Author + information
- Received October 31, 2018
- Revision received December 30, 2018
- Accepted January 1, 2019
- Published online March 4, 2019.
- Peder Langeland Myhre, MD, PhDa,b,∗,
- Muthiah Vaduganathan, MD, MPHa,∗,
- Brian Claggett, PhDa,
- Milton Packer, MDc,
- Akshay S. Desai, MD, MPHa,
- Jean L. Rouleau, MDd,
- Michael R. Zile, MDe,
- Karl Swedberg, MDf,
- Martin Lefkowitz, MDg,
- Victor Shi, MDg,
- John J.V. McMurray, MDh and
- Scott D. Solomon, MDa,∗ (, )@BrighamResearch@pmyhre@mvaduganathan
- aCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- bDivision of Medicine, Akershus University Hospital and University of Oslo, Oslo, Norway
- cBaylor University Medical Center, Dallas, Texas
- dMontreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
- eMedical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina
- fUniversity of Gothenburg, Gothenburg, Sweden
- gNovartis Pharmaceuticals Corporation, East Hanover, New Jersey
- hUniversity of Glasgow, Glasgow, United Kingdom
- ↵∗Address for correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Background Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended.
Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan.
Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF.
Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively).
Conclusions Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
↵∗ Drs. Myhre and Vaduganathan contributed equally to this work as co-first authors.
The PARADIGM-HF trial was funded by Novartis AG. Dr. Myhre has received speaker fees from Novartis; and is supported by a postdoctoral research grant from the South-Eastern Norway Regional Health Authority (from Dr. Helge Røsjø), Akershus University Hospital, Norway (from Dr. Torbjørn Omland), the Norwegian Medical Association, and the Unger Vetlesen Medical Fund. Dr. Vaduganathan has been supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541); and has served on advisory boards for AstraZeneca, Bayer AG, and Baxter Healthcare. Dr. Packer has consulted for Amgen, Actavis, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer, Relypsa, Sanofi, Cytokinetics, and Cardiorentis; and has received personal fees from Akcea, Gilead, Johnson & Johnson, Novo Nordisk, Synthetic Biologics, and Theravance. Dr. Desai has received research grant support from Novartis; and has received consulting fees from Novartis, AstraZeneca, Abbott, Relypsa, Corvidia, Boehringer Ingelheim, Boston Scientific, and DalCor Pharma. Dr. Rouleau has served as a consultant for Novartis and AstraZeneca. Dr. Zile has served as a consultant for, served on the executive committee of, and received grants from Novartis. Dr. Swedberg has received honoraria/consulting fees from Amgen, AstraZeneca, Novartis, Pfizer, Servier, and Vifor; and has received research grants from Amgen and Servier. Dr. Lefkowitz is an employee of Novartis Pharmaceuticals. Prof. McMurray’s employer, University of Glasgow, was paid by Novartis for his time spent as cochairman of the PARADIGM-HF trial, as well as co-principal investigator of ATMOSPHERE and PARAGON-HF trials, and Executive/Steering Committee member for PARADISE-MI and PERSPECTIVE. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi, Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 31, 2018.
- Revision received December 30, 2018.
- Accepted January 1, 2019.
- 2019 American College of Cardiology Foundation
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