{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T23:21:37Z","timestamp":1787872897377,"version":"build-2784847793"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Contemporary guidelines recommend rapid initiation of four classes of guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF); however, real-world persistence, adherence, and dose optimization remain suboptimal. Methods: We analysed a predefined subregistry within the prospective Cardiology Research Dubrava (CaRD) registry, a real-world HF registry at a tertiary centre that includes patients across the ejection-fraction spectrum in whom contemporary HF therapy, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), is introduced or optimised in routine practice. For this analysis, we included patients with newly diagnosed HFrEF (left ventricular ejection fraction (LVEF) \u2264 40%) who were discharged on all four GDMT classes; 167 of 179 patients with newly diagnosed HFrEF during the study period had an available 6-month medication assessment and comprised the final analytic cohort. The four GDMT pillars (beta-blocker; angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI); mineralocorticoid receptor antagonist (MRA); and SGLT2i) were initiated within 4 days when clinically feasible. Medication adherence and target-dose attainment were assessed at 6, 12, and 24 months using a structured self-report questionnaire. Major adverse events (MAE) and all-cause mortality were recorded over 24 months. Patients were classified as adherent if they reported regular intake (\u226580% of prescribed doses) of all four drug classes at 6 months; otherwise, they were classified as nonadherent. Results: Among the 167 analysed patients (median age 64 years, 74% men, median LVEF 30%), regular adherence at 6, 12, and 24 months was 65%, 55%, and 59% for beta-blockers; 66%, 50%, and 49% for ACEi\/ARB\/ARNI; 62%, 52%, and 49% for MRAs; and 84%, 57%, and 68% for SGLT2i. Target doses were achieved in 25\u201333% for beta-blockers, 42\u201350% for ACEi\/ARB\/ARNI, and 73\u201378% for MRAs. At 24 months, 56 survivors (37%) were adherent to all four drug classes. Over 24 months, all-cause mortality was 9.0% and MAE 18.6%, occurring less frequently in adherent vs. nonadherent patients (mortality 0% vs. 13.5%; MAE 8.9% vs. 23.4%). Conclusions: In this real-world, non-randomized HFrEF subregistry, in-hospital initiation of quadruple GDMT was feasible, yet maintaining long-term adherence and achieving target doses remained challenging. These data underscore the gap between guideline recommendations and routine practice and support structured follow-up and protocol-driven titration to optimize implementation.<\/jats:p>","DOI":"10.3390\/jcm15062127","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T09:00:37Z","timestamp":1773219637000},"page":"2127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Two-Year Implementation, Adherence, and Outcomes of Quadruple Guideline-Directed Medical Therapy in Newly Diagnosed HFrEF: Insights from the Prospective CaRD Registry"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2637-9691","authenticated-orcid":false,"given":"Ivana","family":"Jurin","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-6559","authenticated-orcid":false,"given":"Daniel","family":"Lovri\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9137-3014","authenticated-orcid":false,"given":"Karlo","family":"Gjuras","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Health Centre Bjelovar-Bilogora County, 43000 Bjelovar, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9526-3393","authenticated-orcid":false,"given":"\u0160ime","family":"Manola","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3768-9134","authenticated-orcid":false,"given":"Irzal","family":"Had\u017eibegovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"Faculty of Dental Medicine and Health Care, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Udovi\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Rudan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"Department of Nursing, University North, 48000 Koprivnica, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anica","family":"Milinkovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmina","family":"\u0106ati\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"Faculty of Dental Medicine and Health Care, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6666-7694","authenticated-orcid":false,"given":"Marija","family":"Kri\u017eanovi\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3962-2774","authenticated-orcid":false,"given":"Marin","family":"Pavlov","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, University Hospital Dubrava, 10000 Zagreb, Croatia"},{"name":"Department of Nursing, University North, 48000 Koprivnica, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"ref_1","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":"Eur. Heart J."},{"key":"ref_2","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":"ref_3","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","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":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1009492","article-title":"Eplerenone in patients with systolic heart failure and mild symptoms","volume":"364","author":"Zannad","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"CIBIS-II Investigators and Committees (1999). The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet, 353, 9\u201313.","DOI":"10.1016\/S0140-6736(98)11181-9"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1001\/jama.283.10.1295","article-title":"Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The Metoprolol CR\/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group","volume":"283","author":"Hjalmarson","year":"2000","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1161\/01.CIR.0000035653.72855.BF","article-title":"Effect of carvedilol on the morbidity of patients with severe chronic heart failure: Results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study","volume":"106","author":"Packer","year":"2002","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","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":"ref_10","doi-asserted-by":"crossref","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":"ref_11","doi-asserted-by":"crossref","first-page":"e001585","DOI":"10.1136\/openhrt-2021-001585","article-title":"Four pillars of heart failure: Contemporary pharmacological therapy for heart failure with reduced ejection fraction","volume":"8","author":"Straw","year":"2021","journal-title":"Open Heart"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1002\/ejhf.2149","article-title":"Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction","volume":"23","author":"Packer","year":"2021","journal-title":"Eur. J. Heart Fail."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s10741-025-10481-7","article-title":"Initiation and sequencing of guideline-directed medical therapy for heart failure across the ejection fraction spectrum","volume":"30","author":"Shahid","year":"2025","journal-title":"Heart Fail. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1016\/j.jacc.2019.02.015","article-title":"Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction","volume":"73","author":"Greene","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","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":"ref_16","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1093\/eurjhf\/hft134","article-title":"Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry","volume":"15","author":"Maggioni","year":"2013","journal-title":"Eur. J. Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jchf.2018.10.010","article-title":"Contemporary Drug Treatment of Chronic Heart Failure with Reduced Ejection Fraction: The CHECK-HF Registry","volume":"7","author":"Linssen","year":"2019","journal-title":"JACC Heart Fail."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1093\/eurheartj\/ehx026","article-title":"Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: A prospective European study","volume":"38","author":"Ouwerkerk","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1002\/ejhf.887","article-title":"Physicians\u2019 guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: The QUALIFY international registry","volume":"19","author":"Komajda","year":"2017","journal-title":"Eur. J. Heart Fail."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1016\/S0140-6736(22)02076-1","article-title":"Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): A multinational, open-label, randomised, trial","volume":"400","author":"Mebazaa","year":"2022","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1056\/NEJMra050100","article-title":"Adherence to medication","volume":"353","author":"Osterberg","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1056\/NEJMoa1812851","article-title":"Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure","volume":"380","author":"Velazquez","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"D\u2019Amato, A., Prosperi, S., Severino, P., Myftari, V., Labbro Francia, A., Cestie, C., Pierucci, N., Marek-Iannucci, S., Mariani, M.V., and Germano, R. (2024). Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031574"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"von Elm, E., Altman, D.G., Egger, M., Pocock, S.J., G\u00f8tzsche, P.C., and Vandenbroucke, J.P. (2007). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. 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