Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction

Background: Increases in serum creatinine with renin–angiotensin–aldosterone system ( RAAS ) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction ( HFpEF ). The effects of LCZ696 on renal function have not been assessed. Methods and results: A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate ( eGFR ), cystatin C, and urinary albumin to creatinine ratio ( UACR )] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function ( WRF ) was determined as an serum creatinine increase of > 0.3 mg/dL and/or > 25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m2. The eGFR declined less in the LCZ696 group than in the valsartan group ( –1.5 vs. –5.2 mL/min per 1.73 m2; P = 0.002 ). The incidence of WRF was lower in the LCZ696 group ( 12% ) than in the valsartan group ( 18% ) at any time-point, but this difference was not statistically significant ( P = 0.18 ). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group ( 2.4–2.9 mg/mmol ), whereas it remained stable in the valsartan group ( 2.1–2.0 mg/mmol; P for difference between groups = 0.016 ). Conclusion: In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR.