Lower outcome rates but more symptoms, lower QoL and undertreatment in women vs. men with HFrEF
Differential Impact of Heart Failure With Reduced Ejection Fraction on Men and Women
Introduction and methods
Heart failure (HF) trials initiated in the last century highlighted many differences between men and women [1-8], including undertreatment in women compared to men [1-13], which has led to changed assessment and management of patients with HF. These changes may give a new perspective on the management of, and outcomes in, women with HF with reduced ejection fraction (HFrEF). This analysis compared women (n=3.357) and men (n=12.058) with HF enrolled in the two most recent and largest randomized trials of pharmacological therapy in patients with HFrEF.
The Prospective comparison of ARNI [Angiotensin Receptor Neprilysin Inhibitor] with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) and Aliskiren Trial to Minimize OutcomeS in Patients with Heart failure (ATMOSPHERE) trials included HF patients aged ≥18 years with NYHA functional class II to IV, LVEF ≤35%, plasma B-type natriuretic peptide ≥150 pg/mL or NT-pro-BNP ≥600 pg/mL, taking an ACE inhibitor or ARB, beta-blocker, and MRA if indicated. The median follow-up was 26.6 months in the PARADIGM-HF trial and 36.6 months in the ATMOSPHERE trial.
In this analysis, the primary outcome for both trials was studied, consisting of the composite of first HF hospitalization or CV mortality, in women compared with men. Also the components of the primary outcome, sudden death, pump failure death, non-CV death, and all-cause death, and recurrent hospitalizations were compared between women and men. Health-related quality of life (HRQL) was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, with lower scores indicating a poorer HRQL. General quality of life (QoL) was measured using the EQ-5D-3L questionnaire in the PARADIGM-HF trial.
Gender and pre-existing comorbidities
- Except for hypertension and clinically significant valvular disease, women were less likely to have a history of major comorbid conditions, such as AF, and previous MI.
- EQ-5D-3L health scores revealed more often moderate to extreme anxiety or depression (44.0% vs. 29.0%, P<0.001) (PARADIGM-HF trial only), which was especially seen in women with an ischemic etiology.
Gender and HF characteristics and investigations at baseline
- Women experienced more symptoms, with a higher prevalence of dyspnea on effort, paroxysmal nocturnal dyspnea, and more evidence of congestion (peripheral edema, jugular venous congestion, and rales).
- A slightly but significantly higher LVEF was observed in women (29.6% vs. 28.8%), whereas median NT-proBNP was not significantly different (1.448 pg/mL vs. 1.406 pg/mL) between men and women.
- Women had lower mean eGFR and a higher proportion of women had an eGFR <60 mL/min/1.73m².
- Women were significantly more likely to be in a higher NYHA functional class.
- Women had worse median KCCQ scores (71.3 [IQR: 53.4-86.5] vs. 81.3 [IQR: 65.1-92.7], P<0.0001).
Gender and treatment at baseline
- No significant difference in use of a diuretic and MRA was observed, whereas women were less often treated with a beta-blocker.
- Slightly more women received digitalis and ARBs. while less women received an ACE inhibitor.
- Women were less often treated with statins, aspirin, and anticoagulants.
- Women were less likely to have received a device: ICD and cardiac resynchronization therapy.
- Women were less likely to have been enrolled in a disease management program, or to have been prescribed an exercise regimen.
Gender and clinical outcomes
- Women showed a lower rate of the primary composite outcome of first HF hospitalization or CV mortality (HRadj: 0.75, 95%CI: 0.69-0.81), with lower rates and risk of first hospitalization for HF in women (HRadj: 0.80, 95%CI: 0.72-0.89) when looking at the components of this composite.
- Risk of CV death (i.e. sudden death and pump failure death) was lower in women (HRadj: 0.70, 95%CI: 0.63-0.77), and lower compared to HF hospitalization.
Gender and recurrent events
- During follow-up hospitalization for any cause was observed less often in women (3.006 vs. 13.641). Of these, 25.1% were due to HF in women and 26.2% were due to HF in men (IRRadj: 0.69, 95%CI: 0.61-0.79, P<0.001).
An analysis of the PARADIGM-HF and ATMOSPHERE trials with HFrEF patients showed lower rates of HF hospitalization and CV mortality in women, however, they had more symptoms and worse HQRL, compared to men. Further, women appeared relatively undertreated with diuretics, anticoagulants and devices given their greater evidence of congestion, and they were less often referred to a disease management program or prescribed for an exercise regimen. These data suggest tailored therapeutic strategies for women, increased referral to cardiac rehabilitation programs, and more psychosocial support.