Physicians' Academy for Cardiovascular Education

BNP and NT-proBNP provide prognostic information with comparable performance during ARNI therapy in HFrEF

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

Literature - Langeland Myhre P, Vaduganathan M, Claggett B et al. - JACC 2019; DOI: 10.1016/j.jacc.2019.01.018

Introduction and methods

The widely expressed enzyme neprilysin is involved in the degradation of various beneficial vasoactive peptides, including natriuretic peptides (NPs). A-type NP and C-type NP are effectively cleaved by neprilysin, but B-type natriuretic peptide (BNP) is a relatively poor substrate for neprilysin. The inactive fragment N-terminal pro-B-type natriuretic peptide (NT-proBNP) is not affected by neprilysin [1-3].

Therapy with the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan has been linked to an overall increase in BNP. Several clinical guidance documents have therefore questioned the clinical utility and interpretability of BNP in patients treated with sacubitril/valsartan [4-7]. This study assessed the relative prognostic value of BNP and NT-proBNP before and during therapy with sacubitril/valsartan in the PARADIGM-HF trial.

PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) was a randomized, double-blind trial comparing the long-term efficacy and safety of sacubitril/valsartan with enalapril in patients with HF with reduced ejection fraction (HFrEF). After subsequent 4-6 week single-blind run-in phases to test tolerability for enalapril and sacubitril/valsartan, participants were randomized 1:1 to enalapril 10 mg twice daily or sacubitril/valsartan 200 mg twice daily. NP measurements were performed before run-in (baseline), at randomization (after 4-6 weeks of treatment with sacubitril/valsartan), 1 month after randomization (8-10 weeks of treatment with sacubitril/valsartan), and 8 months after randomization (9 months of ARNI treatment. Mean follow up was 2.4 years. Primary outcome was a composite of CV death or first hospitalization for HF.

Main results

Changes in BNP and NT-proBNP during treatment with sacubitril/valsartan

Prognostic value of BNP and NT-proBNP before and during treatment with sacubitril/valsartan

Ratio between NT-proBNP and BNP


PARADIGM-HF demonstrated that early after initiation, treatment with sacubitril/valsartan may result in a meaningful modest increase in circulating BNP levels (~20%) in most, but substantially in some treated patients. During treatment with sacubitril/valsartan, the distribution of BNP levels was shifted right-wards as compared to NT-proBNP levels. Early changes in levels of both NPs are fully explained by effects of treatment with ARNI, and may thus identify patients at higher CV risk. During treatment with ARNI, both biomarkers showed comparable performance in giving clinical prognostic information.


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