{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:40:11Z","timestamp":1786977611518,"version":"build-2736575974"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100\u2009mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25\u2009mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7\u03b1-thiomethylspironolactone (7\u03b1-TMS)] in the high-dose group could have contributed to these neutral results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-na\u00efve, n =\u2009112), concentrations of canrenone and 7\u03b1-TMS increased at 48 and 96\u2009h compared to baseline, and between 48 and 96\u2009h (all P &amp;lt;\u20090.005), indicating that steady-state concentrations had not been reached by 48\u2009h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n =\u200937), concentrations of canrenone increased at 48 and 96\u2009h compared to baseline (both P &amp;lt;\u20090.0005), with a marginal increase between 48 and 96\u2009h (P =\u20090.0507). At 48\u2009h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P &amp;lt;\u20090.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-na\u00efve patients (P &amp;lt;\u20090.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-na\u00efve patients at 48\u2009h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48\u2009h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1802","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T03:14:46Z","timestamp":1585710886000},"page":"1451-1461","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Spironolactone Metabolite Concentrations in Decompensated Heart Failure: Insights from the ATHENA-HF Trial"],"prefix":"10.1093","volume":"22","author":[{"given":"Simon","family":"de Denus","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy , Montreal ,","place":["Canada"]},{"name":"Montreal Heart Institute , Montreal ,","place":["Canada"]},{"name":"Universit\u00e9 de Montreal Beaulieu-Saucier Pharmacogenomics Center , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e9goire","family":"Leclair","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Pierre","family":"Dub\u00e9","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , Montreal ,","place":["Canada"]},{"name":"Universit\u00e9 de Montreal Beaulieu-Saucier Pharmacogenomics Center , Montreal ,","place":["Canada"]},{"name":"Medicine, Universit\u00e9 de Montr\u00e9al , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"St-Jean","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yassamin Feroz","family":"Zada","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , Montreal ,","place":["Canada"]},{"name":"Universit\u00e9 de Montreal Beaulieu-Saucier Pharmacogenomics Center , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essa\u00efd","family":"Oussa\u00efd","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , Montreal ,","place":["Canada"]},{"name":"Universit\u00e9 de Montreal Beaulieu-Saucier Pharmacogenomics Center , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Jutras","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Givertz","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Mentz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University , Durham, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.H. Wilson","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cleveland Clinic , Cleveland, OH ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Pedro","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm, Centre d\u2019Investigations Cliniques-Plurith\u00e9matique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Rouleau","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute , Montreal ,","place":["Canada"]},{"name":"Medicine, Universit\u00e9 de Montr\u00e9al , Montreal ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Stony Brook University , Stony Brook, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas P.","family":"Kalogeropoulos","sequence":"additional","affiliation":[{"name":"Department of Medicine, Emory University , Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,1]]},"reference":[{"key":"2026011721363178200_ejhf1802-bib-0001","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s10741-011-9233-7","article-title":"A re-appraisal of volume status and renal function impairment in chronic heart failure: combined effects of pre-renal failure and venous congestion on renal function","volume":"17","author":"Sinkeler","year":"2012","journal-title":"Heart Fail Rev"},{"key":"2026011721363178200_ejhf1802-bib-0002","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/ejhf.74","article-title":"Decongestion in acute heart failure","volume":"16","author":"Mentz","year":"2014","journal-title":"Eur J Heart Fail"},{"key":"2026011721363178200_ejhf1802-bib-0003","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1093\/eurjhf\/hft100","article-title":"Serum aldosterone is associated with mortality and re-hospitalization in patients with reduced ejection fraction hospitalized for acute heart failure: analysis from the EVEREST trial","volume":"15","author":"Girerd","year":"2013","journal-title":"Eur J Heart