Differences between men and women in guideline-directed medical therapy implementation, tolerability, and outcomes in heart failure with reduced ejection fraction

Abstract Background Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) is well established, but data on differences between men and women in real-world use, tolerability, and outcomes are limited. We examined these differences in contemporary HFrEF patients. Methods and results TITRATE-HF is a prospective registry across 48 Dutch hospitals (inclusion June 2022-February 2024), enrolling patients with de novo, chronic, and worsening heart failure (HF). This analysis studied 3,367 HFrEF patients and compared men and women regarding GDMT implementation, side effects, change in left ventricular ejection fraction (LVEF), and clinical outcomes (composite endpoint: first HF hospitalization or all-cause death). The cohort included 2,408 men (71.5%; 71 years IQR 63-77) and 959 women (28.5%; 72 years IQR 64-79). At 12-month follow-up, 59.0% of men and 59.7% of women received quadruple therapy (p=0.729). Men more often achieved quadruple therapy at ≥50% of target doses (16.2% versus 11.9%, p=0.004). Compared to men, women experienced more downgrades of ARB (11.6% versus 6.9%, p=0.040) and MRA (13.2% versus 10.4%, p=0.038) due to side effects. In de novo HFrEF, women showed greater LVEF improvement than men (15% versus 13%, p=0.005). In chronic HFrEF, women had lower risk of the composite endpoint compared to men (aHR 0.64, 95% CI 0.45–0.91; p=0.015). Conclusions GDMT initiation and sequencing were comparable between men and women, but differences were observed in dose achievement, treatment tolerability, and clinical outcomes. These findings underscore the need for implementation and dosing strategies that account for differences between men and women.