{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T08:07:16Z","timestamp":1791446836922,"version":"4.3.3"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":978,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"FCT Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UIDB\/00051\/2020"],"award-info":[{"award-number":["UIDB\/00051\/2020"]}]},{"name":"FCT Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UIDP\/00051\/2020"],"award-info":[{"award-number":["UIDP\/00051\/2020"]}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["NORTE-01-0145-FEDER-000039"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000039"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["NORTE\u201001\u20100145\u2010FEDER\u2010000039"],"award-info":[{"award-number":["NORTE\u201001\u20100145\u2010FEDER\u2010000039"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Recent heart failure (HF) guidelines have re-classified HF patients with left ventricular ejection fraction (LVEF) between 41% and 49% as HF with mildly reduced ejection fraction (HFmrEF). HFmrEF treatment is often considered a grey zone as no randomized controlled trials (RCTs) were conducted exclusively on these patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>A network meta-analysis (NMA) was performed to compare treatment effect of mineralocorticoid receptor antagonists (MRA), angiotensin receptor neprilysin inhibitor (ARNi), angiotensin receptor blockers (ARB), angiotensin-converting-enzyme inhibitors (ACEi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and beta-blockers (BB) in HFmrEF cardiovascular (CV) outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>RCTs sub-analyses evaluating the efficacy of pharmacological treatment in HFmrEF patients were searched. Hazard ratios (HRs) and their variance were extracted from each RCT for (i) composite of CV death or HF hospitalizations, (ii) CV death, and (iii) HF hospitalizations. A random-effects NMA was performed to compare and assess the treatment efficiency. Six RCTs with subgroup analysis according to participants' ejection fraction, a patient-level pooled meta-analysis of two RCTs, and an individual patient-level analysis of eleven BB RCTs were included, totalling 7966 patients. To our primary endpoint, SGLT2i vs. placebo was the only comparison with significant results, with a 19% risk reduction in the composite of CV death or HF hospitalizations [HR 0.81, 95% confidence interval (CI) 0.67\u20130.98]. In HF hospitalizations, the impact of the pharmacological therapies was more notorious, and ARNi reduced in 40% the risk of HF hospitalizations (HR 0.60, 95% CI 0.39\u20130.92), SGLT2i in 26% (HR 0.74, 95% CI 0.59\u20130.93) and renin\u2013angiotensin system inhibition (RASi) with ARB and ACEi in 28% (HR 0.72, 95% CI 0.53\u20130.98). Although BBs were globally less beneficial, they were the only class that supported a reduced risk of CV death (HR vs. placebo: 0.48, 95% CI 0.24\u20130.95). We did not observe a statistically significant difference in any comparison between active treatments. There was a sound reduction with ARNi on the primary endpoint (HR vs. BB: 0.81, 95% CI 0.47\u20131.41; HR vs. MRA 0.94, 95% CI 0.53\u20131.66) and on HF hospitalizations (HR vs. RASi 0.83, 95% CI 0.62\u20131.11; HR vs. SGLT2i 0.80, 95% CI 0.50\u20131.30).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In addition to SGLT2i, pharmacological treatment recommended for HF with reduced LVEF, namely, ARNi, MRA, and BB, can also be effective in HFmrEF. This NMA did not show significant superiority over any pharmacological class.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.14284","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T05:44:56Z","timestamp":1678427096000},"page":"1822-1834","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Impact of Heart Failure Therapy in Patients with Mildly Reduced Ejection Fraction: A Network Meta-Analysis"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4067-3069","authenticated-orcid":false,"given":"Marta","family":"Leite","sequence":"first","affiliation":[{"name":"Cardiology Department, Centro Hospitalar Vila Nova de Gaia\/Espinho , Vila Nova de Gaia ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Sampaio","sequence":"additional","affiliation":[{"name":"Cardiology Department, Centro Hospitalar Vila Nova de Gaia\/Espinho , Vila Nova de Gaia ,","place":["Portugal"]},{"name":"Cardiovascular Research and Development Center\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto , Porto ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca A.","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Cardiovascular Research and Development Center\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto , Porto ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00edlvia O.","family":"Diaz","sequence":"additional","affiliation":[{"name":"Cardiovascular Research and Development Center\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto , Porto ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f3nio S.","family":"Barros","sequence":"additional","affiliation":[{"name":"Cardiovascular Research and Development Center\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto , Porto ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Fontes-Carvalho","sequence":"additional","affiliation":[{"name":"Cardiology Department, Centro Hospitalar Vila Nova de Gaia\/Espinho , Vila Nova de Gaia ,","place":["Portugal"]},{"name":"Cardiovascular Research and Development