{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T23:48:42Z","timestamp":1791676122304,"version":"4.3.4"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Heart Fail Rev"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The composite of cardiovascular or all-cause death and worsening heart failure (WHF) has become the principal efficacy endpoint of heart failure trials. Yet WHF is not one event: it spans outpatient oral-diuretic escalation, urgent intravenous-diuretic visits, hospitalisation, and HF-related death\u2014tiers that differ markedly in frequency, ascertainment, and prognostic weight. A composite WHF benefit therefore cannot be properly interpreted without knowing which tier carries the signal, and we argue that this tier is both phenotype- and setting-dependent. Two trials published on the same day in 2026 make the point with unusual clarity. In the Dig-RHD trial of digoxin in rheumatic heart disease, the benefit concentrated in outpatient diuretic events, with neutral results at hospitalisation and death; in a contemporaneous meta-analysis of digitalis glycosides in reduced or mildly reduced ejection fraction, the same drug class reduced worsening heart failure mainly through hospitalisation, again without a mortality benefit. We use this contrast to propose a severity-gradient framework for reporting and interpreting worsening heart failure, and discuss its implications for trial design, for the translation of guideline-based evidence across health systems, and for the use of inexpensive therapies such as digoxin in low- and middle-income settings.<\/jats:p>","DOI":"10.1007\/s10741-026-10684-6","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:30:33Z","timestamp":1791667833000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Worsening heart failure is not a single endpoint: a severity-gradient perspective from digoxin in rheumatic heart disease"],"prefix":"10.1007","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9168-4991","authenticated-orcid":false,"given":"Koichiro","family":"Yuji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wakako","family":"Yuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,10]]},"reference":[{"issue":"4","key":"10684_CR1","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.jacc.2022.11.023","volume":"81","author":"SJ Greene","year":"2023","unstructured":"Greene SJ, Bauersachs J, Brugts JJ et al (2023) Worsening heart failure: nomenclature, epidemiology, and future directions: JACC review topic of the week. J Am Coll Cardiol 81(4):413\u2013424. https:\/\/doi.org\/10.1016\/j.jacc.2022.11.023","journal-title":"J Am Coll Cardiol"},{"issue":"17","key":"10684_CR2","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1161\/CIRCULATIONAHA.120.047480","volume":"142","author":"KF Docherty","year":"2020","unstructured":"Docherty KF, Jhund PS, Anand I et al (2020) Effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction: a prespecified analysis of DAPA-HF. Circulation 142(17):1623\u20131632. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.120.047480","journal-title":"Circulation"},{"issue":"19","key":"10684_CR3","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1001\/jama.2023.5942","volume":"329","author":"P Joseph","year":"2023","unstructured":"Joseph P, Roy A, Lonn E, G-CHF Investigators et al (2023) Global variations in heart failure etiology, management, and outcomes. JAMA 329(19):1650\u20131661. https:\/\/doi.org\/10.1001\/jama.2023.5942","journal-title":"JAMA"},{"key":"10684_CR4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2026.7335","author":"G Karthikeyan","year":"2026","unstructured":"Karthikeyan G, Devasenapathy N, Ghosh A et al (2026) Digoxin in patients with symptomatic rheumatic heart disease: a randomized clinical trial. JAMA. https:\/\/doi.org\/10.1001\/jama.2026.7335","journal-title":"JAMA"},{"issue":"8","key":"10684_CR5","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1056\/NEJMoa1603693","volume":"377","author":"DA Watkins","year":"2017","unstructured":"Watkins DA, Johnson CO, Colquhoun SM et al (2017) Global, regional, and national burden of rheumatic heart disease, 1990\u20132015. N Engl J Med 377(8):713\u2013722. https:\/\/doi.org\/10.1056\/NEJMoa1603693","journal-title":"N Engl J Med"},{"issue":"6","key":"10684_CR6","doi-asserted-by":"publisher","first-page":"3898","DOI":"10.1002\/ehf2.14096","volume":"9","author":"S Harikrishnan","year":"2022","unstructured":"Harikrishnan S, Bahl A, Roy A et al (2022) Clinical profile and 90-day outcomes of 10 851 heart failure patients across India: national heart failure registry. ESC Heart Fail 9(6):3898\u20133908. https:\/\/doi.org\/10.1002\/ehf2.14096","journal-title":"ESC Heart Fail"},{"key":"10684_CR7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2026.7886","author":"K Damman","year":"2026","unstructured":"Damman K, van Veldhuisen DJ, Bauersachs J et al (2026) Efficacy and safety of digitalis glycosides in heart failure: a meta-analysis. JAMA. https:\/\/doi.org\/10.1001\/jama.2026.7886","journal-title":"JAMA"},{"issue":"8","key":"10684_CR8","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1056\/NEJM199702203360801","volume":"336","author":"The Digitalis Investigation Group","year":"1997","unstructured":"The Digitalis Investigation Group (1997) The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 336(8):525\u2013533. https:\/\/doi.org\/10.1056\/NEJM199702203360801","journal-title":"N Engl J Med"},{"issue":"12","key":"10684_CR9","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1056\/NEJMoa2415471","volume":"393","author":"U Bavendiek","year":"2025","unstructured":"Bavendiek U, Grosshennig A, Schwab J et al (2025) Digitoxin in patients with heart failure and reduced ejection fraction. N Engl J Med 393(12):1155\u20131165. https:\/\/doi.org\/10.1056\/NEJMoa2415471","journal-title":"N Engl J Med"},{"key":"10684_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-026-04406-6","author":"DJ van Veldhuisen","year":"2026","unstructured":"van Veldhuisen DJ, Rienstra M, Mosterd A et al (2026) Low-dose digoxin in heart failure with reduced or mildly reduced ejection fraction. Nat Med. https:\/\/doi.org\/10.1038\/s41591-026-04406-6","journal-title":"Nat Med"}],"container-title":["Heart Failure Reviews"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10741-026-10684-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10741-026-10684-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10741-026-10684-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T23:04:50Z","timestamp":1791673490000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10741-026-10684-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,10]]},"references-count":10,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["10684"],"URL":"https:\/\/doi.org\/10.1007\/s10741-026-10684-6","relation":{},"ISSN":["1573-7322"],"issn-type":[{"value":"1573-7322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,10]]},"assertion":[{"value":"1 July 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable. This is a perspective article based on previously published, publicly available aggregate trial data; it does not involve new human participant research. The manuscript does not contain clinical studies or patient data.","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable. The manuscript does not contain clinical studies or patient data.","order":2,"name":"Ethics","label":"Consent to participate\/Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"During the preparation of this work the authors used Claude (Anthropic) for AI-assisted improvements to readability and language and to assist in checking references, consistent with the journal's policy on AI-assisted copy editing. The tool was not used for generative editorial work, autonomous content creation, or to draw the scientific conclusions presented. The authors reviewed and edited all content and take full responsibility for the content of the publication.","order":3,"name":"Ethics","label":"Declaration of generative AI use","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Financial interests: Dr Koichiro Yuji has received institutional support from Tokyu Land Corporation for a Social Cooperation Research Department at the University of Tokyo, and consultation fees from Seoritsu Biotech, outside the submitted work. Dr Wakako Yuji declares she has no financial interests. Non-financial interests: none.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"114"}}