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

Key PointsQuestionDo 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? FindingsIn this prospective study of 794 patients with HFrEF who initiated therapy with sacubitril-valsartan, change in log(2)-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). MeaningIn 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. ImportanceIn 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. ObjectiveTo 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 ParticipantsProspective, 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. ExposuresNT-proBNP concentrations among patients treated with sacubitril-valsartan. Main Outcomes and MeasuresThe primary outcome was the correlation between changes in log(2)-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. ResultsAmong 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 log(2)-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/m(2) (difference, -12.25 mL/m(2) [IQR, -12.92 to -11.58]; P<.001) and LVESVI decreased from 61.68 to 45.46 mL/m(2) (difference, -15.29 mL/m(2) [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 RelevanceIn 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 observedreverse cardiac remodeling may provide a mechanistic explanation for the effectsof sacubitril-valsartan in patients with HFrEF. Trial RegistrationClinicalTrials.gov Identifier: NCT02887183 This exploratory cohort study of patients with heart failure with reduced ejection fraction (HFrEF) assesses the association between change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) after starting sacubitril-valsartan and changes in left ventricular ejection fraction, diastolic volume, and other measures of physiologic cardiac function.