{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:26:59Z","timestamp":1791419219635,"version":"4.3.3"},"reference-count":94,"publisher":"Radcliffe Medical Media Ltd","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Card Fail Rev"],"abstract":"<jats:p>Recent advances in medical therapy have significantly improved the prognosis of patients with heart failure and reduced ejection fraction (HFrEF). The established four pillars of HFrEF treatment \u2013 \u03b2-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor\u2013neprilysin inhibitors, mineralocorticoid receptor antagonists and sodium\u2013glucose cotransporter 2 inhibitors \u2013 serve as the foundation for on-going innovations in this domain. However, these represent only the starting point for the therapy and management of heart failure. New medications, new devices and improvements in the use of diuretic therapy are fundamental and recent advancements. This article aims to highlight the latest findings in HFrEF treatment. While emphasising the optimism these developments bring, the article also addresses the significant unresolved challenges that persist in the management of this syndrome, which remains a leading global cause of mortality, morbidity and poor quality of life with high use of resources and healthcare costs.<\/jats:p>","DOI":"10.15420\/cfr.2024.37","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T14:58:41Z","timestamp":1753369121000},"source":"Crossref","is-referenced-by-count":8,"title":["Pharmacological Therapy of HFrEF in 2025: Navigating New Advances and Old Unmet Needs in An Eternal Balance Between Progress and Perplexities"],"prefix":"10.15420","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9985-7407","authenticated-orcid":false,"given":"Massimo","family":"Mapelli","sequence":"first","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7940-9811","authenticated-orcid":false,"given":"Filippo Maria","family":"Rubbo","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS, Milan, Italy; RN GUARD-Heart Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, ASUGI, University of Trieste, Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Costantino","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amelotti","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8345-6382","authenticated-orcid":false,"given":"Piergiuseppe","family":"Agostoni","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino, IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6096","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"ref0","unstructured":"McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599\u2013726. https:\/\/doi.org\/10.1093\/eurheartj\/ehab368; PMID:\u00a034447992."},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Riccardi M, Sammartino AM, Piepoli M, et al. Heart failure: an update from the last years and a look at the near future. ESC Heart Fail 2022;9:3667\u201393. https:\/\/doi.org\/10.1002\/ehf2.14257; PMID:\u00a036546712.","DOI":"10.1002\/ehf2.14257"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Tromp J, Ouwerkerk W, van Veldhuisen DJ, et al. A systematic review and network meta-analysis of pharmacological treatment of heart failure with reduced ejection fraction. JACC Heart Fail 2022;10:73\u201384. https:\/\/doi.org\/10.1016\/j.jchf.2021.09.004; PMID:\u00a034895860.","DOI":"10.1016\/j.jchf.2021.09.004"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival study (CONSENSUS). N Engl J Med 1987;316:1429\u201335. https:\/\/DOI.ORG\/10.1056\/NEJM198706043162301; PMID:\u00a02883575.","DOI":"10.1056\/nejm198706043162301"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293\u2013302. https:\/\/DOI.ORG\/10.1056\/NEJM199108013250501; PMID:\u00a02057034.","DOI":"10.1056\/nejm199108013250501"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Remme