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

Literature - Dewan P, Rørth R, Jhund PS et al. - JACC 2019; 73(1): 29-40

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.

Main results

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).

Conclusion

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.

References

1. Shah MR, Granger CB, Bart BA, et al. Sex-related differences in the use and adverse effects of angiotensin-converting enzyme inhibitors in heart failure: the study of patients intolerant of converting enzyme inhibitors registry. Am J Med 2000;109:489–92.

2. Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation 2001;103: 375–80.

3. Ghali JK, Piña IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation 2002;105:1585–91.

4. Ghali JK, Krause-Steinrauf HJ, Adams KF, et al. Gender differences in advanced heart failure: insights from the BEST study. J Am Coll Cardiol 2003;42:2128–34.

5. Gustafsson F, Torp-Pedersen C, Burchardt H, et al. Female sex is associated with a better

long-term survival in patients hospitalized with congestive heart failure. Eur Heart J 2004;25: 129–35.

6. Majahalme SK, Baruch L, Aknay N, et al. Comparison of treatment benefit and outcome in

women versus men with chronic heart failure (from the Valsartan Heart Failure Trial). Am J Cardiol 2005;95:529–32.

7. O’Meara E, Clayton T, McEntegart MB, et al. Sex differences in clinical characteristics and prognosis in a broad spectrum of patients with heart failure: results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 2007;115:3111–20.

8. Russo AM, Poole JE, Mark DB, et al. Primary prevention with defibrillator therapy in women: Results from the sudden cardiac death in heart failure trial. J Cardiovasc Electrophysiol 2008;19: 720–4.

9. Rathore SS, Foody JM, Wang Y, et al. Sex, quality of care, and outcomes of elderly patients hospitalized with heart failure: findings from the National Heart Failure Project. Am Heart J 2005; 149:121–8.

10. Sheppard R, Behlouli H, Richard H, Pilote L. Effect of gender on treatment, resource utilization, and outcomes in congestive heart failure in Quebec, Canada. Am J Cardiol 2005;95:955–9.

11. Lenzen MJ, Rosengren A, Scholte op Reimer WJM, et al. Management of patients with heart failure in clinical practice: differences between men and women. Heart 2008;94:e10.

12. Yancy CW, Fonarow GC, Albert NM, et al. Influence of patient age and sex on delivery of guideline-recommended heart failure care in the outpatient cardiology practice setting: Findings from IMPROVE HF. Am Heart J 2009;157: 754–62.e2.

13. Linde C, Ståhlberg M, Benson L, et al. Gender, underutilization of cardiac resynchronization therapy, and prognostic impact of QRS prolongation and left bundle branch block in heart failure. Europace 2015;17:424–31.

Find this article online at JACC

Facebook Comments

Register

We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free