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

onlinejacc.org
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

  • Median BNP level increased from 202 ng/L (Q1-Q3: 126-335 ng/L) at baseline to 235 ng/L (Q1-Q3: 128-422 ng/L) after 8 to 10 weeks of treatment with sacubitril/valsartan and decreased to a median of 181 ng/L (Q1-Q3: 109-310 ng/L) after 8 to 10 weeks of treatment with enalapril.
  • After 8-10 weeks of treatment with sacubitril/valsartan, a rightward shift in the distribution of BNP was seen (increased by a median of 19%, Q1: -22%, Q3: +75%), compared with NT-proBNP (reduced by a median of 28%, Q1: -52%, Q3: -1%).
  • Patients with increasing BNP levels (> +10%) during 8-10 weeks of treatment with sacubitril/valsartan were older, more likely to be male, had higher prevalence of previous MI and ischemic cardiomyopathy, and had lower eGFR and BNP levels before therapy, compared to patients with decreasing BNP levels (> -10%).

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

  • BNP and NT-proBNP had similar prognostic value in the total cohort at screening (C-statistics 64.0% and 63.6%, respectively) (P=0.37).
  • BNP levels were correlated with NT-proBNP levels after 4-6 weeks of run-in with enalapril before treatment with sacubitril/valsartan (Spearman’s rank correlation coefficient [rs]=0.77), and at each of the timepoints after ARNI treatment initiation (rs= 0.80 at 4-6 weeks, rs=0.75 at 8-10 weeks of treatment, and rs=0.78 at 9 months of treatment).
  • C-statistics for the primary endpoint ranged from 63% to 67% for BNP and from 64% to 70% for NT-proBNP before and during treatment with sacubitril/valsartan, and there were no significant differences between the 2 biomarkers (P>0.05 for all timepoints).
  • BNP and NT-proBNP levels were associated with the primary outcome both before and during treatment with sacubitril/valsartan (rs= 0.77 and rs= 0.75, respectively). Patients in the highest quartiles of BNP and NT-proBNP, had the highest risk of the primary outcome (HR >4 vs. Q1).
  • Poisson regression suggested that, after multivariable adjustment, there were significant associations between relative changes in both BNP and NT-proBNP and the primary outcome from baseline to 8 to 10 weeks of sacubitril/valsartan.

Ratio between NT-proBNP and BNP

  • The median ratio between NT-proBNP and BNP was 6.3 (Q1-Q3: 4.5 to 8.8) before treatment and reduced to about 3.8 at 4-6 weeks, and remained stable at 8-10 weeks and until after 9 months of therapy with sacubitril/valsartan, while in enalapril-treated patients, the ratio was stable after 8-10 weeks and 9 months of treatment.

Conclusion

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.

References

1. Pankow K, Schwiebs A, Becker M, Siems WE, Krause G, Walther T. Structural substrate conditions required for neutral endopeptidase mediated natriuretic peptide degradation. J Mol Biol 2009;393:496–503.

2. Walther T, Stepan H, Pankow K, Becker M, Schultheiss HP, Siems WE. Biochemical analysis of neutral endopeptidase activity reveals independent catabolism of atrial and brain natriuretic peptide. Biol Chem 2004;385:179–84.

3. Nougué H, Pezel T, Picard F, et al. Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. Eur J Heart Fail 2018 Dec 6 [E-pub ahead of print].

4. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/ AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70:776–803.

5. Yancy CW, Januzzi JL Jr., Allen LA, et al. 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2018;71: 201–30.

6. Lippi G, Sanchis-Gomar F. Monitoring B-type natriuretic peptide in patients undergoing therapy with neprilysin inhibitors. An emerging challenge? Int J Cardiol 2016;219:111–4.

7. Ibrahim NE, Januzzi J. Monitoring biomarkers inpatients receiving neprilysin inhibitors. Curr Emerg Hosp Med Rep 2018;6:8–16.

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