{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:47:07Z","timestamp":1776934027749,"version":"3.51.2"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":295,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The 2021 European heart failure (HF) guidelines recommend the combination of four drugs as a standard therapy (angiotensin-converting enzyme inhibitor [ACEI]\/angiotensin receptor blocker [ARB]\/angiotensin receptor-neprilysin inhibitor [ARNI]; beta-blocker (BB); mineralocorticoid receptor antagonist [MRA]; sodium-glucose co-transporter 2 inhibitor [SGLT2i]) in patients with heart failure and reduced ejection fraction (HFrEF). We investigated if the use of this combined treatment (as opposed to the outdated two-drug ACEI\/ARB and BB therapy) yields a favourable outcome regarding mortality and readmission and evaluated whether an increase in adoption of the newly endorsed therapy can already be observed in clinical routine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We included anonymous data from all patients who were insured at Germany\u2019s largest health insurer (Allgemeine Ortskrankenkasse [AOK]) and had a claims record for hospitalization (2019\u20132021) with the main diagnosis of HF. Mortality and readmission within 91\u2013365 days following the index stay were analysed, and the impact of medication on outcome was compared. 315\u2009342 cases of hospitalization due to HF were included (median 80 years [IQR 72\u201386], 53.7% female). HF drug prescription rates were as follows: ACEI 46.3%, ARB 31.8%, ARNI 12.1%, BB 80.9%, MRA 35.6%, SGLT2i 7.3%. Treatment combinations were prescribed in 35.9% (two-drug) and 3.7% (four-drug). Total mortality was 18.0%, all-cause readmission 32.0%, and HF readmission 16.0%. Mortality risk was significantly lower (adjusted HR = 0.92 [95% CI 0.86\u20130.97]) with the four- versus two-drug treatment. Kaplan\u2013Meier survival was 88.2% for the four-drug therapy [95% CI: 87.6%\u201388.8%] and 83.1% for the two-drug therapy [95% CI: 82.9%\u201383.3%]). Similar benefits were visible for the readmission rates due to all causes (HR = 0.76 [0.73\u20130.80]) and readmission due to HF (HR = 0.90 [0.85\u20130.95]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study suggests that the newly recommended four-drug therapy may lead to lower mortality and readmission rates compared to the outdated two-drug therapy. However, the overall adoption of the four-drug therapy remains limited.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.15280","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:24Z","timestamp":1745971224000},"page":"2791-2802","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prescription of Guideline-Directed Medical Therapy in Heart Failure: Impact on Mortality and Readmission"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-3709","authenticated-orcid":false,"given":"Martin","family":"M\u00f6ckel","sequence":"first","affiliation":[{"name":"Department of Emergency and Acute Medicine, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t and Humboldt-Universit\u00e4t zu Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samipa","family":"Pudasaini","sequence":"additional","affiliation":[{"name":"Department of Emergency and Acute Medicine, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t and Humboldt-Universit\u00e4t zu Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Feldmann","sequence":"additional","affiliation":[{"name":"Department of Emergency and Acute Medicine, Campus Virchow-Klinikum and Campus Charit\u00e9 Mitte, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t and Humboldt-Universit\u00e4t zu Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henning Thomas","family":"Baberg","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology, Helios Klinikum, Berlin-Buch and Medical School Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benny","family":"Levenson","sequence":"additional","affiliation":[{"name":"German Society of Cardiologists in Private Practise (BNK) , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00fcrgen","family":"Malzahn","sequence":"additional","affiliation":[{"name":"Federal Association of the Local Health Care Funds (AOK) , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Mansky","sequence":"additional","affiliation":[{"name":"Faculty of Economics and Management, Division of Structural Development and Quality Management in Healthcare, Technische Universit\u00e4t Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Michels","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Hospital of the Barmherzige Br\u00fcder , Trier ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3085-6259","authenticated-orcid":false,"given":"Christian","family":"G\u00fcnster","sequence":"additional","affiliation":[{"name":"Research Institute of the Local Health Care Funds (WIdO) , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5586-4020","authenticated-orcid":false,"given":"Elke","family":"Jeschke","sequence":"additional","affiliation":[{"name":"Research Institute of the Local Health Care Funds (WIdO) , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"2026021804073381900_ehf215280-bib-0001","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.122.027852","article-title":"Burden, trends, and inequalities of heart failure globally, 1990 to 2019: a secondary analysis based on the global burden of disease 2019 study","volume":"12","author":"Yan","year":"2023","journal-title":"J Am Heart Assoc"},{"key":"2026021804073381900_ehf215280-bib-0002","doi-asserted-by":"publisher","first-page":"3599","DOI":"10.1093\/eurheartj\/ehab368","article-title":"2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur Heart