Angiotensin-Neprilysin Inhibition and Renal Outcome in Men and Women With Heart Failure

Sacubitril/valsartan is known to reduce adverse renal outcomes and slow the decline in estimated glomerular filtration rate (eGFR) compared with renin-angiotensin system (RAS) inhibitors across the entire spectrum of heart failure. However, whether these renoprotective effects differ by sex has not been elucidated. Thus, we aimed to evaluate whether the treatment effect of sacubitril/valsartan versus RAS inhibitors on renal outcomes differs by sex.

Data sets from the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure; ejection fraction ≤40%, n=8399) and PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction; ejection fraction ≥45%, n=4796) trials were integrated in a prespecified pooled analysis. We evaluated the treatment effect (sacubitril/valsartan versus RAS inhibitors) on the prespecified renal composite outcome (death from renal failure, end-stage renal disease, or ≥50% reduction in eGFR) and changes in eGFR slope in female (n=4311) and male (n=8884) patients to determine whether sex modified the effect of sacubitril/valsartan on renal outcomes.

At baseline, women exhibited lower eGFR values than men (67.2±19.7 versus 72.6±20.4 mL/min/1.73 m², P<0.001). Compared with RAS inhibitors, sacubitril/valsartan reduced the renal composite outcome similarly in women (1.1% versus 2.2%, hazard ratio [HR], 0.51 [95% CI, 0.31-0.83]) and in men (1.0% versus 1.7%, HR, 0.60 [95% CI, 0.41-0.86]; P for interaction=0.60). Sacubitril/valsartan attenuated the decline in eGFR compared with RAS inhibitors similarly in women (-1.8 versus -2.2 mL/min/1.73 m² per year, P=0.006) and men (-1.6 versus -2.3 mL/min/1.73 m² per year, P<0.001) (P for interaction for difference in eGFR slopes=0.19).

Sacubitril/valsartan significantly reduces the incidence of renal composite outcome and decelerates the decline in eGFR compared with RAS inhibitors. The renoprotective effects of this drug are uniformly observed in both women and men.