Abstract Introduction The clinical characteristics and determinants for prognosis of patients with a first hospitalisation for heart failure (HF) with reduced left ventricular ejection fraction (LVEF <40%) are poor described and show heterogeneous results that need major investigation. Purpose The aim of our study was to identify the clinical characteristics, prognosis and their main determinants in a prospective registry of patients with HF and reduced LVEF with a first hospital admission for acute heart failure, prognosis and their main determinants in a prospective registry in these patients. Methods We carried out a prospective registry in 2 University Hospitals of patients admitted to cardiology department due to first-time HF hospitalisation with reduced LVEF. 231 admitted consecutively between March 2021 and September 2022 were included, with a mean follow-up of 381 days. Continuous variables were represented as median (interquartile range) and categorical variables as percentage %. A multivariate logistic regression was performed in which age, sex, comorbidities, treatment, rhythm at discharge and improvement in LVEF were included; and using the Wald method, the predictors of rehospitalization and/or death were identified. Data were analysed using SPSS v. 25.0. Results The main baseline characteristics are shown in Table 1. The population had a median age of 71 years, 75% were men, with a high prevalence of arterial hypertension (HBP) (69%) and hyperlipidemia (57%). Quadruple therapy (Na-Glucose cotransporter 2 inhibitor [SGLT2i], Beta-Blocker, mineralocorticoid receptor antagonist [MRA] and angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme inhibitor [ACEi] or Angiotensin-II receptor blocker [ARB]) was achieved in 57% at discharge. The dynamics of NTproBNP was studied from admission to completed up-titration, observing an average reduction of 37% and 32% met the criteria for improved LVEF after. The etiology is described in Figure 1a, with ischemic heart disease being the most represented (31%). Multivariate Cox regression for the combined event of readmission/death from any cause showed that treatment with SGLT2i (OR 0,48 [CI 95%: 0,23-0,98 p:0,04]) and Beta-Blocker (OR 0,35 [CI 95%: 0,14-0,87 p:0,02]) at discharge and improved LVEF (OR 0,33 [CI 95%: 0,15-0,72 p:0,006]) were protective predictors against the event; but diabetes mellitus (DM) was a predictor of a worse prognosis (OR 2,9 [CI 95%: 1,52-5,5 p:0,001]) Fig. 1b. Conclusions Patients with a first admission for HF with reduced LVEF constitute a heterogeneous clinical group. Improvement in LVEF after drug up-titration and treatment with SGLT2i and Beta-blocker are independently associated with a better prognosis. Our findings may have implications for their clinical management.Table 1Figure 1