JAMA SEPTEMBER 17, 2019

Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction

James L. Januzzi Jr., Margaret F. Prescott, Javed Butler, et al.

Bottom Line

The PROVE-HF trial demonstrated that initiation of sacubitril/valsartan in patients with HFrEF leads to significant reductions in NT-proBNP that are significantly associated with positive reverse cardiac remodeling at 12 months.

Key Findings

1. Sacubitril/valsartan therapy was associated with a significant decrease in median NT-proBNP levels, which typically occurred within the first 2 weeks of treatment.

2. Reductions in NT-proBNP at 12 months were significantly correlated with improvements in multiple echocardiographic parameters of reverse cardiac remodeling, including an increase in left ventricular ejection fraction (LVEF; Pearson r = -0.381, P < .001) and decreases in left ventricular end-systolic volume index (LVESVI; Pearson r = 0.405, P < .001) and left ventricular end-diastolic volume index (LVEDVI; Pearson r = 0.320, P < .001).

3. Mean LVEF increased from 28.3% at baseline to 37.8% at 12 months, reflecting a clinically meaningful degree of reverse remodeling.

4. Improvement in markers of cardiac structure and function were observed as early as 6 months and were maintained or progressed through 12 months.

5. The clinical profile of responders (those with greater NT-proBNP reductions) showed better structural improvement, although the associations between biomarker changes and remodeling were generally described as weak to moderate in magnitude.

Study Design

Design

Prospective, single-arm, open-label, phase 4 study

Open-Label

Sample

794

Patients

Duration

12 mo

Median

Setting

Multicenter, US

Population Patients with chronic heart failure with reduced ejection fraction (LVEF ≤40%) and elevated NT-proBNP levels.

Intervention Initiation and titration of sacubitril/valsartan therapy according to US prescribing information.

Comparator None (single-arm study)

Outcome Correlation between the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and the change in echocardiographic measures of cardiac structure and function from baseline to 12 months.

Study Limitations

• The trial utilized a single-arm, open-label, observational design, which precludes definitively attributing all observed cardiac remodeling to sacubitril/valsartan alone, as other guideline-directed medical therapies or natural history may have contributed.

• The lack of a control group prevents direct comparison with other therapeutic regimens.

• Multiple comparisons across various biomarkers and echocardiographic parameters may have increased the risk of Type I error.

• The study was not powered or designed to demonstrate clinical outcome differences (e.g., mortality or hospitalization), limiting the ability to establish a direct causal link between the observed structural remodeling and patient prognosis.

Clinical Significance

The study provides a mechanistic understanding of the clinical benefits seen with sacubitril/valsartan, suggesting that its therapeutic efficacy in HFrEF is mediated, in part, by reverse cardiac remodeling. It validates the use of NT-proBNP as a surrogate biomarker for assessing the physiological response to therapy in clinical practice.

Historical Context

Following the landmark PARADIGM-HF trial, which established the superiority of sacubitril/valsartan over enalapril for reducing cardiovascular death and heart failure hospitalization, the precise mechanism of this benefit remained unclear. PROVE-HF was designed to bridge this knowledge gap by prospectively examining the relationship between biomarker changes and structural cardiac recovery.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action for sacubitril/valsartan and why does NT-proBNP decrease even though the drug contains a neprilysin inhibitor?

Key Response

Sacubitril is a prodrug that inhibits neprilysin, the enzyme responsible for degrading natriuretic peptides (ANP, BNP). While BNP levels may actually rise because degradation is blocked, NT-proBNP is not a substrate for neprilysin. Therefore, a decrease in NT-proBNP directly reflects reduced myocardial wall stress and improved cardiac function, making it a reliable marker of the drug's therapeutic effect on the heart.

Resident

Based on the PROVE-HF findings, how should the early reduction of NT-proBNP influence your clinical timeline for reassessing a patient's Left Ventricular Ejection Fraction (LVEF) for ICD eligibility?

Key Response

PROVE-HF demonstrated that significant reverse remodeling (improvement in LVEF and decrease in volumes) is strongly correlated with early NT-proBNP reduction but continues to progress throughout a 12-month period. This suggests that clinicians might consider delaying ICD implantation beyond the standard 90-day waiting period in patients showing robust biomarker response, as their LVEF may continue to improve above the 35% threshold over the first year.