WJ, Swedberg K, Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527\u201360. https:\/\/doi.org\/10.1053\/euhj.2001.2783; PMID:\u00a011492984.","DOI":"10.1053\/euhj.2001.2783"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (Copernicus) study. Circulation 2002;106:2194\u20139. https:\/\/doi.org\/10.1161\/01.cir.0000035653.72855.bf; PMID:\u00a012390947.","DOI":"10.1161\/01.cir.0000035653.72855.bf"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone evaluation study investigators. N Engl J Med 1999;341:709\u201317. https:\/\/DOI.ORG\/10.1056\/NEJM199909023411001; PMID:\u00a010471456.","DOI":"10.1056\/nejm199909023411001"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11\u201321. https:\/\/doi.org\/10.1056\/NEJMoa1009492; PMID:\u00a021073363.","DOI":"10.1056\/nejmoa1009492"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993\u20131004. https:\/\/doi.org\/10.1056\/NEJMoa1409077; PMID:\u00a025176015.","DOI":"10.1056\/nejmoa1409077"},{"key":"ref10","unstructured":"Pastore MC, Mandoli GE, Giannoni A, et al. Sacubitril\/valsartan reduces indications for arrhythmic primary prevention in heart failure with reduced ejection fraction: insights from DISCover-ARNI, a multicenter Italian register. Eur Heart J Open 2022;2:oeab046. https:\/\/doi.org\/10.1093\/ehjopen\/oeab046; PMID:\u00a035919657."},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Mantegazza V, Volpato V, Mapelli M, et al. Cardiac reverse remodelling by 2D and 3D echocardiography in heart failure patients treated with Sacubitril\/Valsartan. Diagnostics (Basel) 2021;11:1845. https:\/\/doi.org\/10.3390\/diagnostics11101845; PMID:\u00a034679543.","DOI":"10.3390\/diagnostics11101845"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Wang Y, Zhou R, Lu C, et al. Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc 2019;8:e012272. https:\/\/DOI.ORG\/10.1161\/JAHA.119.012272; PMID:\u00a031240976.","DOI":"10.1161\/jaha.119.012272"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Mapelli M, Mattavelli I, Salvioni E, et al. Looking into the kinetics of NT-proBNP and sST2 changes in patients with heart failure treated with Sacubitril\/Valsartan: a hint to different therapeutic pathways. Drugs R D 2023;23:397\u2013402. https:\/\/doi.org\/10.1007\/s40268-023-00438-2; PMID:\u00a037702906.","DOI":"10.1007\/s40268-023-00438-2"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Mapelli M, Salvioni E, de Martino F, et al. Sacubitril\/valsartan use in a real-world population of patients with heart failure and reduced ejection fraction. J Cardiovasc Med (Hagerstown) 2020;21:882\u20138. https:\/\/DOI.ORG\/10.2459\/JCM.0000000000001018; PMID:\u00a032740412.","DOI":"10.2459\/jcm.0000000000001018"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2024;391:1475\u201385. https:\/\/doi.org\/10.1056\/NEJMoa2407107; PMID:\u00a039225278.","DOI":"10.1056\/NEJMe2410904"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Filippatos G, Anker SD, B\u00f6hm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and\/or chronic kidney disease. Eur Heart J 2016;37:2105\u201314. https:\/\/doi.org\/10.1093\/eurheartj\/ehw132.","DOI":"10.1093\/eurheartj\/ehw132"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Pamporis K, Karakasis P, Sagris M, et al. Mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: a systematic review and network meta-analysis of 32 randomized trials. Curr Probl Cardiol 2024;49:102615. https:\/\/doi.org\/10.1016\/j.cpcardiol.2024.102615; PMID:\u00a038692445.","DOI":"10.1016\/j.cpcardiol.2024.102615"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Preda A, Montecucco F, Carbone F, et al. SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits. Cardiovasc Res 2024;120:443\u201360. https:\/\/doi.org\/10.1093\/cvr\/cvae047; PMID:\u00a038456601.","DOI":"10.1093\/cvr\/cvae047"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA\/ACC\/HFSA guideline for the management of heart failure: a report of the American College of Cardiology\/American Heart Association joint committee on clinical practice guidelines. Circulation 2022;145:e895\u2013e1032. https:\/\/DOI.ORG\/10.1161\/CIR.0000000000001063; PMID:\u00a035363499.","DOI":"10.1161\/CIR.0000000000001073"},{"key":"ref20","unstructured":"McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995\u20132008. https:\/\/doi.org\/10.1056\/NEJMoa1911303; PMID:\u00a031535829."},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413\u201324. https:\/\/doi.org\/10.1056\/NEJMoa2022190.","DOI":"10.1056\/NEJMoa2022190"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819\u201329. https:\/\/doi.org\/10.1016\/S0140-6736(20)31824-9; PMID:\u00a032877652.","DOI":"10.1016\/s0140-6736(20)31824-9"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117\u201328. https:\/\/doi.org\/10.1056\/NEJMoa2030183; PMID:\u00a033200892.","DOI":"10.1056\/NEJMoa2030183"},{"key":"ref24","unstructured":"Pitt B, Bhatt DL, Szarek M, et al. Effect of sotagliflozin on early mortality and heart failure-related events: a post hoc analysis of SOLOIST-WHF. JACC Heart Fail 2023;11:879\u201389. https:\/\/doi.org\/10.1016\/j.jchf.2023.05.026; PMID:\u00a037558385."},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Beghini A, Sammartino AM, Papp Z, et al. 2024 update in heart failure. ESC Heart Fail 2025;12:8\u201342. https:\/\/doi.org\/10.1002\/ehf2.14857; PMID:\u00a038806171.","DOI":"10.1002\/ehf2.14857"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382:1883\u201393. https:\/\/doi.org\/10.1056\/NEJMoa1915928; PMID:\u00a032222134.","DOI":"10.1056\/nejmoa1915928"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Michalak M, Armstrong PW. Exploring new cardiovascular pathways: are soluble guanylate cyclase stimulators the right direction? Circ Heart Fail 2018;11:e004813. https:\/\/DOI.ORG\/10.1161\/CIRCHEARTFAILURE.118.004813; PMID:\u00a029545396.","DOI":"10.1161\/circheartfailure.118.004813"},{"key":"ref28","unstructured":"Lee A, Natarajan PP, Cheng RKH, et al. The role of vericiguat in the expanding realm of heart failure pharmacotherapy: an overview of the Victoria trial. 2020. https:\/\/www.acc.org\/latest-in-cardiology\/articles\/2020\/07\/08\/08\/49\/the-role-of-vericiguat-in-the-expanding-realm-of-hf-pharmacotherapy (accessed 13\u00a0October, 2024)."},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Nguyen L, Baker DE. Vericiguat. Hosp Pharm 2023;58:431\u20136. https:\/\/doi.org\/10.1177\/00185787211016338; PMID:\u00a037711406.","DOI":"10.1177\/00185787211016338"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Boettcher M, Gerisch M, Lobmeyer M, et al. Metabolism and pharmacokinetic drug-drug interaction profile of vericiguat, A soluble guanylate cyclase stimulator: results from preclinical and Phase I healthy volunteer studies. Clin Pharmacokinet 2020;59:1407\u201318. https:\/\/doi.org\/10.1007\/s40262-020-00895-x; PMID:\u00a032458378.","DOI":"10.1007\/s40262-020-00895-x"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Correale M, Pelaggi G, Catanoso MC, et al. Vericiguat in heart failure with reduced ejection fraction: hope or solid reality? Heart Fail Rev 2024;29:1135\u201343. https:\/\/doi.org\/10.1007\/s10741-024-10425-7; PMID:\u00a039044114.","DOI":"10.1007\/s10741-024-10425-7"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Pieske B, Pieske-Kraigher E, Lam CSP, et al. Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: the VICTORIA echocardiographic substudy. Eur J Heart Fail 2023;25:1012\u201321. https:\/\/doi.org\/10.1002\/ejhf.2836; PMID:\u00a036994634.","DOI":"10.1002\/ejhf.2836"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Psotka MA, Gottlieb SS, Francis GS, et al. Cardiac calcitropes, myotropes, and mitotropes: JACC review topic of the week. J Am Coll Cardiol 2019;73:2345\u201353. https:\/\/doi.org\/10.1016\/j.jacc.2019.02.051; PMID:\u00a031072579.","DOI":"10.1016\/j.jacc.2019.02.051"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Teerlink JR, Clarke CP, Saikali KG, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. Lancet 2011;378:667\u201375. https:\/\/doi.org\/10.1016\/S0140-6736(11)61219-1; PMID:\u00a021856480.","DOI":"10.1016\/s0140-6736(11)61219-1"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Teerlink JR, Felker GM, McMurray JJV, et al. Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure: the ATOMIC-AHF study. J Am Coll Cardiol 2016;67:1444\u201355. https:\/\/doi.org\/10.1016\/j.jacc.2016.01.031; PMID:\u00a027012405.","DOI":"10.1016\/j.jacc.2016.01.031"},{"key":"ref36","unstructured":"Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105\u201316. https:\/\/doi.org\/10.1056\/NEJMoa2025797; PMID:\u00a033185990."},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Lewis GD, Voors AA, Cohen-Solal A, et al. Effect of omecamtiv mecarbil on exercise capacity in chronic heart failure with reduced ejection fraction: the METEORIC-HF randomized clinical trial. JAMA 2022;328:259\u201369. https:\/\/doi.org\/10.1001\/jama.2022.11016; PMID:\u00a035852527.","DOI":"10.1001\/jama.2022.11016"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Zhou S, Liu Y, Huang X, et al. Omecamtiv mecarbil in the treatment of heart failure: the past, the present, and the future. Front Cardiovasc Med 2024;11:1337154. https:\/\/doi.org\/10.3389\/fcvm.2024.1337154; PMID:\u00a038566963.","DOI":"10.3389\/fcvm.2024.1337154"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989\u20131002. https:\/\/doi.org\/10.1056\/NEJMoa2032183; PMID:\u00a033567185.","DOI":"10.1056\/nejmoa2032183"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834\u201344. https:\/\/doi.org\/10.1056\/NEJMoa1607141; PMID:\u00a027633186.","DOI":"10.1056\/nejmoa1607141"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023;389:2221\u201332. https:\/\/doi.org\/10.1056\/NEJMoa2307563; PMID:\u00a037952131.","DOI":"10.1056\/NEJMoa2307563"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail 2017;19:69\u201377. https:\/\/doi.org\/10.1002\/ejhf.657; PMID:\u00a027790809.","DOI":"10.1002\/ejhf.657"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial. JAMA 2016;316:500\u20138. https:\/\/doi.org\/10.1001\/jama.2016.10260; PMID:\u00a027483064.","DOI":"10.1001\/jama.2016.10260"},{"key":"ref44","unstructured":"Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet 2024;404:773\u201386. https:\/\/doi.org\/10.1016\/S0140-6736(24)01498-3; PMID:\u00a039181597."},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Ferreira JP, Mogensen UM, Jhund PS, et al. Serum potassium in the PARADIGM-HF trial. Eur J Heart Fail 2020;22:2056\u201364. https:\/\/doi.org\/10.1002\/ejhf.1987; PMID:\u00a032809261.","DOI":"10.1002\/ejhf.1987"},{"key":"ref46","doi-asserted-by":"crossref","unstructured":"Toto F, Salvioni E, Magr\u00ec D, et al. Does moderate hyperkalemia influence survival in HF? Insights from the MECKI score data base. Int J Cardiol 2023;371:273\u20137. https:\/\/doi.org\/10.1016\/j.ijcard.2022.09.030; PMID:\u00a036115445.","DOI":"10.1016\/j.ijcard.2022.09.030"},{"key":"ref47","unstructured":"Butler J, Anker SD, Lund LH, et al. Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial. Eur Heart J 2022;43:4362\u201373. https:\/\/doi.org\/10.1093\/eurheartj\/ehac401; PMID:\u00a035900838."