Highlights from

ACC 2019

American College of Cardiology Annual Scientific Session & Expo

New Orleans 16-18 March 2019

BNP still a reliable prognostic marker before and during sacubitril/valsartan treatment

Despite an initial increase in B-Type Natriuretic Peptide (BNP) after initiation of treatment with sacubitril/valsartan in approximately 60% of patients, it has been assessed that BNP remains a reliable prognostic marker before and during treatment with sacubitril/valsartan.

Natriuretic peptides are substrates of neprilysin, and BNP concentrations rise with neprilysin inhibition. This has led to inquisitions into the clinical validity of measuring BNP in sacubitril/valsartan-treated patients and the use of N-terminal pro-BNP (NT-proBNP) being preferred and recommended. Vaduganathan et al. aimed to determine the prognostic performance of BNP before and during treatment with sacubitril/valsartan [1].

Study design

Data was analysed from the randomised, double-blind, parallel group, active-controlled PARADIGM-HF trial, which compared the long-term efficacy and safety of sacubitril/valsartan with enalapril in patients with heart failure with reduced ejection fraction (HFrEF) [1,2]. NP measurements were analysed in a central laboratory from frozen venous blood samples drawn before run-in (n=1,656), after run-in with both enalapril and sacubitril/valsartan (time of randomisation, n=2,075 in both study arms), 1 month after randomisation (n=994 in the sacubitril/valsartan arm; n=1,007 in the enalapril arm), and 8 months after randomisation (n=908 in the sacubitril/valsartan arm; n=901 in the enalapril arm). The researchers assessed the association between both biomarkers and the primary outcome (i.e. cardiovascular death + heart failure hospitalisation) that occurred after each time-point.

Increase after 8-10 weeks on sacubitril/valsartan treatment

Median BNP concentration before both run-in phases and any treatment exposure was 202 ng/L (Q1-Q3 126-335 ng/L). Median BNP increased to 235 ng/L (Q1-Q3 128-422 ng/L) after 8-10 weeks of sacubitril/valsartan, with 18% of patients experiencing a doubling and 6% experienced a tripling of BNP during the first 8-10 weeks; 14% had stable concentrations (approximately 10% change). BNP concentrations at 8-10 weeks of treatment were available in 24% of all patients in PARADIGM-HF. 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 compared with NT-pro-BNP. However, both peptides retained their prognostic accuracy (C-statistics of 63-67% for BNP and C-statistics of 64-70% for NT-proBNP) with no difference between the two biomarkers. Increases in both BNP and NT-proBNP during 8-10 weeks of sacubitril/valsartan were associated with worse outcomes (P=0.003 and P=0.005, respectively).


Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. As NT-proBNP is less directly influenced by neprilysin inhibition, it may lead to less clinical confusion when measured within 8-10 weeks of starting therapy. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors [3].

  1. Vaduganathan M, et al. B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial. Abstract 915-08. ACC 2019, 16-18 March, New Orleans, USA.
  2. Mcmurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  3. Mcmurray JJ, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062-73.

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