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Treatment adherence to guideline-directed medical therapy (GDMT) remains a major challenge in the management of HF, despite the availability of guideline-directed medical therapy (GDMT). Polypharmacy and regimen complexity contribute to poor adherence, particularly among older adults and in resource-limited settings. The polypill strategy, involving fixed-dose combinations of essential HF medications, has emerged as a potential solution to simplify treatment regimens, enhance adherence, and improve clinical outcomes. This review explores the potential of polypill therapy as a pragmatic strategy to simplify HF treatment and improve adherence. Drawing on its successful application in other cardiovascular diseases, we propose two implementation approaches for HF: early low-dose initiation for newly diagnosed patients or switching to a pre-specified dose polypill for stable, optimized patients. This review discusses formulations tailored to different HF phenotypes and highlights ongoing clinical trials assessing the efficacy and safety of the polypill in the HF setting. While the polypill approach offers promising benefits, i.e., improved adherence, affordability, and streamlined care, critical considerations regarding the selection of optimal drug components, identification and elimination of potential drug-drug interactions, the definition of appropriate flexible dose combinations, and patient-specific factors are crucial. Future research, particularly real-world clinical trials, is essential to comprehensively evaluate the efficacy, safety, and feasibility of polypill therapy in diverse HF patient populations, ensuring its responsible integration into clinical practice across diverse healthcare settings to mitigate the persistent burden of HF.<\/jats:p>","DOI":"10.1007\/s10741-025-10559-2","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T01:58:26Z","timestamp":1757123906000},"page":"1415-1422","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polypill in heart failure: a pathway to simplified treatment and improved adherence and outcomes"],"prefix":"10.1007","volume":"30","author":[{"given":"Kalliopi","family":"Keramida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Savarese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5640-0332","authenticated-orcid":false,"given":"Gerasimos","family":"Filippatos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Yusuf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"10559_CR1","unstructured":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017. 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KK and SY reports no COI.\u00a0GF reports lecture fees and \/or advisory and \/or trial committee membership by Bayer, Boehringer Ingelheim, Servier, Novartis, Impulse Dynamics, Vifor, Medtronic, Merck, Cardior, Novo Nordisc and Research Grants from the European Union.\u00a0GS reports grants and personal fees from CSL Vifor, Boehringer Ingelheim, AstraZeneca, Servier, Novartis, Cytokinetics, Pharmacosmos, Medtronic, Bayer, and personal fees from Roche, Abbott, Edwards Lifescience, TEVA, Menarini, INTAS, GETZ, Laboratori Guidotti, and grants from Boston Scientific, Merck, all outside the submitted work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}