},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Tardif JC, Rouleau J, Chertow GM, et al. Potassium reduction with sodium zirconium cyclosilicate in patients with heart failure. ESC Heart Fail 2023;10:1066\u201376. https:\/\/doi.org\/10.1002\/ehf2.14268; PMID:\u00a036564955.","DOI":"10.1002\/ehf2.14268"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Bismpos D, Wintrich J, H\u00f6velmann J, B\u00f6hm M. Latest pharmaceutical approaches across the spectrum of heart failure. Heart Fail Rev 2024;29:675\u201387. https:\/\/doi.org\/10.1007\/s10741-024-10389-8; PMID:\u00a038349462.","DOI":"10.1007\/s10741-024-10389-8"},{"key":"ref50","unstructured":"Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895\u2013904. https:\/\/doi.org\/10.1016\/S0140-6736(20)32339-4; PMID:\u00a033197395."},{"key":"ref51","unstructured":"Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet 2022;400:2199\u2013209. https:\/\/doi.org\/10.1016\/S0140-6736(22)02083-9; PMID:\u00a036347265."},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Mentz RJ, Garg J, Rockhold FW, et al. Ferric carboxymaltose in heart failure with iron deficiency. N Engl J Med 2023;389:975\u201386. https:\/\/doi.org\/10.1056\/NEJMoa2304968, Epub. PMID:\u00a037632463.","DOI":"10.1056\/nejmoa2304968"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Salah HM, Savarese G, Rosano GMC, et al. Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis. ESC Heart Fail 2023;10:1473\u201380. https:\/\/doi.org\/10.1002\/ehf2.14310; PMID:\u00a036734033.","DOI":"10.1002\/ehf2.14310"},{"key":"ref54","unstructured":"Authors\/Task Force Members:, McDonagh TA, Metra M, et\u00a0al. 2023 Focused Update of the 2021 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. Eur J Heart Fail 2024;26:5\u201317. https:\/\/doi.org\/10.1002\/ejhf.3024; PMID:\u00a038169072."},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Abuelazm M, Ali S, AlBarakat MM, et al. Istaroxime for patients with acute heart failure: a systematic review and meta-analysis of randomized controlled trials. Diseases 2023;11:183. https:\/\/doi.org\/10.3390\/diseases11040183; PMID:\u00a038131989.","DOI":"10.3390\/diseases11040183"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Van Tassell B, Mihalick V, Thomas G, et al. Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study. J Transl Med 2022;20:270. https:\/\/doi.org\/10.1186\/s12967-022-03466-9; PMID:\u00a035706006.","DOI":"10.1186\/s12967-022-03466-9"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Ross R, Blair SN, Arena R, et al. Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: A scientific statement from the American Heart Association. Circulation 2016;134:e653\u201399. https:\/\/DOI.ORG\/10.1161\/CIR.0000000000000461; PMID:\u00a027881567.","DOI":"10.1161\/cir.0000000000000461"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Kourek C, Briasoulis A, Papamichail A, et al. Beyond quadruple therapy and current therapeutic strategies in heart failure with reduced ejection fraction: medical therapies with potential to become part of the therapeutic armamentarium. Int J Mol Sci 2024;25:3113. https:\/\/doi.org\/10.3390\/ijms25063113; PMID:\u00a038542088.","DOI":"10.3390\/ijms25063113"},{"key":"ref59","doi-asserted-by":"crossref","unstructured":"Perin EC, Borow KM, Henry TD, et al. Randomized trial of targeted transendocardial mesenchymal precursor cell therapy in patients with heart failure. J Am Coll Cardiol 2023;81:849\u201363. https:\/\/doi.org\/10.1016\/j.jacc.2022.11.061; PMID:\u00a036858705.","DOI":"10.1016\/j.jacc.2022.11.061"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Yi T, Li M, Fan F, et al. Haemodynamic