In a patient receiving Entresto (sacubitril/valsartan), is B-type natriuretic peptide (BNP) an unreliable marker for assessing heart‑failure severity?

BNP is NOT meaningless in patients on Entresto, but NT-proBNP is the preferred biomarker for monitoring heart failure severity

When monitoring patients on Entresto (sacubitril/valsartan), measure NT-proBNP rather than BNP to avoid clinical confusion, especially within the first 8-10 weeks of therapy. However, both biomarkers retain their prognostic value during chronic treatment.

Why BNP Becomes Problematic on Entresto

Entresto inhibits neprilysin, the enzyme that normally degrades BNP. This mechanism causes:

• BNP levels to increase or remain paradoxically stable despite clinical improvement 1
• In the PARADIGM-HF trial, Entresto increased plasma BNP while simultaneously decreasing NT-proBNP 1
• 18% of patients experience a doubling of BNP and 6% see a tripling within 8-10 weeks of starting Entresto 2

This creates a clinical dilemma: rising BNP might reflect neprilysin inhibition (good) rather than worsening heart failure (bad).

NT-proBNP: The Superior Choice

NT-proBNP is not a substrate for neprilysin, making it immune to the confounding effects of Entresto 3:

• NT-proBNP consistently decreases with Entresto therapy (17-32% reduction in clinical trials) 1
• The 2021 ACC Expert Consensus explicitly states: "NT-proBNP measurement may be preferable in this setting" 3
• Avoids the "rightward shift" in biomarker distribution seen with BNP 2

Both Biomarkers Retain Prognostic Value

Critical nuance: Despite the confounding effects on absolute values, both BNP and NT-proBNP predict outcomes during chronic Entresto therapy 3, 2:

• C-statistics for BNP: 63-67%
• C-statistics for NT-proBNP: 64-70%
• Rising levels of either biomarker during treatment predict worse outcomes (p=0.003 for BNP, p=0.005 for NT-proBNP) 2

Practical Clinical Algorithm

First 8-10 weeks of Entresto:

• Use NT-proBNP exclusively to avoid misinterpreting BNP increases as clinical deterioration 3
• If BNP rises during this period, do not automatically assume worsening heart failure

After 8-10 weeks (chronic therapy):

• Either biomarker is acceptable for monitoring 3, 2
• Focus on trends rather than absolute values
• Rising trends of either biomarker warrant clinical reassessment

During acute decompensation:

• Both BNP and NT-proBNP rise markedly and return to baseline in parallel after treatment 4
• Either can be used to diagnose acute decompensated heart failure, even in patients on chronic Entresto

Common Pitfalls to Avoid

1. Don't panic over isolated BNP increases in the first 2-3 months of Entresto—this may reflect therapeutic neprilysin inhibition, not treatment failure
2. Don't use BNP to guide dose titration early in therapy; clinical assessment and NT-proBNP are more reliable
3. Don't assume BNP is "useless"—it retains prognostic value for predicting cardiovascular death and HF hospitalization during chronic treatment 3, 2

The Bottom Line

BNP is not meaningless on Entresto, but it requires careful interpretation. Switch to NT-proBNP for cleaner, more interpretable monitoring, especially during drug initiation. Both biomarkers work for long-term prognostication once patients are stable on therapy.