Center\u2014UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto , Porto ,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,10]]},"reference":[{"key":"2026012114102821700_ehf214284-bib-0001","doi-asserted-by":"crossref","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":"European Heart Journal"},{"key":"2026012114102821700_ehf214284-bib-0002","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.117.008081","article-title":"Machine learning methods improve prognostication, identify clinically distinct phenotypes, and detect heterogeneity in response to therapy in a large cohort of heart failure patients","volume":"7","author":"Ahmad","year":"2018","journal-title":"J Am Heart Assoc"},{"key":"2026012114102821700_ehf214284-bib-0003","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/ejhf.1106","article-title":"Is ejection fraction in heart failure a limitation or an opportunity?","volume":"20","author":"Lund","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0004","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1016\/j.jacc.2018.08.2162","article-title":"Ejection fraction pros and cons: JACC state-of-the-art review","volume":"72","author":"Marwick","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"2026012114102821700_ehf214284-bib-0005","doi-asserted-by":"crossref","DOI":"10.3389\/fcvm.2021.683418","article-title":"Heart failure with mid-range ejection fraction: every coin has two sides","volume":"8","author":"Zhu","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"2026012114102821700_ehf214284-bib-0006","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1002\/ejhf.945","article-title":"A comprehensive population-based characterization of heart failure with mid-range ejection fraction","volume":"19","author":"Koh","year":"2017","journal-title":"Eur J Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0007","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/ehf2.12455","article-title":"Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry\u00ae","volume":"6","author":"Ibrahim","year":"2019","journal-title":"ESC Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0008","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/ejhf.483","article-title":"Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review","volume":"18","author":"van Riet","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0009","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.jacc.2013.11.053","article-title":"The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries","volume":"63","author":"Ambrosy","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2026012114102821700_ehf214284-bib-0010","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/ehf2.12283","article-title":"Characteristics and long-term prognosis of patients with heart failure and mid-range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-analysis","volume":"5","author":"Lauritsen","year":"2018","journal-title":"ESC Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0011","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1002\/ejhf.798","article-title":"Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)","volume":"19","author":"Rickenbacher","year":"2017","journal-title":"Eur J Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0012","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1001\/jama.2013.905","article-title":"Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial","volume":"309","author":"Edelmann","year":"2013","journal-title":"JAMA"},{"key":"2026012114102821700_ehf214284-bib-0013","doi-asserted-by":"crossref","first-page":"631","DOI":"10.7326\/0003-4819-137-8-200210150-00006","article-title":"Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study","volume":"137","author":"Gottdiener","year":"2002","journal-title":"Ann Intern Med"},{"key":"2026012114102821700_ehf214284-bib-0014","first-page":"E895","article-title":"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","volume":"145","author":"Heidenreich","year":"2022","journal-title":"Circulation"},{"key":"2026012114102821700_ehf214284-bib-0015","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41433-022-01943-5","article-title":"A clinician's guide to network meta-analysis","volume":"36","author":"Phillips","year":"2022","journal-title":"Eye"},{"key":"2026012114102821700_ehf214284-bib-0016","doi-asserted-by":"crossref","first-page":"777","DOI":"10.7326\/M14-2385","article-title":"The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations","volume":"162","author":"Hutton","year":"2015","journal-title":"Ann Intern Med"},{"key":"2026012114102821700_ehf214284-bib-0017","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/eurheartj\/ehab798","article-title":"Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction","volume":"43","author":"Butler","year":"2022","journal-title":"Eur Heart J"},{"key":"2026012114102821700_ehf214284-bib-0018","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/eurheartj\/ehv464","article-title":"Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction","volume":"37","author":"Solomon","year":"2016","journal-title":"Eur Heart J"},{"key":"2026012114102821700_ehf214284-bib-0019","doi-asserted-by":"crossref","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration's tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"2026012114102821700_ehf214284-bib-0020","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.jclinepi.2010.04.026","article-title":"GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables","volume":"64","author":"Guyatt","year":"2011","journal-title":"J