changes of interatrial shunting devices for heart failure: a systematic review and meta-analysis. ESC Heart Fail 2022;9:1987\u201395. https:\/\/doi.org\/10.1002\/ehf2.13911; PMID:\u00a035322588.","DOI":"10.1002\/ehf2.13911"},{"key":"ref61","doi-asserted-by":"crossref","unstructured":"Kulkarni SS, Sakaria AK, Mahajan SK, Shah KB. Lutembacher\u2019s syndrome. J Cardiovasc Dis Res 2012;3:179\u201381. https:\/\/doi.org\/10.4103\/0975-3583.95381; PMID:\u00a022629045.","DOI":"10.4103\/0975-3583.95381"},{"key":"ref62","unstructured":"Baumgartner H, Bonhoeffer P, De Groot NMS, et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31:2915\u201357. https:\/\/doi.org\/10.1093\/eurheartj\/ehq249; PMID:\u00a020801927."},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Guimaraes L, Del Val D, Bergeron S, et al. Interatrial shunting for treating acute and chronic left heart failure. Eur Cardiol 2020;15:e18. https:\/\/doi.org\/10.15420\/ecr.2019.04; PMID:\u00a032419849.","DOI":"10.15420\/ecr.2019.04"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Pfeiffer M, Boehmer J, Gorcsan J, et al. In vivo fluid dynamics of the Ventura interatrial shunt device in patients with heart failure. ESC Heart Fail 2024;11:2499\u2013509. https:\/\/doi.org\/10.1002\/ehf2.14859; PMID:\u00a038773938.","DOI":"10.1002\/ehf2.14859"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Rod\u00e9s-Cabau J, Lindenfeld J, Abraham WT, et al. Interatrial shunt therapy in advanced heart failure: outcomes from the open-label cohort of the RELIEVE-HF trial. Eur J Heart Fail 2024;26:1078\u201389. https:\/\/doi.org\/10.1002\/ejhf.3215; PMID:\u00a038561314.","DOI":"10.1002\/ejhf.3215"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Butter C, Wellnhofer E, Schlegl M, et al. Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption. J Card Fail 2007;13:137\u201342. https:\/\/doi.org\/10.1016\/j.cardfail.2006.11.004; PMID:\u00a017395055.","DOI":"10.1016\/j.cardfail.2006.11.004"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Fastner C, Yuecel G, Rudic B, et al. Cardiac contractility modulation in patients with ischemic versus non-ischemic cardiomyopathy: results from the MAINTAINED Observational Study. Int J Cardiol 2021;342:49\u201355. https:\/\/doi.org\/10.1016\/j.ijcard.2021.07.048; PMID:\u00a034329680.","DOI":"10.1016\/j.ijcard.2021.07.048"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Nadeem M, Tariq EF, Aslam HM, et al. All-cause mortality outcomes of usage of cardiac contractility modulation in patients with dilated cardiomyopathy ineligible for cardiac re-synchronization therapy: an updated meta-analysis of randomized controlled trials. Cureus 2020;12:e10627. https:\/\/doi.org\/10.7759\/cureus.10627; PMID:\u00a033123440.","DOI":"10.7759\/cureus.10627"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Liu X, Yang HJ, Ping HQ, et al. The safety and efficacy of cardiac contractility modulation in heart failure: a meta-analysis of clinical trials. Herz 2017;42:766\u201375. https:\/\/doi.org\/10.1007\/s00059-016-4514-5; PMID:\u00a028101624.","DOI":"10.1007\/s00059-016-4514-5"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Blanco C, Madej T, Mangner N, et al. Baroreflex activation therapy in patients with heart failure with reduced ejection fraction: a single-centre experience. ESC Heart Fail 2023;10:3373\u201384. https:\/\/doi.org\/10.1002\/ehf2.14508; PMID:\u00a037667319.","DOI":"10.1002\/ehf2.14508"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"van Bilsen M, Patel HC, Bauersachs J, et al. The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2017;19:1361\u201378. https:\/\/doi.org\/10.1002\/ejhf.921; PMID:\u00a028949064.","DOI":"10.1002\/ejhf.921"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Floras