Fail"},{"key":"2026011721363178200_ejhf1802-bib-0004","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1159\/000168356","article-title":"Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention","volume":"11","author":"Hensen","year":"1991","journal-title":"Am J Nephrol"},{"key":"2026011721363178200_ejhf1802-bib-0005","doi-asserted-by":"crossref","first-page":"21A","DOI":"10.1016\/0002-9149(93)90241-4","article-title":"Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor","volume":"71","author":"van Vliet","year":"1993","journal-title":"Am J Cardiol"},{"key":"2026011721363178200_ejhf1802-bib-0006","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ejim.2013.08.711","article-title":"Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure","volume":"25","author":"Ferreira","year":"2014","journal-title":"Eur J Intern Med"},{"key":"2026011721363178200_ejhf1802-bib-0007","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1001\/jamacardio.2017.2198","article-title":"Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial","volume":"2","author":"Butler","year":"2017","journal-title":"JAMA Cardiol"},{"key":"2026011721363178200_ejhf1802-bib-0008","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3109\/03602537808993782","article-title":"Spironolactone: disposition, metabolism, pharmacodynamics, and bioavailability","volume":"8","author":"Karim","year":"1978","journal-title":"Drug Metab Rev"},{"key":"2026011721363178200_ejhf1802-bib-0009","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S0090-9556(25)08434-X","article-title":"Hepatic metabolism of spironolactone. Production of 3-hydroxy-thiomethyl metabolites","volume":"22","author":"Los","year":"1994","journal-title":"Drug Metab Dispos"},{"key":"2026011721363178200_ejhf1802-bib-0010","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/j.1365-2885.2009.01130.x","article-title":"A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog","volume":"33","author":"Guyonnet","year":"2010","journal-title":"J Vet Pharmacol Ther"},{"key":"2026011721363178200_ejhf1802-bib-0011","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1365-2125.1982.tb01383.x","article-title":"Relative potency and structure activity relationships of aldosterone antagonists in healthy man: correlation with animal experience","volume":"13","author":"McInnes","year":"1982","journal-title":"Br J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0012","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/clpt.1982.62","article-title":"Relative potency of amiloride and spironolactone in healthy man","volume":"31","author":"McInnes","year":"1982","journal-title":"Clin Pharmacol Ther"},{"key":"2026011721363178200_ejhf1802-bib-0013","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ahj.2004.08.005","article-title":"Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE)","volume":"149","author":"Adams","year":"2005","journal-title":"Am Heart J"},{"key":"2026011721363178200_ejhf1802-bib-0014","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1007\/s40262-014-0189-3","article-title":"Clinical pharmacokinetics of drugs in patients with heart failure: an update (part 2, drugs administered orally)","volume":"53","author":"Ogawa","year":"2014","journal-title":"Clin Pharmacokinet"},{"key":"2026011721363178200_ejhf1802-bib-0015","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.jchf.2016.06.003","article-title":"Rationale and design of the ATHENA-HF trial: Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure","volume":"4","author":"Butler","year":"2016","journal-title":"JACC Heart Fail"},{"key":"2026011721363178200_ejhf1802-bib-0016","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1056\/NEJMc1612601","article-title":"Spironolactone metabolites in TOPCAT \u2013 new insights into regional variation","volume":"376","author":"de Denus","year":"2017","journal-title":"N Engl J Med"},{"key":"2026011721363178200_ejhf1802-bib-0017","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/j.1552-4604.1989.tb03339.x","article-title":"Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites","volume":"29","author":"Gardiner","year":"1989","journal-title":"J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0018","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1007\/s00228-018-02615-8","article-title":"Is there a potential association between spironolactone and the risk of new-onset diabetes in a cohort of older patients with heart failure?","volume":"75","author":"Korol","year":"2019","journal-title":"Eur J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0019","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1161\/CIRCHEARTFAILURE.113.000709","article-title":"Guideline concordance of testing for hyperkalemia and kidney dysfunction during initiation of mineralocorticoid receptor antagonist therapy in patients with heart failure","volume":"7","author":"Allen","year":"2014","journal-title":"Circ Heart Fail"},{"key":"2026011721363178200_ejhf1802-bib-0020","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1016\/0016-5085(92)91730-R","article-title":"Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites","volume":"102","author":"Sungaila","year":"1992","journal-title":"Gastroenterology"},{"key":"2026011721363178200_ejhf1802-bib-0021","volume-title":"Clinical