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We read with interest the letter by Siniorakis et al. referring to our paper, ‘‘Sacubitril/valsartan: a practical guide’’ published in the Journal, and we do agree that biochemical issues on natriuretic peptides in the context of sacubitril/valsartan treatment are complex and controversial. Nevertheless, we have to keep in mind that our purpose was to provide physicians with clear and practical guidance to everyday practice, and our recommendations are based on the evidence of clinical arguments. There is ample literature about the effects of neprilysin and its inhibition by neprilysin inhibitors like sacubitril on the natriuretic peptide system -protein modifications, endopeptide scissions -and their identification by immunoassays from different manufacturers. The effects of neprilysin inhibition are variable and poorly predictable in BNP assays from different manufacturers; change in one BNP assay may not necessarily be comparable to another one and there is definitely heterogeneity across assays with respect to how much change is observed. This variation is logical because neprilysin cleaves the BNP molecule in several places, which also reflect binding sites for the various BNP immunoassays. Sacubitril/valsartan leads to a somewhat more predictable decrease in NT-proBNP, as measured by different assays. There is also wide between-patient variability in BNP response to sacubitril/valsartan, including the initial variable increase in BNP after initiation of the ARNi in HFrEF patients -no increase in BNP in some patients, variable increases in others -compared to a more homogeneous NT-proBNP decrease.

Response to the Letter to the Editor “When sacubitril/valsartan met neprilysin and B-type natriuretic peptide in the labyrinth of biochemistry”