{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:46:06Z","timestamp":1790063166916,"version":"4.0.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2016,8,1]],"date-time":"2016-08-01T00:00:00Z","timestamp":1470009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (\u22650.5\u2009ng\/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14\u20131.38, P &amp;lt; 0.001 per 0.5\u2009ng\/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5\u20130.7\u2009ng\/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67\u20130.89, P &amp;lt; 0.001) while high serum concentrations (1.6\u20132.0\u2009ng\/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12\u20131.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5\u20130.7\u2009ng\/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings favour targeting serum concentrations from 0.5 to 0.7\u2009ng\/mL when dosing digoxin in patients with heart failure and reduced EF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.584","type":"journal-article","created":{"date-parts":[[2016,8,5]],"date-time":"2016-08-05T04:49:04Z","timestamp":1470372544000},"page":"1072-1081","source":"Crossref","is-referenced-by-count":61,"title":["Dose Response Characterization of the Association of Serum Digoxin Concentration with Mortality Outcomes in the Digitalis Investigation Group Trial"],"prefix":"10.1093","volume":"18","author":[{"suffix":"Jr","given":"Kirkwood F.","family":"Adams","sequence":"first","affiliation":[{"name":"Departments of Medicine and Radiology, School of Medicine, Division of Cardiology, University of North Carolina at Chapel Hill , Chapel Hill, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Emory University , Atlanta, GA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Herbert","family":"Patterson","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy , Chapel Hill, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Gattis Stough","sequence":"additional","affiliation":[{"name":"Departments of Clinical Research and Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences , Buies Creek, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry L.","family":"Bauman","sequence":"additional","affiliation":[{"name":"Departments of Pharmacy Practice and Medicine, Section of Cardiology, Colleges of Pharmacy and Medicine, University of Illinois at Chicago , Chicago, IL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"van Veldhuisen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd A.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill , Chapel Hill, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani","family":"Sabbah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Wayne State University, Henry Ford Health System , Detroit, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John I.","family":"Mackowiak","sequence":"additional","affiliation":[{"name":"Center for Outcomes Research , Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector O.","family":"Ventura","sequence":"additional","affiliation":[{"name":"John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine , New Orleans, LA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalal K.","family":"Ghali","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Mercer University School of Medicine , Macon, GA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,8,5]]},"reference":[{"key":"2026011721154634500_ejhf584-bib-0001","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/ejhf.64","article-title":"A perspective on re-evaluating digoxin's role in the current management of patients with chronic systolic heart failure: targeting serum concentration to reduce hospitalization and improve safety profile","volume":"16","author":"Adams","year":"2014","journal-title":"Eur J Heart Fail"},{"key":"2026011721154634500_ejhf584-bib-0002","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1161\/CIRCULATIONAHA.105.560110","article-title":"Contemporary use of digoxin in the management of cardiovascular disorders","volume":"113","author":"Gheorghiade","year":"2006","journal-title":"Circulation"},{"key":"2026011721154634500_ejhf584-bib-0003","author":"Withering","year":"1785"},{"key":"2026011721154634500_ejhf584-bib-0004","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1056\/NEJM199702203360801","article-title":"The effect of digoxin on mortality and morbidity in patients with heart failure","volume":"336","author":"The Digitalis Investigation Group","year":"1997","journal-title":"N Engl J Med"},{"key":"2026011721154634500_ejhf584-bib-0005","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJM197105062841801","article-title":"Digitalis intoxication. 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