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Two biomarkers yield comparable CV risk prediction before, during sacubitril/valsartan treatment
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NEW ORLEANS — B-type natriuretic peptide and N-terminal proBNP were equally effective at predicting risk for major adverse CV events in patients with HF with reduced ejection fraction taking sacubitril/valsartan, according to data presented at the American College of Cardiology Scientific Session.
However, in some patients, circulating BNP spikes soon after initiation of sacubitril/valsartan (Entresto, Novartis), so that phenomenon must be considered if using BNP to predict risk, the researchers said. An additional finding from the study was that a large spike in either biomarker was associated with worse clinical outcomes.
“Interestingly, based on the mechanism of action of sacubitril/valsartan, the metabolism of BNP — one of the most commonly measured biomarkers in heart failure — is affected,” Scott D. Solomon, MD, Edward D. Frohlich Distinguished Chair and professor of medicine at Harvard Medical School and senior physician at Brigham and Women’s Hospital, told Cardiology Today. “Expert panels have recommended against the measurement of BNP among patients receiving sacubitril/valsartan. Unfortunately, BNP is the only available natriuretic peptide assay at many hospitals worldwide. As the clinical uptake of sacubitril/valsartan increases in clinical practice, we undertook this study to clarify whether BNP can continue to be reliably used in patients receiving this therapy. We leveraged data from the large PARADIGM-HF trial, which supported the initial approval of sacubitril/valsartan, to interrogate this clinically relevant question.”
Muthiah Vaduganathan, MD, MPH, fellow in cardiovascular medicine at Brigham and Women’s Hospital, and Peder Langeland Myhre, MD, PhD, postdoctoral researcher at Brigham and Women’s Hospital and Akershus University Hospital and University of Oslo, Norway, and colleagues analyzed 2,001 patients assigned sacubitril/valsartan in PARADIGM-HF for whom BNP measurements were available at 8 to 10 weeks. The results were simultaneously published in the Journal of the American College of Cardiology.
Median BNP was 202 ng/L (interquartile range [IQR], 126-335) at baseline, but rose to 235 ng/L (IQR, 128-433) at 8 to 10 weeks, according to the researchers.
At 8 to 10 weeks, 18% of patients had a doubling of BNP and 6% had a tripling of BNP, the researchers found.
“The increase in BNP during treatment with sacubitril/valsartan is modest — approximately 20% increase — in most, but more substantial in some — 18% with doubling,” Solomon said in an interview. “The rise in BNP occurs early after treatment initiation — peak effect in 8 to 10 weeks. Importantly, early increases in BNP were associated with increased risk of subsequent clinical events.”
There were few cases of a spike in NT-proBNP at 8 to 10 weeks, according to the researchers, who found that prognostic accuracy of both biomarkers was not affected by sacubitril/valsartan (C statistic for BNP, 63% to 67%; C statistic for NT-proBNP, 64% to 70%). There was no difference in the accuracy between the biomarkers.
Elevation of either biomarker at 8 to 10 weeks was associated with worse outcomes (P for BNP = .003; P for NT-proBNP = .005).
“We found that both natriuretic peptides comparably predicted risk of subsequent cardiovascular events both before and during treatment with sacubitril/valsartan. Use of sacubitril/valsartan did not appear to influence the prognostic value and clinical utility of these two commonly measured biomarkers,” Solomon told Cardiology Today. “Hospitals with BNP as the only natriuretic peptide assay can safely and reliably continue measuring this biomarker, when indicated, in patients with heart failure treated with sacubitril/valsartan, but should keep in mind a small — on average, approximately 20% — increase in BNP levels shortly after treatment initiation. Importantly, large increases in BNP levels after starting sacubitril/valsartan should not be ascribed to drug effects alone, and identify high-risk patients.”
The presentation was nominated for a Young Investigator Award. – by Erik Swain
Reference s :
Vaduganathan M, et al. Abstract 915-08. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
Myhre PL, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2019.01.018.
Disclosure s : PARADIGM-HF was funded by Novartis. Myhre reports he has received speaker fees from Novartis. Solomon reports he has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Celladon, Gilead, GlaxoSmithKline, Ionis Pharmaceutics, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur and Theracos, and has consulted for Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Takeda and Theracos. Vaduganathan reports he serves on advisory boards for AstraZeneca, Baxter Healthcare and Bayer. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Gregg C. Fonarow, MD
This new analysis of the biomarker substudy of PARADIGM-HF shows that there is a modest rise in BNP levels early after treating with sacubitril/valsartan, whereas there is a modest fall in NT-proBNP. However, patients with an increase in either level after initiation were at increased risk for clinical events.
Either biomarker may be used, but should not switch back and forth in the same patients. These findings demonstrate that both forms of the natriuretic peptide assay provide similar prognostic information among patients with HFrEF when being treated with sacubitril/valsartan. Some clinicians may favor NT-proBNP since early changes in levels may be easier to interpret.
Current guidelines recommend the use of BNP or NT-proBNP for aiding with diagnosis as well as providing prognostic information. These findings reinforce the prognostic significance of on-treatment NT-proBNP and BNP levels in patients with HFrEF. Serial testing of levels specifically for reducing mortality or hospitalizations has yielded mixed results in clinical trials.
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