JS, Ponikowski P. The sympathetic\/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 2015;36:1974\u201382b. https:\/\/doi.org\/10.1093\/eurheartj\/ehv087; PMID:\u00a025975657.","DOI":"10.1093\/eurheartj\/ehv087"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Zile MR, Lindenfeld J, Weaver FA, et al. Baroreflex activation therapy in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol 2020;76:1\u201313. https:\/\/doi.org\/10.1016\/j.jacc.2020.05.015; PMID:\u00a032616150.","DOI":"10.1016\/j.jacc.2020.05.015"},{"key":"ref74","doi-asserted-by":"crossref","unstructured":"Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797\u2013805. https:\/\/doi.org\/10.1056\/NEJMoa1005419; PMID:\u00a021366472.","DOI":"10.1056\/NEJMoa1005419"},{"key":"ref75","doi-asserted-by":"crossref","unstructured":"Trull\u00e0s JC, Casado J, Morales-Rull JL, et al. Prevalence and outcome of diuretic resistance in heart failure. Intern Emerg Med 2019;14:529\u201337. https:\/\/doi.org\/10.1007\/s11739-018-02019-7; PMID:\u00a030610440.","DOI":"10.1007\/s11739-018-02019-7"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209\u201316. https:\/\/doi.org\/10.1016\/j.ahj.2004.08.005; PMID:\u00a015846257.","DOI":"10.1016\/j.ahj.2004.08.005"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Trull\u00e0s JC, Casado J, Cobo-Marcos M, et al. Combinational diuretics in heart failure. Curr Heart Fail Rep 2024;21:1\u201311. https:\/\/doi.org\/10.1007\/s11897-024-00659-9; PMID:\u00a038589570.","DOI":"10.1007\/s11897-024-00659-9"},{"key":"ref78","doi-asserted-by":"crossref","unstructured":"Mullens W, Dauw J, Martens P, et al. Acetazolamide in acute decompensated heart failure with volume overload. N Engl J Med 2022;387:1185\u201395. https:\/\/doi.org\/10.1056\/NEJMoa2203094; PMID:\u00a036027559.","DOI":"10.1056\/NEJMoa2203094"},{"key":"ref79","unstructured":"Trull\u00e0s JC, Morales-Rull JL, Casado J, et al. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J 2023;44:411\u201321. https:\/\/doi.org\/10.1093\/eurheartj\/ehac689; PMID:\u00a036423214."},{"key":"ref80","unstructured":"Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med 2022;28:568\u201374. https:\/\/doi.org\/10.1038\/s41591-021-01659-1; PMID:\u00a035228754."},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Cox ZL, Sarrell BA, Cella MK, et al. Multinephron segment diuretic therapy to overcome diuretic resistance in acute heart failure: a single-center experience. J Card Fail 2022;28:21\u201331. https:\/\/doi.org\/10.1016\/j.cardfail.2021.07.016; PMID:\u00a034403831.","DOI":"10.1016\/j.cardfail.2021.07.016"},{"key":"ref82","doi-asserted-by":"crossref","unstructured":"Blowey DL. Diuretics in the treatment of hypertension. Pediatr Nephrol 2016;31:2223\u201333. https:\/\/doi.org\/10.1007\/s00467-016-3334-4; PMID:\u00a026983630.","DOI":"10.1007\/s00467-016-3334-4"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Damman K, Ng Kam Chuen MJ, MacFadyen RJ, et al. Volume status and diuretic therapy in systolic heart failure and the detection of early abnormalities in renal and tubular function. J Am Coll Cardiol 2011;57:2233\u201341. https:\/\/doi.org\/10.1016\/j.jacc.2010.10.065; PMID:\u00a021616283.","DOI":"10.1016\/j.jacc.2010.10.065"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Miura M, Sugimura K, Sakata Y, et al. Prognostic impact of loop diuretics in patients with chronic heart failure \u2013 effects of addition of renin-angiotensin-aldosterone system inhibitors and \u03b2-blockers. Circ J 2016;80:1396\u2013403. https:\/\/doi.org\/10.1253\/circj.CJ-16-0216; PMID:\u00a027170200.","DOI":"10.1253\/circj.cj-16-0216"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Okoye C, Mazzarone