Author + information
- Received April 22, 2016
- Revision received September 7, 2016
- Accepted September 12, 2016
- Published online December 6, 2016.
- Michael R. Zile, MDa,∗ (, )
- Brian L. Claggett, PhDb,
- Margaret F. Prescott, PhDc,
- John J.V. McMurray, MDd,
- Milton Packer, MDe,
- Jean L. Rouleau, MDf,
- Karl Swedberg, MDg,
- Akshay S. Desai, MDb,
- Jianjian Gong, PhDc,
- Victor C. Shi, MDc and
- Scott D. Solomon, MDb
- aMedical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina
- bBrigham and Women’s Hospital, Boston, Massachusetts
- cNovartis Pharmaceuticals Corporation, East Hanover, New Jersey
- dUniversity of Glasgow, Glasgow, United Kingdom
- eBaylor University Medical Center, Dallas, Texas
- fMontreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
- gUniversity of Gothenburg, Gothenburg, Sweden
- ↵∗Reprint requests and correspondence:
Dr. Michael R. Zile, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Thurmond/Gazes, 114 Doughty Street, Room 323, Charleston, South Carolina 29425.
Background Natriuretic peptides (NP) have prognostic value in heart failure (HF), although the clinical importance of changes in NP from baseline is unclear.
Objectives The authors assessed whether a reduction in N-terminal pro–B-type NP (NT-proBNP) was associated with a decrease in HF hospitalization and cardiovascular mortality (primary endpoint) in patients with HF and reduced ejection fraction, whether treatment with sacubitril/valsartan reduced NT-proBNP below specific partition values more than enalapril, and whether the relationship between changes in NT-proBNP and changes in the primary endpoint were dependent on assigned treatment.
Methods In PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial), baseline NT-proBNP was measured in 2,080 patients; 1,292 had baseline values >1,000 pg/ml and were reassessed at 1 and 8 months. We related change in NT-proBNP to outcomes.
Results One month after randomization, 24% of the baseline NT-proBNP levels >1,000 pg/ml had fallen to ≤1,000 pg/ml. Risk of the primary endpoint was 59% lower in patients with a fall in NT-proBNP to ≤1,000 pg/ml than in those without such a fall. In sacubitril/valsartan-treated patients, median NT-proBNP was significantly lower 1 month after randomization than in enalapril-treated patients, and it fell to ≤1,000 pg/ml in 31% versus 17% of patients treated with sacubitril/valsartan and enalapril, respectively. There was no significant interaction between treatment and the relationship between change in NT-proBNP and the subsequent risk of the primary endpoint.
Conclusions Patients who attained a significant reduction in NT-proBNP had a lower subsequent rate of cardiovascular death or HF hospitalization independent of the treatment group. Treatment with sacubitril/valsartan was nearly twice as likely as enalapril to reduce NT-proBNP to values ≤1,000 pg/ml. (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) [PARADIGM-HF]; NCT01035255.)
This study was funded by Novartis. All authors have consulted for and received research support from Novartis, sponsor of the PARADIGM-HF trial. Drs. Prescott, Gong, and Shi are employees of Novartis. Professor McMurray’s employer, University of Glasgow, was paid by Novartis for Professor McMurray’s time spent as co-chairman of the PARADIGM-HF trial. Dr. Packer has served as a consultant for Admittance Technologies, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Celyad, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Pfizer, Sanofi, Takeda, and ZS Pharma. Dr. Swedberg has received honoraria from Novartis for sponsored lectures; has served as a consultant for AstraZeneca and Amgen and he has also received research support from Servier. Dr. Desai has served as a consultant for St. Jude Medical, Relypsa, Sanofi, and Merck.
- Received April 22, 2016.
- Revision received September 7, 2016.
- Accepted September 12, 2016.
- The Authors