Clin Epidemiol"},{"key":"2026012114102821700_ehf214284-bib-0021","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022)","author":"Higgins JPT TJCJCMLTPMWV"},{"key":"2026012114102821700_ehf214284-bib-0022","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1002\/ejhf.1149","article-title":"Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum","volume":"20","author":"Lund","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026012114102821700_ehf214284-bib-0023","doi-asserted-by":"crossref","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":"2026012114102821700_ehf214284-bib-0024","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1093\/eurheartj\/ehx564","article-title":"Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials","volume":"39","author":"Cleland","year":"2018","journal-title":"Eur Heart J"},{"key":"2026012114102821700_ehf214284-bib-0025","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","article-title":"Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction","volume":"387","author":"Solomon","year":"2022","journal-title":"New England Journal of Medicine."},{"key":"2026012114102821700_ehf214284-bib-0026","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1038\/s41591-022-01971-4","article-title":"Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER","volume":"28","author":"Jhund","year":"2022","journal-title":"Nat Med"},{"key":"2026012114102821700_ehf214284-bib-0027","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S0140-6736(03)14285-7","article-title":"Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial","volume":"362","author":"Yusuf","year":"2003","journal-title":"Lancet"},{"key":"2026012114102821700_ehf214284-bib-0028","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1056\/NEJMoa1313731","article-title":"Spironolactone for heart failure with preserved ejection fraction","volume":"370","author":"Pitt","year":"2014","journal-title":"N Engl J Med"},{"key":"2026012114102821700_ehf214284-bib-0029","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1093\/eurheartj\/ehl250","article-title":"The perindopril in elderly people with chronic heart failure (PEP-CHF) study","volume":"27","author":"Cleland","year":"2006","journal-title":"Eur Heart J"},{"key":"2026012114102821700_ehf214284-bib-0030","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1056\/NEJMoa0805450","article-title":"Irbesartan in patients with heart failure and preserved ejection fraction","volume":"359","author":"Massie","year":"2008","journal-title":"New England Journal of Medicine."},{"key":"2026012114102821700_ehf214284-bib-0031","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin\u2013neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"New England Journal of Medicine"},{"key":"2026012114102821700_ehf214284-bib-0032","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1056\/NEJMoa1908655","article-title":"Angiotensin\u2013neprilysin inhibition in heart failure with preserved ejection fraction","volume":"381","author":"Solomon","year":"2019","journal-title":"New England Journal of Medicine."},{"key":"2026012114102821700_ehf214284-bib-0033","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in heart failure with a preserved ejection fraction","volume":"385","author":"Anker","year":"2021","journal-title":"New England Journal of Medicine"},{"key":"2026012114102821700_ehf214284-bib-0034","first-page":"91","article-title":"Novel paradigms in the therapeutic management of heart failure with preserved ejection fraction: clinical perspectives","volume":"9","author":"El Shear","year":"2019","journal-title":"Am J Cardiovasc Dis"},{"key":"2026012114102821700_ehf214284-bib-0035","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22157976","article-title":"Cardioprotection by SGLT2 inhibitors\u2014does it all come down to Na+?","volume":"22","author":"Trum","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"key":"2026012114102821700_ehf214284-bib-0036","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/eurheartj\/ehi115","article-title":"Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)","volume":"26","author":"Flather","year":"2005","journal-title":"Eur Heart J"},{"key":"2026012114102821700_ehf214284-bib-0037","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/jebm.12443","article-title":"Progress and challenges of network meta-analysis","volume":"14","author":"Tian","year":"2021","journal-title":"J Evid Based Med"}],"container-title":["ESC Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ehf2.14284","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ehf2.14284","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/10\/3\/1822\/65017754\/eschf_10_3_1822.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/10\/3\/1822\/65017754\/eschf_10_3_1822.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T19:11:40Z","timestamp":1769022700000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eschf\/article\/10\/3\/1822\/8304699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,10]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,10]]},"published-print":{"date-parts":[[2023,6,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ehf2.14284","relation":{},"ISSN":["2055-5822"],"issn-type":[{"value":"2055-5822","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6]]},"published":{"date-parts":[[2023,3,10]]},"assertion":[{"value":"2022-07-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}