Sex Differences in All-Cause and Cardiovascular Mortality During Long-Term Follow-Up in Patients with HFrEF

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.