{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:51:45Z","timestamp":1790095905369,"version":"4.0.1"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2016,11,20]],"date-time":"2016-11-20T00:00:00Z","timestamp":1479600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"EMPHASIS-HF study was funded by Pfizer, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K+ &amp;lt;4.0 mmol\/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow-up was 21 months. Baseline hypokalaemia and hypokalaemia during follow-up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow-up was associated with worse outcomes in multivariable analyses [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.05\u20131.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group (HR 1.37, 95% CI 1.05\u20131.79, P = 0.02) but not in the eplerenone group (HR 0.87, 95% CI 0.62\u20131.23, P = 0.44; P for interaction = 0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo (HR 0.44, 95% 0.30\u20130.64, P &amp;lt; 0.0001 vs. 0.69, 95% CI 0.57\u20130.83, P = 0.0001; P for interaction = 0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow-up (HR 0.69, 95% CI 0.59\u20130.80, P &amp;lt; 0.001). A potassium level &amp;gt;4.0 mmol\/L at 1 month after randomization mediated 26.0% (0.6\u201351.4%) of the eplerenone treatment effect (P = 0.04).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.688","type":"journal-article","created":{"date-parts":[[2016,11,20]],"date-time":"2016-11-20T23:22:40Z","timestamp":1479684160000},"page":"792-799","source":"Crossref","is-referenced-by-count":44,"title":["Impact of Eplerenone on Cardiovascular Outcomes in Heart Failure Patients with Hypokalaemia"],"prefix":"10.1093","volume":"19","author":[{"given":"Patrick","family":"Rossignol","sequence":"first","affiliation":[{"name":"Inserm, Centre d'Investigations Cliniques-Plurith\u00e9matique 14-33, and Inserm U1116 , Nancy ,","place":["France"]},{"name":"CHU Nancy, P\u00f4le de Cardiologie , Vandoeuvre l\u00e8s Nancy ,","place":["France"]},{"name":"Universit\u00e9 de Lorraine \u00a0","place":["France"]},{"name":"F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Girerd","sequence":"additional","affiliation":[{"name":"Inserm, Centre d'Investigations Cliniques-Plurith\u00e9matique 14-33, and Inserm U1116 , Nancy ,","place":["France"]},{"name":"CHU Nancy, P\u00f4le de Cardiologie , Vandoeuvre l\u00e8s Nancy ,","place":["France"]},{"name":"Universit\u00e9 de Lorraine \u00a0","place":["France"]},{"name":"F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Bakris","sequence":"additional","affiliation":[{"name":"ASH Comprehensive Hypertension Center, The University of Chicago Medicine , Chicago, IL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly","family":"Vardeny","sequence":"additional","affiliation":[{"name":"University of Wisconsin School of Pharmacy , Madison, WI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Claggett","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"The British Heart Foundation Cardiovascular Research Centre, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Swedberg","sequence":"additional","affiliation":[{"name":"Sahlgrenska Academy, University of Gothenburg , Gothenburg ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Krum","sequence":"additional","affiliation":[{"name":"Monash University , Melbourne, VIC ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"van Veldhuisen","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Shi","sequence":"additional","affiliation":[{"name":"Pfizer , NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Spanyers","sequence":"additional","affiliation":[{"name":"Pfizer , NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Vincent","sequence":"additional","affiliation":[{"name":"Pfizer , NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renaud","family":"Fay","sequence":"additional","affiliation":[{"name":"Inserm, Centre d'Investigations Cliniques-Plurith\u00e9matique 14-33, and Inserm U1116 , Nancy ,","place":["France"]},{"name":"CHU Nancy, P\u00f4le de Cardiologie , Vandoeuvre l\u00e8s Nancy ,","place":["France"]},{"name":"Universit\u00e9 de Lorraine \u00a0","place":["France"]},{"name":"F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohra","family":"Lamiral","sequence":"additional","affiliation":[{"name":"Inserm, Centre d'Investigations Cliniques-Plurith\u00e9matique 14-33, and Inserm U1116 , Nancy ,","place":["France"]},{"name":"CHU Nancy, P\u00f4le de Cardiologie , Vandoeuvre l\u00e8s Nancy ,","place":["France"]},{"name":"Universit\u00e9 de Lorraine \u00a0","place":["France"]},{"name":"F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Inserm, Centre d'Investigations Cliniques-Plurith\u00e9matique 14-33, and Inserm U1116 , Nancy ,","place":["France"]},{"name":"CHU Nancy, P\u00f4le de Cardiologie , Vandoeuvre l\u00e8s Nancy ,","place":["France"]},{"name":"Universit\u00e9 de Lorraine \u00a0","place":["France"]},{"name":"F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"Pitt","sequence":"additional","affiliation":[{"name":"University of Michigan School of Medicine , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,11,20]]},"reference":[{"key":"2026011721184664500_ejhf688-bib-0001","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.ijcard.2014.11.004","article-title":"Time to retrieve the best benefits from renin angiotensin aldosterone system (RAAS) inhibition in heart failure patients with reduced ejection fraction: lessons from randomized controlled trials and registries","volume":"177","author":"Rossignol","year":"2014","journal-title":"Int J Cardiol"},{"key":"2026011721184664500_ejhf688-bib-0002","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1016\/j.jacc.2013.04.086","article-title":"Safety and efficacy of eplerenone in patients at high-risk for hyperkalemia and\/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure)","volume":"62","author":"Eschalier","year":"2013","journal-title":"J Am Coll Cardiol"},{"key":"2026011721184664500_ejhf688-bib-0003","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1161\/CIRCHEARTFAILURE.114.001104","article-title":"Incidence, predictors and outcomes related to hypo and hyperkalemia in severe heart failure patients treated with a mineralocorticoid receptor antagonist","volume":"7","author":"Vardeny","year":"2014","journal-title":"Circ Heart Fail"},{"key":"2026011721184664500_ejhf688-bib-0004","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ijcard.2011.06.121","article-title":"The meaning of hypokalemia in heart failure","volume":"158","author":"Bielecka-Dabrowa","year":"2012","journal-title":"Int J Cardiol"},{"key":"2026011721184664500_ejhf688-bib-0005","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1093\/eurheartj\/ehm091","article-title":"A propensity-matched study of the association of low serum potassium levels and mortality in chronic heart failure","volume":"28","author":"Ahmed","year":"2007","journal-title":"Eur Heart J"},{"key":"2026011721184664500_ejhf688-bib-0006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijcard.2008.05.047","article-title":"A propensity-matched study of low serum potassium and mortality in older adults with chronic heart failure","volume":"137","author":"Alper","year":"2009","journal-title":"Int J Cardiol"},{"key":"2026011721184664500_ejhf688-bib-0007","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1016\/j.jacc.2011.04.049","article-title":"Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects. Insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy","volume":"58","author":"Rossignol","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"2026011721184664500_ejhf688-bib-0008","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 and Survival Study in Heart Failure (EMPHASIS-HF)","volume":"7","author":"Rossignol","year":"2014","journal-title":"Circ Heart Fail"},{"key":"2026011721184664500_ejhf688-bib-0009","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":"Zannad","year":"2011","journal-title":"N Engl J Med"},{"key":"2026011721184664500_ejhf688-bib-0010","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1093\/eurjhf\/hfq049","article-title":"Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF)","volume":"12","author":"Zannad","year":"2010","journal-title":"Eur J Heart Fail"},{"key":"2026011721184664500_ejhf688-bib-0011","doi-asserted-by":"crossref","first-page":"137","DOI":"10.7326\/0003-4819-139-2-200307150-00013","article-title":"National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification","volume":"139","author":"Levey","year":"2003","journal-title":"Ann Intern Med"},{"key":"2026011721184664500_ejhf688-bib-0012","author":"Hertzmark","year":"2012"},{"key":"2026011721184664500_ejhf688-bib-0013","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1002\/(SICI)1097-0258(19970715)16:13<1515::AID-SIM572>3.0.CO;2-1","article-title":"Estimating the proportion of treatment effect explained by a surrogate marker","volume":"16","author":"Lin","year":"1997","journal-title":"Stat