# Cardiac biomarkers response under angiotensin receptor–neprilysin inhibitor: a sub-analysis of the NATRIUM-HF study

## TL;DR

This study shows that BNP and NT-proBNP levels rise during acute fluid overload and diuretic treatment, even as patients improve clinically, suggesting limited value in frequent short-term measurements.

## Contribution

The study reveals that natriuretic peptides lag behind clinical decongestion in acute heart failure, challenging their use for very early serial monitoring.

## Key findings

- S/V therapy reduced baseline BNP and NT-proBNP levels significantly.
- BNP and NT-proBNP levels continued to rise during diuretic treatment despite clinical improvement.
- Short-term serial NP measurements provide limited clinical value in acute HF.

## Abstract

Natriuretic peptides (NPs) are central to the diagnostic and therapeutic management of heart failure (HF), yet their short-term dynamics under sacubitril/valsartan (S/V) therapy and during acute volume changes remain incompletely characterized. We aimed to assess changes in circulating biomarkers and response to standardized acute intravascular volume expansion and diuretic treatment before and after S/V initiation.

We studied 229 ambulatory patients with HF with reduced ejection fraction receiving guideline-directed medical therapy who initiated S/V. Patients were evaluated at three outpatient visits: before S/V initiation and after 2 and 3 months of treatment. At each visit, participants underwent a standardized 9-hour protocol including volume infusion followed by diuretic administration. BNP, NT-proBNP, MR-proANP, and neprilysin activity were measured serially alongside clinical assessment and natriuresis.

Across visits, initiation of S/V was associated with lower concentrations of BNP (−8%, P = .009) and NT-proBNP (−35%, P < .001). During the acute protocol, both BNP and NT-proBNP increased significantly over time (timepoint effect P < .001), with parallel trajectories before and after S/V initiation and no visit-by-time interaction (P = .17 for BNP; P = .95 for NT-proBNP). Despite marked natriuresis and improvement in clinical signs following diuretic administration, BNP and NT-proBNP continued to rise during the 9-hour observation period.

In a controlled acute volume overload setting, BNP and NT-proBNP provide comparable information, but their short-term dynamics lag behind clinical decongestion. Routine serial NP measurements at very short time intervals are unlikely to add incremental clinical value in the early phase of acute HF.

Graphical AbstractIn a controlled model of acute fluid overload, both BNP and NT-proBNP increased significantly over 9 hours following a 3-hour volume infusion (H3–H6) and subsequent diuretic administration (H6–H9), both before and after ARNI therapy. Natriuresis increased rapidly after diuretic treatment, whereas circulating natriuretic peptides continued to rise. This temporal dissociation limits the clinical value of very early serial natriuretic peptide measurements.For image description, please refer to the figure legend and surrounding text.

In a controlled model of acute fluid overload, both BNP and NT-proBNP increased significantly over 9 hours following a 3-hour volume infusion (H3–H6) and subsequent diuretic administration (H6–H9), both before and after ARNI therapy. Natriuresis increased rapidly after diuretic treatment, whereas circulating natriuretic peptides continued to rise. This temporal dissociation limits the clinical value of very early serial natriuretic peptide measurements.