J"},{"key":"2026021804073381900_ehf215280-bib-0003","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1016\/j.jacc.2024.05.014","article-title":"2024 update to the 2020 ACC\/AHA clinical performance and quality measures for adults with heart failure: a report of the American Heart Association\/American College of Cardiology Joint Committee on Performance Measures","volume":"84","author":"Writing Committee","year":"2024","journal-title":"J Am Coll Cardiol"},{"key":"2026021804073381900_ehf215280-bib-0004","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur Heart J"},{"key":"2026021804073381900_ehf215280-bib-0005","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators","volume":"341","author":"Pitt","year":"1999","journal-title":"N Engl J Med"},{"key":"2026021804073381900_ehf215280-bib-0006","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1002\/ejhf.592","article-title":"2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"18","author":"Ponikowski","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0007","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1093\/eurheartj\/ehs104","article-title":"ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC","volume":"33","author":"McMurray","year":"2012","journal-title":"Eur Heart J"},{"key":"2026021804073381900_ehf215280-bib-0008","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1161\/CIRCULATIONAHA.119.044586","article-title":"Sacubitril\/valsartan across the Spectrum of ejection fraction in heart failure","volume":"141","author":"Solomon","year":"2020","journal-title":"Circulation"},{"key":"2026021804073381900_ehf215280-bib-0009","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and renal outcomes with empagliflozin in heart failure","volume":"383","author":"Packer","year":"2020","journal-title":"N Engl J Med"},{"key":"2026021804073381900_ehf215280-bib-0010","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1001\/jama.1995.03520420066040","article-title":"Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials","volume":"273","author":"Garg","year":"1995","journal-title":"JAMA"},{"key":"2026021804073381900_ehf215280-bib-0011","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1056\/NEJM199605233342101","article-title":"The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group","volume":"334","author":"Packer","year":"1996","journal-title":"N Engl J Med"},{"key":"2026021804073381900_ehf215280-bib-0012","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/ejhf.2333","article-title":"ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"24","author":"McDonagh","year":"2022","journal-title":"Eur J Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0013","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1002\/ejhf.1234","article-title":"Incremental benefit of drug therapies for chronic heart failure with reduced ejection fraction: a network meta-analysis","volume":"20","author":"Komajda","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0014","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0140-6736(20)30748-0","article-title":"Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials","volume":"396","author":"Vaduganathan","year":"2020","journal-title":"Lancet"},{"key":"2026021804073381900_ehf215280-bib-0015","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1002\/ehf2.14600","article-title":"Pharmacoutilization and adherence to sacubitril\/valsartan in real world: the REAL.IT study in HFrEF","volume":"11","author":"Iacoviello","year":"2024","journal-title":"ESC Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0016","volume-title":"Mitglieder und Versicherte der gesetzlichen Krankenversicherung (GKV)","author":"Bundesministerium f\u00fcr Gesundheit","year":"2023"},{"key":"2026021804073381900_ehf215280-bib-0017","first-page":"54","article-title":"Arbeitsgruppe Erhebung und Nutzung von Sekundardaten der Deutschen Gesellschaft fur Sozialmedizin und P, Arbeitsgruppe Epidemiologische Methoden der Deutschen Gesellschaft fur Epid e m, Deutschen Gesellschaft fur Medizinische Informatik BuE, Deutschen Gesellschaft fur Sozialmedizin und P. [Good practice of secondary data analysis, first revision]","volume":"70","year":"2008","journal-title":"Gesundheitswesen"},{"key":"2026021804073381900_ehf215280-bib-0018","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1097\/00005650-199801000-00004","article-title":"Comorbidity measures for use with administrative data","volume":"36","author":"Elixhauser","year":"1998","journal-title":"Med Care"},{"key":"2026021804073381900_ehf215280-bib-0019","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1002\/pst.433","article-title":"Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies","volume":"10","author":"Austin","year":"2011","journal-title":"Pharm Stat"},{"key":"2026021804073381900_ehf215280-bib-0020","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1002\/sim.5984","article-title":"The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments","volume":"33","author":"Austin","year":"2014","journal-title":"Stat Med"},{"key":"2026021804073381900_ehf215280-bib-0021","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1002\/ejhf.1858","article-title":"Epidemiology of heart failure","volume":"22","author":"Groenewegen","year":"2020","journal-title":"Eur J Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0022","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1161\/CIRCRESAHA.116.307547","article-title":"Cardiovascular disease in women: clinical perspectives","volume":"118","author":"Garcia","year":"2016","journal-title":"Circ Res"},{"key":"2026021804073381900_ehf215280-bib-0023","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.rec.2017.03.001","article-title":"Trends and characteristics of hospitalization for heart failure in a population setting from 2003 to 