Sex differences in functional capacity, non-cardiac comorbidity, guideline-directed medical therapy and all-cause mortality in HFrEF/HFmrEF

Introduction Heart failure (HF) is a heterogeneous syndrome with well recognized differences between men and women. We intended to investigate sex differences in symptom burden, non-cardiac comorbidities and GDMT use, and to explore whether the association between optimal GDMT and all-cause mortality differs by sex. Methods Patients with HF and left ventricular ejection fraction (LVEF) <50% from the Norwegian Heart Failure Registry between 2015 and 2023, comprising >90% of patients treated at the nurse-led HF clinics across Norway with the aim of optimizing and uptitrating GDMT, were analyzed. Data collected include demographics, comorbidities, medications, biomarker values (including creatinine,TSAT and NT-proBNP), LVEF, New York Heart Association (NYHA) class, 6-minute walk test (6MWT). Optimal GDMT was defined as triple therapy (renin angiotensin system acting agents, betablockers and mineralocorticoid receptor antagonist) before 2022, and quadruple therapy (triple therapy plus an SGLT2 inhibitor) from 2022 onwards, and analysed using logistic regression adjusted for, BMI, ejection fraction, 6MWT, NYHA category, comorbidities, NT-proBNP, iron deficiency (TSAT <20%), and creatinine. For survival analyses, follow-up started at first HF clinic visit and was censored after 36 months. We used inverse probability of treatment weighting (IPTW) and Cox regression to evaluate associations between quadruple GDMT and all-cause mortality and tested for sex and treatment interaction. Results 12,527 patients with HFrEF were included. Median (Q1-Q3) age was 72 (62–78) years and 25.9% were women. Women were older (73 [64–80] vs 71 [62–78] years) and had lower BMI (25.6 [22.4–29.8] vs 26.7 [23.9–30.2] kg/m²). Women had reduced functional capacity with shorter 6MWT (390 [272–475] vs 450 [360–540] m) and more severe symptoms (NYHA III/IV 31.8% vs 25.8%). NT-proBNP was higher in women (1630 [720–3471] vs 1336 [575–2873] pg/mL), and iron deficiency was more prevalent (40.0% vs 32.3%). Men had more frequently diabetes (26.1% vs 20.8%) and peripheral vascular disease (9.6% vs 8.3%). Overall, 53% of patients received optimal GDMT, with lower rates in women than men (47% vs 54%). In the adjusted GDMT model, women had significantly lower odds of receiving quadruple GDMT compared with men (OR 0.72, 95% CI 0.65–0.80, p<0.001). In an IPTW-weighted Cox regression, 36-month all-cause mortality did not differ by sex (women vs men HR 0.97, 95% CI 0.85–1.12, p0.720). Optimal GDMT was associated with lower mortality in women (HR 0.59, 95% CI 0.50–0.70, p<0.001) and for men (HR 0.65, 95% CI 0.46-0.92, p=0.015) with no evidence of effect modification by sex (interaction p=0.588). Conclusion Despite higher NT-proBNP and worse functional status, women had 28% lower odds of receiving quadruple GDMT. Optimal GDMT was associated with lower mortality with no evidence of sex-specific differences, supporting equitable implementation in eligible patients.