Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure.","volume":"6","author":"M Vaduganathan","year":"2018","journal-title":"JACC Heart Fail"},{"issue":"27","key":"pone.0259485.ref022","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1093\/eurheartj\/ehw132","article-title":"A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and\/or chronic kidney disease","volume":"37","author":"G Filippatos","year":"2016","journal-title":"Eur Heart J"},{"issue":"1","key":"pone.0259485.ref023","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1161\/CIRCHEARTFAILURE.113.000792","article-title":"Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization 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