Sex-related differences in contemporary HFrEF management: insights from the Italian OpTIMa-HF Registry

Background/Introduction Despite strong trial evidence and guideline recommendations, real-world implementation of guideline-directed medical therapy (GDMT) in heart failure (HF) with reduced ejection fraction (HFrEF) remains suboptimal and heterogeneous. Sex-related differences may represent an additional layer of complexity, further influencing GDMT implementation. Purpose The OpTIMa-HF Registry is an Italian multicenter registry aimed at describing HF management across diverse outpatient care settings. The purpose of this subanalysis was to investigate sex-related differences in GDMT implementation among HFrEF patients enrolled in the registry. Methods A sex-stratified analysis of HFrEF patients pooled from the retrospective and prospective phases of the registry was performed. Women and men were compared for baseline clinical characteristics, drug prescription rates and doses, combination therapy, and guideline-defined contraindications among untreated patients. Sex-specific multivariable logistic regression models explored predictors of non-prescription of quadruple therapy among patients receiving three drug classes. Results Among 2174 HFrEF patients, women accounted for 24.7% (n=537). Compared with men, women were slightly older, with a more symptomatic profile. Prescription rates were similar for renin-angiotensin-aldosterone system inhibitors, angiotensin receptor neprilysin inhibitor (ARNI), beta-blockers, and sodium/glucose cotransporter 2 inhibitors (SGLT2i), whereas mineralocorticoid receptor antagonists (MRA) and loop diuretics were more frequently prescribed in women (80.3% vs 76.1%, p=0.047; 79.5% vs 72.0%, p<0.001). Implantable cardioverter-defibrillator (ICD) implantation was significantly lower in women (39.3% vs 48.3%; p<0.001). Among untreated patients, contraindications were uncommon overall but were significantly more frequent for ARNI in women (34.7% vs 24.7%; p=0.018), while SGLT2i contraindications were similar (11.7% vs 9.6%). ARNI-based quadruple therapy was slightly higher in women (49.7% vs 44.9%; p=0.050), whereas dose intensity did not differ by sex. Predictors of non-prescription of the fourth pillar differed by sex: in men, higher EF, higher potassium, eGFR <30 mL/min/1.73m², and device-based therapy were associated with non-prescription; in women, older age and non-ischaemic aetiology were the main predictors. Conclusion(s) In this nationwide outpatient registry, overall GDMT prescription and dosing intensity were broadly similar by sex, with higher MRA and diuretic use but lower ICD implantation in women. Sex-specific predictors of incomplete quadruple therapy suggest that tailored implementation strategies may help close residual treatment gaps and optimize HFrEF care.