PROVE HF: Impact of Sacubitril/valsartan on Atrial Natriuretic Peptide in Patients with HFrEF

4 Mar, 21

Introduction

Neprilysin inhibition is associated with increased levels of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan. Atrial natriuretic peptide (ANP), like B-type natriuretic peptide (BNP) affects many physiological processes that may impact the treatment of heart failure (HF). Neprilysin inhibition with sacubitril/valsartan is associated with changes in N-terminal pro-B type natriuretic peptide (NT-proBNP) and improved cardiac remodelling, but it is not known whether change in ANP levels (due to sacubitril/valsartan treatment) would also improve cardiac remodelling.

Aim

To determine associations between longitudinal change in ANP and reverse cardiac remodelling after initiating sacubitril/valsartan in patients with HF with reduced ejection fraction (HFrEF).

Patient Profile

Patients with HFrEF with left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class II to IV within past 6 months (age ≤18 years)

Methods

Study Design

Pre-specified exploratory analysis of PROVE-HF trial
PROVE-HF was a phase 4, open-label, single-group, 52-week study conducted across 78 sites in the United States

Treatment Strategy

Along with the standard treatment patients received sacubitril/valsartan twice daily (dose was increased every 2 to 4 weeks to achieve the target dose of 97/103 mg)

Assessments

Echocardiographic (ECG) assessment conducted at 6 and 12 months included:
- LVEF
- Left atrial volume index (LAVI)
Biomarker assessment included:
- ANP
- NT-proBNP
- Urinary cyclic guanosine monophosphate (cGMP)

Results

Of the 794 patients of the PROVE -HF study, blood samples were available for 144 patients, who were included in this analysis (mean age: 64.5 years; LVEF: 30.8%).
Following the initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with a high rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001), the trend continued further from day 30 to 45. There was a further trend toward a second increase from day 30 to day 45. The maximal increase was seen at 3 months (203 pg/ml) (p = 0.07). The ANP levels had doubled at maximal rise.
As per longitudinal analyses, early rise in ANP correlated with a subsequent increase in urinary cGMP, particularly between baseline and month 2. The steepest rise in ANP (that occurred between baseline and day 14) was mirrored by a decrease in NT-proBNP, though the trajectory of both biomarkers differed thereafter. Thus, rise in ANP continued through month 3 while NT-proBNP concentrations remained relatively stable.
Treatment with sacubitril/valsartan was associated with a significant improvement in LVEF every 14 days, by 12 months; LVEF had risen to 41.6%. On the contrary, LAVI had reduced to 27.2 ml/m² by 12 months.,
After initiating treatment with sacubitril/valsartan, rise in ANP was positively associated with improvement in LVEF and LAVI. Larger early increase in ANP was associated with larger later improvements in LVEF and LAVI (p < 0.001 for both). In fact, early increase in ANP was associated with more robustly with reductions in LAVI rather than with increase in LVEF.

Conclusions

Amongst patients with HFrEF, the concentrations of ANP doubled after initiating sacubitril/valsartan treatment.
Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodelling in terms of gain in LVEF and particular reduction in LAVI.
ANP represents an important target for neprilysin. The association of neprilysin inhibition (in the form of sacubitril/valsartan treatment) and rise in ANP should be explored further.

J Am Coll Cardiol HF. 2021;9:127–36.