Neprilysin inhibitors (ARNi) effectively reduce death and hospitalization in moderate heart failure patients but fail to show benefits in advanced heart failure or post-heart attack patients without heart failure.
Effective in class II-III, not advanced HFARNi therapy's benefits are population-dependent — possibly because advanced HF patients have blunted responses to the natriuretic peptides that neprilysin inhibition preserves
What the researchers found
ARNi (angiotensin receptor-neprilysin inhibitor) therapy effectively reduces death and hospitalization in heart failure patients with NYHA functional class II-III symptoms. However, clinical trials failed to show benefits when compared to ACE inhibitors or ARBs in two populations: patients with advanced HF with reduced ejection fraction, and post-MI patients with left ventricular dysfunction but without HF. The review proposes that in advanced HF, downstream blunting of natriuretic peptide response limits efficacy, while post-MI patients without HF may not need increased natriuretic peptide availability.
Why it matters
Neprilysin inhibitors represented a major advance in heart failure treatment, but understanding their limitations is equally important. By clarifying which patients benefit (moderate HF) and which don't (advanced HF, post-MI without HF), this review helps clinicians make better prescribing decisions and highlights the importance of peptide biology in cardiovascular disease.
How the study worked
Contemporary review article analyzing recent clinical trial data on neprilysin inhibition in heart failure, examining mechanisms of action, and discussing unanswered questions about specific patient populations where the therapy may or may not be effective.
What this study cannot tell us
This is a narrative review, not a systematic review or meta-analysis. The interpretations of why ARNi fails in certain populations are hypothetical and require further confirmation. Long-term effects of ARNi on albuminuria, obesity, glycemic control, lipid profile, blood pressure, and cognitive function remain understudied.
How to read the evidence
This is a review synthesizing data from multiple large clinical trials (including PARADIGM-HF, PIONEER-HF, PARADISE-MI). The underlying evidence base is strong (randomized controlled trials), though the mechanistic explanations are interpretive.
When this study was published
Published in 2023, this review incorporates data from the most recent major ARNi clinical trials, making it a current and comprehensive assessment of where neprilysin inhibition stands in heart failure treatment.
The bigger picture
This review illustrates how peptide biology directly translates to clinical medicine. Neprilysin's role in breaking down multiple vasoactive peptides makes it a powerful therapeutic target, but the mixed clinical results reveal that simply increasing peptide levels isn't always the answer. Understanding when and why peptide modulation works is key to developing more targeted cardiovascular therapies.
Questions still open
- Could combining neprilysin inhibition with strategies to restore natriuretic peptide responsiveness improve outcomes in advanced heart failure?
- What are the long-term effects of chronically elevated natriuretic peptide levels on kidney function, metabolism, and cognition?
- Are there biomarkers that can predict which heart failure patients will respond to ARNi therapy?
Common questions
What is neprilysin and why does inhibiting it help heart failure?
Why doesn't neprilysin inhibition work for all heart failure patients?
Read the original research
Neprilysin Inhibitors in Heart Failure: The Science, Mechanism of Action, Clinical Studies, and Unanswered Questions.
JACC. Basic to translational science, 8(1), 88-105
Citation
Bozkurt, Biykem; Nair, Ajith P; Misra, Arunima; Scott, Claire Z; Mahar, Jamal H; Fedson, Savitri. (2023). Neprilysin Inhibitors in Heart Failure: The Science, Mechanism of Action, Clinical Studies, and Unanswered Questions.. JACC. Basic to translational science, 8(1), 88-105. https://doi.org/10.1016/j.jacbts.2022.05.010