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Original Investigation
September 2, 2019

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

Author Affiliations
  • 1Massachusetts General Hospital, Boston
  • 2Baim Institute for Clinical Research, Boston, Massachusetts
  • 3Novartis Pharmaceuticals, East Hanover, New Jersey
  • 4University of Mississippi Medical Center, Jackson
  • 5Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina
  • 6University of California, San Diego School of Medicine, San Diego
  • 7Detroit Medical Center, Detroit, Michigan
  • 8Brigham and Women’s Hospital, Boston, Massachusetts
JAMA. 2019;322(11):1085-1095. doi:10.1001/jama.2019.12821
Key Points

Question  Do changes in NT-proBNP correlate with changes in cardiac structure and function in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan?

Findings  In this prospective study of 794 patients with HFrEF who initiated therapy with sacubitril-valsartan, change in log2–NT-proBNP concentrations over 12 months correlated with changes in left ventricular (LV) ejection fraction (r = −0.381), LV end-diastolic volume index (r = 0.320), LV end-systolic volume index (r = 0.405), left atrial volume index (r = 0.263), and ratio of early diastolic filling/early diastolic annular velocity (r = 0.269).

Meaning  In this exploratory analysis of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months.

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

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