T, Cargiolli C, Guarino D. Discontinuation of loop diuretics in older patients with chronic stable heart failure: a narrative review. Drugs Aging 2023;40:981\u201390. https:\/\/doi.org\/10.1007\/s40266-023-01061-1; PMID:\u00a037620655.","DOI":"10.1007\/s40266-023-01061-1"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Pellicori P, Cleland JGF, Zhang J, et al. Cardiac dysfunction, congestion and loop diuretics: their relationship to prognosis in heart failure. Cardiovasc Drugs Ther 2016;30:599\u2013609. https:\/\/doi.org\/10.1007\/s10557-016-6697-7; PMID:\u00a027819111.","DOI":"10.1007\/s10557-016-6697-7"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Mullens W, Damman K. Response to letters on \u201cThe use of diuretics in heart failure with congestion \u2013 a position statement from the Heart Failure Association of the European Society of Cardiology\u201d. Eur J Heart Fail 2019;21:949\u201350. https:\/\/doi.org\/10.1002\/ejhf.1477; PMID:\u00a031066143.","DOI":"10.1002\/ejhf.1477"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"Rohde LE, Rover MM, Figueiredo Neto JA, et al. Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial. Eur Heart J 2019\u00a0;40:3605\u201312. https:\/\/doi.org\/10.1093\/eurheartj\/ehz554; PMID:\u00a031424503.","DOI":"10.1093\/eurheartj\/ehz554"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Romano G, Vitale G, Bellavia D, et al. Is diuretic withdrawal safe in patients with heart failure and reduced ejection fraction? A retrospective analysis of our outpatient cohort. Eur J Intern Med 2017;42:e11\u20133. https:\/\/doi.org\/10.1016\/j.ejim.2017.03.025; PMID:\u00a028390780.","DOI":"10.1016\/j.ejim.2017.03.025"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Shah SJ, Sharma K, Borlaug BA, et al. Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials. Eur Heart J 2024;45:3254\u201369. https:\/\/doi.org\/10.1093\/eurheartj\/ehae322; PMID:\u00a038739118.","DOI":"10.1093\/eurheartj\/ehae322"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Stolfo D, Lund LH, Benson L, et al. Real-world use of sodium\u2013glucose cotransporter 2 inhibitors in patients with heart failure and reduced ejection fraction: data from the Swedish Heart Failure Registry. Eur J Heart Fail 2023;25:1648\u201358. https:\/\/doi.org\/10.1002\/ejhf.2971; PMID:\u00a037419495.","DOI":"10.1002\/ejhf.2971"},{"key":"ref92","doi-asserted-by":"publisher","unstructured":"Kerwagen F, Koehler K, Vettorazzi E, et al. Remote patient management of heart failure across the ejection fraction spectrum: a pre-specified analysis of the TIM-HF2 trial. Eur J Heart Fail 2023;25:1671\u201381. https:\/\/doi.org\/10.1002\/ejhf.2948; PMID:\u00a037368507.","DOI":"10.1002\/ejhf.2948"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Zito A, Princi G, Romiti GF, et al. Device-based remote monitoring strategies for congestion-guided management of patients with heart failure: a systematic review and meta-analysis. Eur J Heart Fail 2022;24:2333\u201341. https:\/\/doi.org\/10.1002\/ejhf.2655; PMID:\u00a036054801.","DOI":"10.1002\/ejhf.2655"}],"container-title":["Cardiac Failure Review"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cfrjournal.com\/articleindex\/cfr.2024.37","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T14:58:46Z","timestamp":1753369126000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cfrjournal.com\/articleindex\/cfr.2024.37"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":94,"URL":"https:\/\/doi.org\/10.15420\/cfr.2024.37","relation":{},"ISSN":["2057-7559","2057-7540"],"issn-type":[{"value":"2057-7559","type":"electronic"},{"value":"2057-7540","type":"print"}],"subject":[],"published":{"date-parts":[[2025,7,24]]},"article-number":"e18"}}