Pharmacokinetic and Pharmacodynamic Concepts. Applied Clinical Pharmacokinetics","author":"Bauer","year":"2015","edition":"3rd ed"},{"key":"2026011721363178200_ejhf1802-bib-0022","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/S0002-9149(96)00465-1","article-title":"Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES])","volume":"78","year":"1996","journal-title":"Am J Cardiol"},{"key":"2026011721363178200_ejhf1802-bib-0023","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.cardfail.2015.07.011","article-title":"N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements until a 30% reduction is attained during acute decompensated heart failure admissions and comparison with discharge NT-proBNP levels: implications for in-hospital guidance of treatment","volume":"21","author":"Stienen","year":"2015","journal-title":"J Card Fail"},{"key":"2026011721363178200_ejhf1802-bib-0024","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.jacc.2003.09.044","article-title":"Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure","volume":"43","author":"Logeart","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"2026011721363178200_ejhf1802-bib-0025","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.cardfail.2006.06.003","article-title":"Changes in plasma N-terminal proBNP levels and ventricular filling pressures during intensive unloading therapy in elderly with decompensated congestive heart failure and preserved left ventricular systolic function","volume":"12","author":"Cioffi","year":"2006","journal-title":"J Card Fail"},{"key":"2026011721363178200_ejhf1802-bib-0026","doi-asserted-by":"crossref","first-page":"G19","DOI":"10.1093\/eurheartj\/suw045","article-title":"The bumpy road to drug development for acute heart failure","volume":"18","author":"Hamo","year":"2016","journal-title":"Eur Heart J Suppl"},{"key":"2026011721363178200_ejhf1802-bib-0027","doi-asserted-by":"crossref","first-page":"94","DOI":"10.2165\/00003088-198815020-00002","article-title":"Clinical pharmacokinetics in heart failure. An updated review","volume":"15","author":"Shammas","year":"1988","journal-title":"Clin Pharmacokinet"},{"key":"2026011721363178200_ejhf1802-bib-0028","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2165\/00003088-197601060-00001","article-title":"Pharmacokinetics in patients with cardiac failure","volume":"1","author":"Benowitz","year":"1976","journal-title":"Clin Pharmacokinet"},{"key":"2026011721363178200_ejhf1802-bib-0029","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/BF00606407","article-title":"Elimination of canrenone in congestive heart failure and chronic liver disease","volume":"11","author":"Jackson","year":"1977","journal-title":"Eur J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0030","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/BF00560381","article-title":"Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure","volume":"7","author":"Sadee","year":"1974","journal-title":"Eur J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0031","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/clpt.1985.206","article-title":"New insights into the pharmacokinetics of spironolactone","volume":"38","author":"Overdiek","year":"1985","journal-title":"Clin Pharmacol Ther"},{"key":"2026011721363178200_ejhf1802-bib-0032","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/BF00542109","article-title":"Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man","volume":"25","author":"Krause","year":"1983","journal-title":"Eur J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0033","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/bcp.13760","article-title":"The influence of heart failure on the pharmacokinetics of cardiovascular and non-cardiovascular drugs: a critical appraisal of the evidence","volume":"85","author":"Mangoni","year":"2019","journal-title":"Br J Clin Pharmacol"},{"key":"2026011721363178200_ejhf1802-bib-0034","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s11886-012-0259-9","article-title":"The comorbidity conundrum: a focus on the role of noncardiovascular chronic conditions in the heart failure patient","volume":"14","author":"Page","year":"2012","journal-title":"Curr Cardiol Rep"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fejhf.1802","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejhf.1802","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ejhf.1802","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/22\/8\/1451\/66111856\/eurjhf_22_8_1451.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/22\/8\/1451\/66111856\/eurjhf_22_8_1451.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T02:37:49Z","timestamp":1768703869000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/22\/8\/1451\/8385162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,1]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,4,1]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.1802","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8]]},"published":{"date-parts":[[2020,4,1]]},"assertion":[{"value":"2019-11-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}