Med"},{"key":"2026011721184664500_ejhf688-bib-0014","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/sim.4780020219","article-title":"Tests for interaction in epidemiologic studies: a review and a study of power","volume":"2","author":"Greenland","year":"1983","journal-title":"Stat Med"},{"key":"2026011721184664500_ejhf688-bib-0015","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jclinepi.2003.08.009","article-title":"Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test","volume":"57","author":"Brookes","year":"2004","journal-title":"J Clin Epidemiol"},{"key":"2026011721184664500_ejhf688-bib-0016","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1056\/NEJMoa064039","article-title":"Surgery versus prolonged conservative treatment for sciatica","volume":"356","author":"Peul","year":"2007","journal-title":"N Engl J Med"},{"key":"2026011721184664500_ejhf688-bib-0017","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2011-000385","article-title":"Postoperative atrial fibrillation predicts long-term survival after aortic-valve surgery but not after mitral-valve surgery: a retrospective study","volume":"1","author":"Girerd","year":"2011","journal-title":"BMJ Open"},{"key":"2026011721184664500_ejhf688-bib-0018","doi-asserted-by":"crossref","first-page":"719","DOI":"10.3945\/ajcn.110.007153","article-title":"Subcutaneous adipose tissue in relation to subclinical atherosclerosis and cardiometabolic risk factors in midlife women","volume":"93","author":"Wildman","year":"2011","journal-title":"Am J Clin Nutr"},{"key":"2026011721184664500_ejhf688-bib-0019","doi-asserted-by":"crossref","first-page":"5589","DOI":"10.1200\/JCO.2008.16.7254","article-title":"EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan","volume":"26","author":"Takano","year":"2008","journal-title":"J Clin Oncol"},{"key":"2026011721184664500_ejhf688-bib-0020","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/art.23570","article-title":"Graded activity for workers with low back pain: who benefits most and how does it work?","volume":"59","author":"Staal","year":"2008","journal-title":"Arthritis Rheum"},{"key":"2026011721184664500_ejhf688-bib-0021","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S0008-6363(99)00017-6","article-title":"Electrophysiological remodeling in hypertrophy and heart failure","volume":"42","author":"Tomaselli","year":"1999","journal-title":"Cardiovasc Res"},{"key":"2026011721184664500_ejhf688-bib-0022","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jacc.2003.06.021","article-title":"What is the optimal serum potassium level in cardiovascular patients?","volume":"43","author":"Macdonald","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"2026011721184664500_ejhf688-bib-0023","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1161\/CIRCHEARTFAILURE.109.899526","article-title":"Hypokalemia and outcomes in patients with chronic heart failure and chronic kidney disease: findings from propensity-matched studies","volume":"3","author":"Bowling","year":"2010","journal-title":"Circ Heart Fail"},{"key":"2026011721184664500_ejhf688-bib-0024","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/eurheartj\/eht386","article-title":"Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis","volume":"35","author":"Damman","year":"2014","journal-title":"Eur Heart J"},{"key":"2026011721184664500_ejhf688-bib-0025","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.ijcard.2014.02.034","article-title":"Incident hyperkalemia may be an independent therapeutic target in low ejection fraction heart failure patients: insights from the heaal study","volume":"173","author":"Rossignol","year":"2014","journal-title":"Int J Cardiol"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fejhf.688","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fejhf.688","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/19\/6\/792\/66328262\/eurjhf_19_6_792.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/19\/6\/792\/66328262\/eurjhf_19_6_792.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T02:20:21Z","timestamp":1768702821000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/19\/6\/792\/8418595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,20]]},"references-count":25,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,11,20]]},"published-print":{"date-parts":[[2017,6,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.688","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,6]]},"published":{"date-parts":[[2016,11,20]]}}}