B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial

Abstract

Background: Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended.

Objectives: The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan.

Methods: BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF.

Results: Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively).

Conclusions: Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).

Keywords: biomarker; heart failure; natriuretic peptides; prognostication; risk stratification; treatment.

Figure 1.. Natriuretic Peptide Trajectories in the PARADIGM-HF Trial.

Median concentration of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) before (V2) and during (V5, V7, V10) treatment with sacubitril/valsartan and enalapril.

Figure 2.. Distribution of Natriuretic Peptide Responses after 8–10 Week Treatment with Sacubitril/Valsartan.

The gold histogram represents changes in B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) during 8–10 weeks of treatment with sacubitril/valsartan, presented as % change from pre-run-in to 1 month after randomization. The histogram corresponds to the secondary (right-sided) Y-axis. The solid black line represents an estimation by Poisson regression of the association between change in natriuretic peptides and the primary outcome after adjusting for age, sex, race, body mass index, diabetes mellitus, hypertension, coronary artery disease, systolic blood pressure, estimated glomerular filtration rate, and pre-run-in natriuretic peptide concentrations. Dotted lines represent the 95% confidence intervals. Incidence rates are displayed on the primary (left-sided) Y-axis.

Figure 3 (Central Illustration).. Association Between Natriuretic Peptide Concentrations and Subsequent Cardiovascular Events Before and During Treatment with Sacubitril/Valsartan.

Association between log-transformed B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the primary outcome before (V2) and during (V5, V7 and V10) treatment with sacubitril/valsartan after adjusting for age, sex, race, body mass index, diabetes mellitus, hypertension, coronary artery disease, and systolic blood pressure at the same visit, estimated glomerular filtration rate at the same visit. Spearman’s rank correlation coefficients (r_s) were calculated to characterize the correlation between BNP and NT-proBNP at each time-point. Abbreviations: CI = confidence interval; HR = hazard ratio.