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

Abstract

Importance: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain.

Objective: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function.

Design, setting, and participants: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018.

Exposures: NT-proBNP concentrations among patients treated with sacubitril-valsartan.

Main outcomes and measures: The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months.

Results: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%).

Conclusions and relevance: In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF.

Trial registration: ClinicalTrials.gov Identifier: NCT02887183.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Januzzi reported receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Drs Prescott, Rocha, and Williamson and Mr McCague are employees of Novartis Pharmaceuticals Inc. Dr Butler reported receiving personal fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, StealthPeptide, V-Wave Limited, and Vifor and research support from the National Institutes of Health (NIH), Patient-Centered Outcomes Research Institute, and the European Union. Dr Felker reported receiving personal fees from Novartis, Bristol-Myers Squibb, Medtronic, Innolife, EBR Systems, Arena, Abbott, Alnylam, SC Pharma, Rocket, Sphingotec, LivaNova, Cardionomic, Relypsa, V-Wave, and MyoKardia; grants from the National Heart, Lung, and Blood Institute (NHLBI), the American Heart Association, and Merck; and grants and personal fees from Amgen, Cytokinetics, and Roche Diagnostics. Dr Maisel reported receiving consulting income from Abbott Vascular, Ortho Clinical Diagnostics, and Novartis. Dr Pina reported receiving consulting income from Relypsa and Novartis. Dr Rocha reported receiving personal fees from Novartis Pharma. Dr Shah reported receiving research support through Brigham and Women’s Hospital from Novartis and personal fees from Philips Ultrasound and Bellerophon Therapeutics. Dr Solomon reported receiving grants from Novartis, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos and personal fees from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AOBiome, Janssen, Cardiac Dimensions, and Tenaya. No other disclosures were reported.

Figures

Figure 1.. Concentrations of N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) Across Study Visits

Reduction in NT-proBNP was evident by the first follow-up visit and was sustained throughout the 12 months. Concentrations of NT-proBNP were included if collected 6 or more hours from the first dose of sacubitril-valsartan. Distributions of NT-proBNP at each time point can be found in eTable 2 and eFigure 3 in Supplement 3.

Figure 2.. Scatterplots Detailing Correlations Between Baseline and 12-Month Concentrations of Log2-Transformed N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) and Contemporaneous Change in LVEF, LVEDVI, LVESVI, LAVI, and E/e′

A mean regression line is detailed with 95% prediction limits demonstrated in dashed lines. The shaded regions indicate 95% confidence limits.