Introduction and objectives: Guidelines recommend early initiation of the 4 pillars of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF), but real-world evidence on quadruple therapy (QT) at discharge remains limited in Latin America.

Methods: We conducted a retrospective cohort study of consecutive patients with HFrEF discharged from a tertiary cardiovascular center in Colombia (2022-2026). Patients were classified as receiving QT, defined as all 4 GDMT pillars, or incomplete therapy (IT, 0-3 pillars). Propensity-score optimal full matching was performed using 26 covariates. The primary endpoint was 30-day death or readmission. The robustness of the mortality findings was assessed using the primary estimator and 4 sensitivity analyses.

Results: Among 3839 patients (median age, 68.2 years; 71.2% male), 2758 (71.8%) were discharged on QT. The 30-day composite endpoint occurred in 751 patients (19.6%). QT was associated with a lower risk of death or readmission (RR, 0.71; 95%CI, 0.58-0.88; P = .001). Mortality showed a consistent direction of association (RR, 0.61; 95%CI, 0.37-1.01; P = .052), with the 95%CI excluding unity in all 4 sensitivity analyses. Readmission was lower with QT (cause-specific HR, 0.73; 95%CI, 0.56-0.95; P = .017). Findings in the Chagas subgroup (n = 614) were directionally consistent with those in the overall cohort, with no significant treatment-by-subgroup interaction.

Conclusions: In this Latin American HFrEF cohort, QT at discharge was associated with a lower risk of 30-day death or readmission. The magnitude of the mortality association may partly reflect residual confounding rather than a pharmacological effect. These findings support the feasibility of QT prescription in a tertiary care setting in a low- and middle-income country.