In Reply In the LCZ696 in Hospitalized Advanced Heart Failure (LIFE) trial,1 we did not observe a statistically significant difference between sacubitril/valsartan and valsartan with respect to the time-averaged proportional change in the area under the curve (AUC) for N-terminal pro–brain natriuretic peptide (NT-proBNP) levels through 24 weeks of therapy, relative to the baseline levels of NT-proBNP (primary end point), in patients with chronic advanced heart failure with a reduced ejection fraction.1 Based on their prior work, which showed that brain natriuretic peptide (BNP) is an endogenous neprilysin inhibitor when BNP levels exceed 916 pg/mL (to convert to nanograms per liter, multiply by 1),2 Vodovar and colleagues suggest that, in the advanced heart failure population that was studied in the LIFE trial, high circulating levels of BNP may have attenuated the pharmacological differences between sacubitril/valsartan and valsartan by inhibiting sacubitril-mediated degradation of BNP.
Mann DL, Hernandez AF, Braunwald E. Could Neprilysin Be Already Inhibited by BNP in the LIFE Trial?—Reply. JAMA Cardiol. 2022;7(6):657–658. doi:10.1001/jamacardio.2022.0787
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