ARNI-induced NT-proBNP changes associated with cardiac remodeling changes in HFrEF
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
Introduction and methods
Cardiac remodeling during progression of heart failure with reduced ejection fraction (HFrEF) can lead to reduced left ventricular ejection fractions (LVEF) and increased left ventricular (LV) volumes [1-3]. Myocardial remodeling, associated with increased CV risk, is an important target of HF therapies . Previous studies have revealed that a reduction in NT-proBNP concentration correlates with reverse LV remodeling [5,6]. Treatment with the angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/valsartan has been associated with decreased NT-proBNP concentrations . However, the effect of sacubitril/valsartan on cardiac remodeling has remained unclear.
This study examined the correlation between sacubitril/valsartan induced NT-proBNP concentration changes and long-term changes in measures of cardiac volume and function in HFrEF patients.
The Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) trial was a phase 4, 12-month, open-label, single-group study of 654 patients with HFrEF started on sacubitril/valsartan, conducted in the US. NT-proBNP concentrations were measured in blood samples which were obtained at baseline, every 2 weeks until day 60 and at 3, 6, 9, and 12 months after the start of the study. Echocardiography measurements were performed at baseline, 6 months and 12 months. Measurements included LVEF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI) and the ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e').
Primary endpoint was the correlation between changes in the concentration of NT-proBNP and cardiac remodeling, assessed by change in LVEDVI, LVESVI, LVEF, LAVI and E/e’ from baseline to 12 months.
- Median NT-proBNP concentration decreased from 816 pg/mL (IQR: 332-1822) at baseline to 455 pg/mL (IQR, 153-1090) at 12 months.
- There was a correlation between the change in log2-Transformed NT-proBNP and LVEF (r=−0.381 [IQR, −0.448 to −0.310]; P<0.001). LVEDVI (r=0.320 [IQR, 0.246 to 0.391]; P<0.001), LVESVI (r=0.405 [IQR, 0.335 to 0.470]; P<0.001), LAVI (r=0.263 [IQR, 0.186 to 0.338]; P<0.001), and E/e′ (r=0.269 [IQR, 0.182 to 0.353]; P<0.001).
- Weaker correlations were observed between log2-Transformed NT-proBNP and remodeling indices at 6 months.
- LVEF increased with least-square mean improvements of 9.4% (95% CI: 8.8% to 9.9%; P<0. 001) from baseline to 12 months. Mean LVEDVI was changed with −12.25 mL/m² at 12 months (95% CI:−12.92 to −11.58; P<0.001) from baseline. LVESVI changed with −15.29 mL/m² (95% CI: −16.03 to −14.55; P<0.001) at 12 months . A mean change in LAVI of −7.57 mL/m² (95% CI: −7.98 to −7.15; P<0.001) was observed at 12 months. The change in E/e′ ratio was −1.30 (95% CI: −1.74 to −0.86; P<0.001) at 12 months.
In this study of HFrEF patients, initiation of sacubitril/valsartan led to reduced NT-proBNP concentrations and was associated with an increase in LVEF and decrease in LVEDVI, LVESVI, LAVI and E/e′ after 12 months. These improvements were also observed after 6 months, albeit less pronounced. These results may help in understanding the mechanisms that result in the effects of sacubitril/valsartan in patients with HFrEF.