- Sacubitril/valsartan is now a mainstay therapy for heart failure with reduced ejection failure, but questions remain about whether an increase in B-type natriuretic peptide (BNP) is clinically meaningful
- This study used multiple assays to examine the effect of sacubitril/valsartan titration on a broad range of natriuretic peptides in 23 stable ambulatory patients
- Neprilysin inhibition tended to increase BNP concentrations, but increases were more likely in patients with higher baseline values, and each individual BNP assay behaved somewhat differently
- N-terminal-proBNP concentrations decreased relatively consistently across visits, although there was variability between assays and in magnitude of decline
- Clinicians cannot assume concentrations of BNP or other natriuretic peptides will rise after treatment with sacubitril/valsartan, and they should keep in mind that changes in one assay may not be superimposable with another
Sacubitril/valsartan, an angiotensin receptor blocker and neprilysin inhibitor, is now a mainstay of treatment for heart failure with reduced ejection fraction (HFrEF). Neprilysin is an endopeptidase responsible for the breakdown of numerous vasoactive peptides, including B-type natriuretic peptide (BNP).
In the pivotal PARADIGM-HF trial of sacubitril/valsartan, initiation of the drug led to increased concentrations of BNP. The elevations were relatively modest and showed a slight subsequent downward trend. However, questions remain about the effects of neprilysin inhibition on BNP—especially because only one BNP assay was used in PARADIGM-HF—and whether changes in BNP actually predict major adverse outcomes.
Nasrien E. Ibrahim, MD, associate director of the Resynchronization & Advanced Cardiac Therapeutics Program, and James L. Januzzi Jr., MD, director of the Dennis and Marilyn Barry Fellowship in Cardiology Research, both in the Massachusetts General Hospital Corrigan Minehan Heart Center, and colleagues have used several different assays to measure concentrations of multiple natriuretic peptides in patients taking sacubitril/valsartan. In the Journal of the American College of Cardiology, they say that across all assays, effects of the drug on BNP and N-terminal pro-BNP (NT-proBNP) were variable and unpredictable.
The researchers studied 23 consecutive stable patients with HFrEF who started sacubitril/valsartan per the U.S. package insert. Patients returned for dose titration every two to three weeks until the maximum tolerated or target dose was achieved, followed by a final visit four weeks later.
Blood samples collected at baseline and each follow-up visit were used to measure BNP (five assays) and NT-proBNP (three assays), as well as five other natriuretic peptides. The article names the assays used and reports how results varied among them.
Neprilysin inhibition generally led to a modest increase in BNP concentrations, but some assays registered no increase and others demonstrated a decrease. The largest magnitude of BNP increase appeared by the second follow-up visit and occurred in patients with higher baseline BNP concentrations.
NT-proBNP is not subject to degradation by neprilysin. Its concentrations decreased relatively consistently across visits, although there was variability between assays and in the magnitude of decline. The largest reductions occurred in patients with higher baseline concentrations.
Applying the Results to the Clinic
Clinicians cannot assume that concentrations of BNP or other natriuretic peptides will rise after treatment with sacubitril/valsartan. Furthermore, changes in one assay may not be superimposable with another.
An open-label study at Mass General is underway to understand the mechanism of sacubitril/valsartan and changes in biomarkers during treatment. Until the results are available, caution is needed when interpreting BNP concentrations during sacubitril/valsartan treatment.
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