Fellow

The PROVE-HF trial observed improvements in Left Atrial Volume Index (LAVI) and E/e' ratios alongside ventricular changes. How does this integrate with our understanding of sacubitril/valsartan's effect on diastolic function compared to ACE inhibitors?

Key Response

The reduction in LAVI and E/e' signifies improved left ventricular filling pressures and diastolic relaxation. While PARADIGM-HF proved mortality benefit, PROVE-HF provides the mechanistic evidence that neprilysin inhibition provides superior reduction in atrial stretch and diastolic load compared to standard RAS blockade alone, likely due to the synergistic effects of increased cyclic GMP from preserved natriuretic peptides.

Attending

How does the 'remodeling-biomarker' correlation in PROVE-HF challenge the current standard of care regarding 'stable' HFrEF patients who are currently well-managed on ACE inhibitors or ARBs?

Key Response

PROVE-HF demonstrates that switching to sacubitril/valsartan induces active reverse remodeling even in patients who were previously considered stable. This suggests that the goal of therapy should not just be 'stability' but 'structural recovery,' providing a strong argument for transitioning all eligible HFrEF patients to ARNI therapy regardless of their perceived clinical stability on older agents.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

What are the limitations of using Spearman rank correlation coefficients to describe the relationship between NT-proBNP and cardiac volumes in an open-label study design, and how could a longitudinal mixed-effects model enhance these findings?

Key Response

Spearman correlations provide a snapshot of association but do not account for the within-patient trajectory of change over time or the non-linear nature of remodeling. A longitudinal mixed-effects model would better handle the repeated measures at 6 and 12 months, allowing researchers to quantify the 'rate' of remodeling and determine if the biomarker reduction is a leading or lagging indicator of structural change.

Journal Editor

Given the lack of a control group in this prospective observational study, how do we distinguish the reverse remodeling effects of sacubitril/valsartan from the natural history of recovery or the optimization of background beta-blocker therapy?

Key Response

This is a critical threat to internal validity. Without a comparator arm (e.g., enalapril), it is difficult to isolate the 'ARNI effect.' However, the strength and consistency of the correlation between NT-proBNP (a specific target of the drug's pathway) and the magnitude of structural change across all subgroups provide a compelling, albeit not definitive, mechanistic link that supports the trial's conclusions.

Guideline Committee

Should the PROVE-HF data lead to a formal recommendation in the AHA/ACC/HFSA guidelines regarding the use of serial NT-proBNP monitoring to guide the titration of GDMT?

Key Response

While the 2022 AHA/ACC/HFSA guidelines give a Class 2a recommendation for using NT-proBNP to achieve 'optimal' GDMT, PROVE-HF provides the structural evidence linking these targets to reverse remodeling. However, the committee must weigh whether this justifies the cost of serial testing, as the trial was not designed as a 'management' study (like BIOSTAT-CHF) but rather a mechanistic one, leaving the question of 'NP-guided therapy' vs 'dose-guided therapy' partially unanswered.

Clinical Landscape

Noteworthy Related Trials

2001

VAL-HEFT

n = 5,010 · NEJM

Tested

Valsartan

Population

Patients with heart failure

Comparator

Placebo

Endpoint

All-cause mortality and morbidity

Key result: Valsartan reduced the combined endpoint of mortality and morbidity, particularly when added to standard therapy.

2014

PARADIGM-HF

n = 8,442 · NEJM

Tested

Sacubitril-valsartan

Population

Patients with heart failure with reduced ejection fraction

Comparator

Enalapril

Endpoint

Composite of CV death or hospitalization for heart failure

Key result: Sacubitril-valsartan was superior to enalapril in reducing the risk of death and hospitalization for heart failure.

2019

PIONEER-HF

n = 881 · NEJM

Tested

Sacubitril-valsartan

Population

Patients hospitalized with acute decompensated heart failure

Comparator

Enalapril

Endpoint

Time-averaged proportional change in NT-proBNP concentration

Key result: Initiation of sacubitril-valsartan in stabilized acute heart failure patients resulted in a greater reduction in NT-proBNP levels compared to enalapril.

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