ARNI may reduce adverse kidney outcomes in HF patients
Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure
Introduction and methods
Use of angiotensin-converting enzyme inhibitors (ACEi) or mineralocorticoid receptor antagonists (MRAs) in patients with HFrEF has been associated with a decline in eGFR in post-hoc analyses [1,2]. In HFpEF patients, no renal benefits were observed with MRAs and an accelerated decline in renal function was observed with RAS inhibition [3-5]. In post-hoc analyses of HFrEF and HFpEF trials, decline in eGFR slowed with treatment of combined angiotensin-neprilysin inhibition [6,7].
This analysis examined the effect of sacubitril/valsartan on hard renal outcomes in heart failure and explored treatment effects according to ejection fraction by pre-specified pooling of data from the PARADIGM-HF and PARAGON-HF trials.
PARADIGM-HF and PARAGON-HF were randomized, double-blind trials in which sacubitril/valsartan was compared to a RAS inhibitor in patients with symptomatic heart failure and elevated natriuretic peptides. PARADIGM-HF enrolled 8399 patients with LVEF ≤40% and PARAGON-HF enrolled 4796 patients with LVEF ≥45%. One of the exclusion criteria was an eGFR <30 mL/min/1.73 m2 (at screening) or <25 mL/min/1.73 m2 (at randomization), or decrease >35% between screening and randomization.
The primary renal outcome was a composite of ≥50% reduction in eGFR, ESRD or death from renal causes.
- The composite renal endpoint occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and in 123 of the 6601 patients (1.9%) in the RASi group (HR 0.56, 95%CI: 0.42-0.75, P<0.001).
- The treatment effect according to baseline EF was non-linear (P-interaction-0.35 for continuous EF and P-interaction=0.001 for categories of EF) and was most pronounced for those with baseline EF between 30% and 60%.
- There was no effect modification of treatment according to baseline eGFR.
- Mean decline in eGFR was -1.8 (95%CI: -1.9 to -1.7) mL/min/1.73 m² per year in the sacubitril/valsartan group and -2.4 (95%CI:-2.5 to -2.2) mL/min/1.73 m² per year in the RASi group (adjusted mean difference of 0.6, 95%CI: 0.4-0.7, P<0.001), and no evidence for effect modification according to baseline EF.
In this pooled analysis of PARADIGM-HF and PARAGON-HF consisting of patients with HFrEF and HFpEF, treatment with sacubitril/valsartan resulted in a reduction of the composite renal outcome and slowed the decline in eGFR compared with RAS inhibition.
The reduction in the renal composite outcome with use of sacubitril/valsartan compared with RAS inhibition was independent of baseline renal function and most pronounced in those with baseline EF between 30% and 60%.
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