Comparing High- Versus Low-Dose Entresto in Heart Failure Patients: A 2025 Meta-Analysis

TL;DR

A 2025 meta-analysis found that high-dose Entresto reduces NT-proBNP levels more than low-dose, but does not significantly improve heart ejection fraction in heart failure patients.

Contribution

This study is the first meta-analysis comparing high- versus low-dose Entresto in heart failure patients, revealing dose-dependent effects on NT-proBNP levels.

Findings

High-dose Entresto significantly reduces NT-proBNP levels compared to low-dose.

No significant difference in left ventricular ejection fraction (LVEF) improvement between high- and low-dose groups.

High-dose Entresto shows potential for greater cardiac stress reduction despite no LVEF benefit.

Abstract

Entresto (sacubitril/valsartan) is widely used for the treatment of heart failure with
reduced ejection fraction (HFrEF) due to its ability to enhance natriuretic peptide
activity and inhibit the renin-angiotensin-aldosterone system (RAAS). However, its effects
on various cardiovascular outcomes require further evaluation. Therefore, a meta-analysis
of existing clinical studies was conducted to compare the effectiveness of high-dose vs.
low-dose Entresto in treating chronic heart failure. A systematic search was performed
using three databases: PubMed, ClinicalTrials, and Cochrane. The meta-analysis included
nine randomized controlled trials comprising 4,011 patients with HFrEF. The inclusion
criteria were: studies that evaluated patients (>18 years of age) with heart failure
(these doses were generally divided into high (97/103 mg) and low (24/26 mg), with four
studies using different dosing ranges relative to these categories); studies with relevant
primary outcome; and studies written in English.

The primary outcomes include: heart failure hospitalization, all-cause mortality, left
ventricular ejection fraction (LVEF), N-terminal prohormone of brain natriuretic peptide
(NT-proBNP) levels, New York Heart Association (NYHA) functional class, and systolic blood
pressure over a minimum follow-up period of three months.

We excluded studies with no quantitative outcome data, follow-up period (of at least
three months), and dose-group comparisons. Additionally, studies were excluded if they
were: case reports; meta-analyses; systematic reviews; conference abstracts; non-human
studies or publications in any other language than English.

The risk of bias (RoB) was assessed using the Robvis tool and classified into low,
moderate, serious, and critical risk of bias categories. The results of this assessment
were illustrated via a traffic light plot.

A random effects statistical model was used in this study. Heterogeneity for LVEF was
found to be substantial (I2 of 93.1%). Subgroup analysis found the source of
this to be the dosing groups used in these studies, by excluding studies with less than or
equal to 200 mg as their high-dose group. Heterogeneity for NT-proBNP was also substantial
(I2 of 98%). Subgroup analysis could not localize a source of this
heterogeneity, particularly when applied to dosing groups (high-dose groups with less than
or equal to 200 mg of sacubitril/ valsartan).

The analysis revealed there was no statistically significant difference between LVEF
improvement between low- and high-dose groups (1.95 (95% confidence interval (CI): -1.32
to 5.22); p=0.242). A meta-analysis of these studies showed a statistically significant
reduction in NT-proBNP with Entresto. The pooled effect size was -667.24 (95% CI: -1312.69
to -21.8; p=0.04), indicating a significant decline in NT-proBNP levels in patients
receiving a higher dose of Entresto. These findings suggest that while higher doses of
Entresto do not significantly improve LVEF compared to lower doses, they are associated
with a greater reduction in NT-proBNP levels, indicating improved cardiac stress and
function. This supports the potential dose-dependent benefits of Entresto in managing
heart failure with reduced ejection fraction. Further large-scale studies are warranted to
explore the long-term impact of high-dose Entresto on clinical outcomes to optimize dosing
strategies for HFrEF patients.

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