Background/Objectives: Traditionally, risk stratification in heart failure with reduced ejection fraction (HFrEF) patients has been a static process. This study aims to identify clinical predictors and causes of mortality at different stages of the disease, distinguishing between early mortality (≤1 year) and late mortality (>1 year), as well as cardiovascular and non-cardiovascular causes. Methods: This is an observational, longitudinal study of a cohort of 1510 patients with HFrEF followed up in a specialist heart failure unit between 2011 and 2023. Patients were categorized into three groups: alive (n = 1093), early mortality (n = 55) and late mortality (n = 362). Multivariate Cox regression models were used to identify mortality independent predictors in each period. Results: During the first year, cardiovascular and non-cardiovascular mortality showed a relatively balanced distribution, with a slight predominance of non-cardiovascular causes (52.8%). Progression of heart failure remained the leading individual cause of early death (38.2%). Independent predictors of early cardiovascular death included ischemic etiology (HR 2.78; 95% CI: 1.20–6.40; p = 0.01), NYHA functional class (HR 4.38; 95% CI: 2.18–8.81; p < 0.001) and renal function (HR 0.60; 95% CI: 0.44–0.84; p = 0.002). In contrast, late mortality (>1 year) was predominantly due to non-cardiovascular causes (59.7%), notably cancer (24.3%) and infections (7.5%). Late all-cause mortality was independently associated with age (HR 1.35; 95% CI: 1.17–1.56; p < 0.001), hypertension (HR 1.38; 95% CI: 1.06–1.81; p = 0.015) and ischemic etiology (HR 1.45; 95% CI: 1.16–1.80; p < 0.001). In the follow-up, the improvement of left ventricular ejection fraction (LVEF) emerged as a protective factor against long-term all-cause mortality (HR 0.77; 95% CI: 0.63–0.94; p = 0.01) and, even more markedly, against late cardiovascular mortality (HR 0.47; 95% CI: 0.33–0.66; p < 0.001), whereas baseline LVEF at diagnosis lacked significant predictive value in either model. Conclusions: Mortality in HFrEF is a dynamic process. Early survival is determined by hemodynamic stability, renal function and functional severity, whilst late survival is predominantly driven by non-cardiovascular comorbidities, biological aging, and ventricular remodeling trajectory. The improvement of LVEF during follow-up is a more reliable prognostic marker than the baseline measurement, suggesting that clinical management should shift from early pharmacological optimization towards a multidisciplinary approach focused on long-term non-cardiovascular risk.

Background/Objectives: Sex-related differences in prognosis among patients with heart failure with reduced ejection fraction (HFrEF) have been described, but their association with long-term all-cause and cardiovascular mortality remains incompletely characterised. This study investigated these associations in a real-world HFrEF cohort, accounting for non-cardiovascular death as a competing event. Methods: We conducted a single-centre, retrospective, longitudinal observational study of 1510 consecutive patients with HFrEF followed between 2011 and 2023; 1158 (76.7%) were men and 352 (23.3%) were women. All-cause mortality was assessed using Kaplan–Meier methods and Cox regression. Multivariable models used a complete-case approach. Cardiovascular mortality was analysed using cause-specific Cox regression and the Fine–Gray model, with non-cardiovascular death and death of unknown cause treated as competing events. Interaction terms between sex and year of inclusion were used to assess potential changes in the association across the study period. Results: No statistically significant between-sex difference in cumulative all-cause mortality was detected at one year (3.7% in men vs. 3.8% in women; p = 0.95). Exploratory pointwise comparisons showed higher cumulative mortality in men at five years (24.8% vs. 16.0%; p = 0.002) and ten years (49.3% vs. 39.8%; p = 0.046). After multivariable adjustment, male sex was associated with higher all-cause mortality (HR, 1.95; 95% CI, 1.47–2.59; p < 0.001). Male sex was also associated with cardiovascular mortality in the cause-specific analysis (HR, 2.46; 95% CI, 1.54–3.92; p < 0.001) and after accounting for non-cardiovascular death as a competing event (subdistribution HR, 2.12; 95% CI, 1.32–3.39; p = 0.002). No significant interaction was observed between sex and year of inclusion. Conclusions: In this real-world HFrEF cohort, male sex remained associated with higher all-cause and cardiovascular mortality after adjustment for measured baseline covariates. The association with cardiovascular mortality persisted in competing-risk analysis. These observational findings do not establish a causal or time-varying effect of sex.