Global real-world data on heart failure with reduced ejection fraction: challenges in optimization and sex disparities

Aims Despite the advancements in the treatment of patients with heart failure with reduced ejection fraction (HFrEF), clinical inertia regarding the prescription of the four classes of guideline-directed medical therapies (GDMT) remains prevalent. This study aims to assess how adherence and time of prescription to GDMT in HFrEF impact mortality. Additionally, it seeks to evaluate sex differences in prescription and outcome. Methods and results The study retrospectively analysed data worldwide using the TriNetX database. Patients with HFrEF were divided into four groups (G1–G4) based on the number of classes of GDMT prescribed. The primary endpoint was all-cause mortality. Additional analysis was performed in the G4 group to examine the impact of the time to reach quadruple therapy on mortality. An age-matched subgroup analysis was conducted to assess whether sex influenced mortality. The total cohort included 17 668 patients (68% men, mean age 66.7 ± 14.6). Only 20% of patients received quadruple therapy; the least heart failure (HF) medications prescribed were mineralocorticoid receptor antagonists (39%) and sodium-glucose cotransporter-2 inhibitors (33%), especially among older and frail patients. Each additional HF therapy was associated with significant mortality reduction (P-value < 0.001 for each additional class prescribed). However, the timing of full treatment implementation within the first year did not significantly affect mortality in the G4 group. No significant sex-based differences in survival were found in the age-matched analysis. Conclusion Clinical inertia remains a critical issue, especially in those who may most benefit from HF therapy. Further clinical trials should specifically assess sex-related differences in drug efficacy and patient characteristics.