Sacubitril/Valsartan vs Enalapril for Physical Activity Improvement in HFrEF

Sacubitril/valsartan was associated with greater improvements in physical and social activities in patients with heart failure with reduced ejection fraction than enalapril.

A study published in JAMA Cardiology reported that sacubitril/valsartan, when administered to patients with heart failure with reduced ejection fraction (HFrEF), was associated with greater improvements in social and physical activities (eg, sexual relationships and the ability to complete household chores) than enalapril.1

In this secondary analysis of the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; Identifier: NCT01035255) trial, a total of 8399 patients with HFrEF (New York Heart Association [NYHA] class II-IV and left ventricular ejection fraction ≤40%) were assigned to either a 200-mg twice-daily dose of sacubitril/valsartan (n=4187) or a 10-mg twice-daily dose of enalapril (n=4212).2 The 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered to patients to assess health-related quality of life (HRQL) at time of randomization and at 4-, 8-, and 36-month follow-up.

For this analysis, investigators focused on the effect of sacubitril/valsartan vs enalapril for improving the physical and social limitation domains of the KCCQ at 8 to36 months or until the final visit.

Approximately 90.7% (n=7618) of the patients included in the trial completed the KCCQ at baseline, with jogging and sexual relationships being the most frequently reported limitations. At baseline, the greatest limitations associated with physical and social activities were reported more often in patients who were women (P <.001), older (P <.001), had worse NYHA class (P <.001), and presented with higher N-terminal pro-brain natriuretic peptide levels (P <.001).

In addition, patients who answered “limited for other reasons” in the sexual limitations domain at baseline were significantly older (69 vs 62 years; P <.001), more likely to be women (881 of 2367 [37.2%] vs 759 of 5251 [14.5%]; P <.001), had worse NYHA class (mean of 2.3 vs 2.2; P <.001), and had higher KCCQ social activity mean scores (72.6 vs 71.3; P =.04).

At 8 months, patients who received sacubitril/valsartan reported greater improvements in completing household chores than those who received enalapril (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P <.001). Sexual relationships were also improved to a greater degree in the sacubitril/valsartan vs enalapril group in the adjusted analysis (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P =.002). These reported improvements in household chores and sexual relationships were sustained through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60]; P <.001; and 2.36 [95% CI, 1.01-3.71]; P =.001, respectively).

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The lack of an objective system for measuring improvements in sexual relationships and physical function may have potentially limited the findings.

According to the investigators, improvement of “HRQL remains an elusive target in heart failure,” yet the findings from this study demonstrate that sacubitril/valsartan may be an option for establishing firm improvements in some patients with HFrEF.


  1. Chandra A, Lewis EF, Claggett BL, et al. Effects of sacubitril/valsartan on physical and social activity limitations in patients with heart failure: a secondary analysis of the PARADIGM-HF trial [published online April 4, 2018]. JAMA Cardiol. doi:10.1001/jamacardio.2018.0398
  2. McMurray JJV, Packer M, Desai AS, et al; for the PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.