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Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides \u2013 although regularly used for HF treatment \u2013 remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with chronic HF, New York Heart Association (NYHA) functional class III\u2013IV and left ventricular ejection fraction (LVEF) \u2264\u200940%, or patients in NYHA functional class II and LVEF \u2264\u200930% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8\u201318\u2009ng\/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and\/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1452","type":"journal-article","created":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T06:10:25Z","timestamp":1553062225000},"page":"676-684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Rationale and Design of the DIGIT-HF Trial (DIGitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure): A Randomized, Double-Blind, Placebo-Controlled Study"],"prefix":"10.1093","volume":"21","author":[{"given":"Udo","family":"Bavendiek","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School , Hannover ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Berliner","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School , Hannover ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas Aguirre","family":"D\u00e1vila","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Hannover Medical School , Hannover ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Schwab","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Center, Clinical Center Nuernberg, Paracelsus Medical University , Nuernberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Maier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University Medical Center Regensburg , Regensburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian A.","family":"Philipp","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Intensive Care Medicine, Elbe Clinic Stade , Stade ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Rieth","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Kerckhoff Heart, Rheuma and Thoracic Center , Bad Nauheim ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Westenfeld","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf , Duesseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Piorkowski","sequence":"additional","affiliation":[{"name":"Department of Electrophysiology, Heart Center, University of Technology Dresden , Dresden ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Hannover Medical School , Hannover ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"H\u00e4nselmann","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School , Hannover ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximiliane","family":"Oldhafer","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical 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