Sacubitril/Valsartan vs Standard Heart Drugs: Who Benefits Most from the Natriuretic Peptide Approach | Research

The takeaway

Sacubitril/valsartan reduces heart failure hospitalizations across all patients but only lowers mortality in those with ejection fraction below 40%, according to a meta-analysis of 25,167 patients.

15% fewer hospitalizations, 12% lower mortality (EF≤40%)
Sacubitril/valsartan reduced heart failure rehospitalization by 15% across all patients and cut all-cause mortality by 12% in those with reduced ejection fraction

What the researchers found

In a meta-analysis of 14 randomized trials (25,167 patients), sacubitril/valsartan reduced heart failure rehospitalization by 15% compared to ACE inhibitors or ARBs regardless of ejection fraction (RR: 0.85; P=0.00001). All-cause mortality was reduced by 12% but only in patients with ejection fraction ≤40% (RR: 0.88; P=0.0006) — no mortality benefit was seen in patients with higher ejection fractions. Notably, cardiovascular mortality was not significantly reduced in any ejection fraction group.

Why it matters

Sacubitril/valsartan works by blocking neprilysin — the enzyme that breaks down natriuretic peptides — allowing these protective peptides to remain active longer. This meta-analysis clarifies which heart failure patients benefit most: those with reduced ejection fraction get both fewer hospitalizations and lower mortality, while those with preserved ejection fraction only get fewer hospitalizations. This distinction helps clinicians target the drug to the right patients.

The numbers in context

14 trials · n=25,167 · HF rehospitalization: RR 0.85, P=0.00001 · All-cause mortality (EF≤40%): RR 0.88, P=0.0006 · All-cause mortality (EF>40%): RR 0.97, P=0.67 · CV mortality: RR 0.90, P=0.13 (NS)

How the study worked

Systematic review and meta-analysis of randomized clinical trials comparing sacubitril/valsartan to ACE inhibitors or ARBs. Databases searched: PubMed, EMBASE, Scopus, Cochrane Central Register (inception to November 2023). Random effects model used. Risk ratios with 95% CI reported. Heterogeneity assessed with I² test. Publication bias assessed via funnel plots and Egger test. Registered in PROSPERO (CRD42024497661).

Who was studied

25,167 patients with heart failure across the ejection fraction spectrum, from 14 randomized clinical trials

What this study cannot tell us

Results for cardiovascular mortality did not reach statistical significance, which may reflect insufficient power for this specific endpoint. The EF>40% subgroup showed no mortality benefit, but fewer trials may have been available in this population. Individual trial designs and populations varied across the 14 included studies.

How to read the evidence

This is a systematic review and meta-analysis of 14 randomized clinical trials totaling over 25,000 patients — the highest level of clinical evidence. It was pre-registered in PROSPERO, used rigorous methodology, and was published in a JACC journal.

When this study was published

Published in 2025 with data through November 2023, this is a current and comprehensive meta-analysis. It represents the most up-to-date pooled evidence for sacubitril/valsartan across the ejection fraction spectrum.

The bigger picture

Sacubitril/valsartan is the most prominent drug that works by enhancing natriuretic peptide signaling — it blocks the enzyme (neprilysin) that degrades BNP and ANP, letting these protective peptides work longer. This meta-analysis refines our understanding of where this peptide-boosting strategy works best: the clearest benefits are in reduced-ejection-fraction heart failure, where natriuretic peptide enhancement translates to both fewer hospitalizations and longer survival.

Questions still open

Why does sacubitril/valsartan reduce hospitalizations but not mortality in heart failure with preserved ejection fraction — is the pathophysiology fundamentally different?
Could higher doses or longer treatment duration reveal a mortality benefit in the EF>40% population?
Are there biomarkers (like baseline NT-proBNP levels) that better predict which individual patients will benefit most?

Common questions

How does sacubitril/valsartan relate to peptides?

Sacubitril blocks neprilysin, the enzyme that breaks down natriuretic peptides (BNP and ANP) — natural hormones that protect your heart by lowering blood pressure, reducing fluid overload, and decreasing heart strain. By preventing their breakdown, the drug lets these beneficial peptides work longer and harder.

Does sacubitril/valsartan work for all types of heart failure?

This meta-analysis shows it reduces hospitalizations for all heart failure patients, but it only reduces death risk in those whose heart pumps poorly (ejection fraction ≤40%). For patients with preserved pumping function, the drug helps keep them out of the hospital but hasn't been proven to extend life.

Read the original research

Sacubitril/Valsartan vs ACE Inhibitors or ARBs: A Systematic Review and Meta-Analysis of Randomized Trials.

JACC. Advances, 4(3), 101598

View on PubMed ↗Publisher’s paper ↗

Citation

Evbayekha, Endurance; Idowu, Abiodun Benjamin; LaRue, Shane. (2025). Sacubitril/Valsartan vs ACE Inhibitors or ARBs: A Systematic Review and Meta-Analysis of Randomized Trials.. JACC. Advances, 4(3), 101598. https://doi.org/10.1016/j.jacadv.2025.101598