2013","volume":"70","author":"Fernandez Gasso","year":"2017","journal-title":"Rev Esp Cardiol (Engl Ed)"},{"key":"2026021804073381900_ehf215280-bib-0024","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1002\/ejhf.1818","article-title":"Trends in prevalence of comorbidities in heart failure clinical trials","volume":"22","author":"Khan","year":"2020","journal-title":"Eur J Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0025","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1007\/s42399-021-01005-z","article-title":"Impact of COVID-19 on heart failure hospitalizations","volume":"3","author":"Babapoor-Farrokhran","year":"2021","journal-title":"SN Compr Clin Med"},{"key":"2026021804073381900_ehf215280-bib-0026","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3238\/arztebl.2020.0545","article-title":"German forum of university emergency departments in the Society of University Clinics of Germany EV. Medical emergencies during the COVID-19 pandemic","volume":"117","author":"Slagman","year":"2020","journal-title":"Dtsch Arztebl Int"},{"key":"2026021804073381900_ehf215280-bib-0027","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1007\/s00392-022-02074-3","article-title":"Medical and cardio-vascular emergency department visits during the COVID-19 pandemic in 2020: is there a collateral damage? A retrospective routine data analysis","volume":"111","author":"Slagman","year":"2022","journal-title":"Clin Res Cardiol"},{"key":"2026021804073381900_ehf215280-bib-0028","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.jacc.2023.05.040","article-title":"Global comparison of readmission rates for patients with heart failure","volume":"82","author":"Foroutan","year":"2023","journal-title":"J Am Coll Cardiol"},{"key":"2026021804073381900_ehf215280-bib-0029","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.2147\/TCRM.S340587","article-title":"Mortality and readmission rates after heart failure: a systematic review and meta-analysis","volume":"17","author":"Lan","year":"2021","journal-title":"Ther Clin Risk Manag"},{"key":"2026021804073381900_ehf215280-bib-0030","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in patients with heart failure and reduced ejection fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N Engl J Med"},{"key":"2026021804073381900_ehf215280-bib-0031","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.jacc.2018.04.070","article-title":"Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry","volume":"72","author":"Greene","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"2026021804073381900_ehf215280-bib-0032","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0167-5273(01)00600-3","article-title":"Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials","volume":"82","author":"Faris","year":"2002","journal-title":"Int J Cardiol"},{"key":"2026021804073381900_ehf215280-bib-0033","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1093\/eurjhf\/hft050","article-title":"EURObservational research Programme: regional differences and 1-year follow-up results of the heart failure pilot survey (ESC-HF pilot)","volume":"15","author":"Maggioni","year":"2013","journal-title":"Eur J Heart Fail"},{"key":"2026021804073381900_ehf215280-bib-0034","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.amjmed.2019.06.040","article-title":"Prior heart failure hospitalization and outcomes in patients with heart failure with preserved and reduced ejection fraction","volume":"133","author":"Malik","year":"2020","journal-title":"Am J Med"},{"key":"2026021804073381900_ehf215280-bib-0035","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1287434","article-title":"Sex differences in mortality and hospitalization in heart failure with preserved and mid-range ejection fraction: a systematic review and meta-analysis of cohort studies","volume":"10","author":"Deng","year":"2023","journal-title":"Front Cardiovasc Med"},{"key":"2026021804073381900_ehf215280-bib-0036","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2458-10-637","article-title":"Age- and gender-specific risk of death after first hospitalization for heart failure","volume":"10","author":"Vaartjes","year":"2010","journal-title":"BMC Public Health"},{"key":"2026021804073381900_ehf215280-bib-0037","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.pcad.2022.11.013","article-title":"Updates on obesity and the obesity paradox in cardiovascular diseases","volume":"78","author":"Tutor","year":"2023","journal-title":"Prog Cardiovasc Dis"},{"key":"2026021804073381900_ehf215280-bib-0038","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1055\/s-0031-1275711","article-title":"Structural differences between health insurance funds and their impact on health services research: results from the Bertelsmann health-care monitor","volume":"74","author":"Hoffmann","year":"2012","journal-title":"Gesundheitswesen"},{"key":"2026021804073381900_ehf215280-bib-0039","volume-title":"InEK GmbH. Nutzungsbedingungen","author":"InEK DatenBrowser","year":"2024"}],"container-title":["ESC Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/12\/4\/2791\/66954358\/eschf_12_4_2791.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/12\/4\/2791\/66954358\/eschf_12_4_2791.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T09:07:37Z","timestamp":1771405657000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eschf\/article\/12\/4\/2791\/8488038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,29]]},"published-print":{"date-parts":[[2025,8,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ehf2.15280","relation":{},"ISSN":["2055-5822"],"issn-type":[{"value":"2055-5822","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,4,29]]},"assertion":[{"value":"2024-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}