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Comment & Response
May 4, 2022

Could Neprilysin Be Already Inhibited by BNP in the LIFE Trial?

Author Affiliations
  • 1Université de Paris, INSERM UMR-S 942, Paris, France
  • 2Department of Cardiology, Hôpital Lariboisière Fernand Widal, Assistance Publique–Hôpitaux de Paris, Paris, France
JAMA Cardiol. 2022;7(6):656-657. doi:10.1001/jamacardio.2022.0784

To the Editor In the LCZ696 in Hospitalized Advanced Heart Failure (LIFE) trial, the authors reported no benefit of sacubitril/valsartan over valsartan on the primary end points or decrease in plasma N-terminal pro–brain natriuretic peptide (NT-proBNP).1 Data from Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) already hinted this result, as the primary end point was not met in patients with New York Heart Association heart failure class III or IV, although the extent of the error bar suggested the lack of benefit only affected the most severe patients.2 Besides the low recruitment and lack of statistical power, brain natriuretic peptide (BNP)–mediated neprilysin inhibition could also account for those results. We showed that human BNP is an endogenous neprilysin inhibitor when greater than 916 pg/mL (to convert to nanograms per liter, multiply by 1),3 which questioned the rationale for neprilysin pharmacological inhibition above this BNP threshold. In a cohort of 73 patients with heart failure with reduced ejection fraction (median [IQR] NT-proBNP, 1201 [571-1997] pg/mL) treated with sacubitril/valsartan, we found 5 (6.8%) with BNP levels greater than 916 pg/mL and neprilysin inhibition before initiating sacubitril/valsartan.4 At day 30 after the introduction of sacubitril/valsartan, 4 of these patients had BNP levels less than 916 pg/mL, neprilysin being inhibited by sacubitril thereafter. In the LIFE trial, the NT-proBNP plasma levels were much higher compared with the PARADIGM-HF cohort and our cohort, anticipating that a significant proportion of patients enrolled in the LIFE trial have BNP levels greater than 916 pg/mL with little chance to decrease their BNP value lower than 916 pg/mL, and therefore their neprilysin is already inhibited by BNP at enrollment and throughout the trial. A subgroup analysis of LIFE, selecting only patients with BNP levels less than 916 pg/mL at day 30 would be interesting to analyze to confirm our hypothesis. Overall, plasma BNP levels greater than 916 pg/mL at day 30 appears to be a good candidate biomarker to identify patients who will benefit the most to sacubitril/valsartan, especially in advanced heart failure.

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