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Introduction Sacubitril/valsartan (S/V) promotes reverse cardiac remodeling in patients with HFrEF. Neprilysin inhibition results in increase of several vasoactive peptides that may mediate effects of S/V, however its effects on atrial natriuretic peptide (ANP) are largely unknown. Effects of ANP are mediated by cyclic guanosine monophosphate (cGMP). Hypothesis Longitudinal change in ANP concentration following initiation of S/V is associated with reverse cardiac remodeling. Methods Within a prospective open-label study of initiation and titration of S/V in patients with HFrEF, this pre-specified sub-study included patients in whom ANP was measured from samples collected in protease inhibitors to minimize its degradation. Concentrations of ANP and cGMP were measured at baseline and serially through 12 months of treatment. Echocardiographic assessment of LVEF and left atrial volume index (LAVi) was performed at baseline, 6 and 12 months. Results Among 144 participants (mean age 64.5 years; LVEF 30.8%), median ANP concentration at baseline was 102 pg/mL. Following initiation of S/V, ANP increased steeply and consistently during the first 2 months, with a significant increase in log-transformed ANP concentration at Day 14 (from 4.60 pg/mL to 5.05 pg/mL; Δ = 0.453; P Conclusions Concentrations of ANP increase substantially after initiation of S/V in patients with HFrEF. Larger early increases in ANP after S/V initiation were associated with greater magnitude of reverse cardiac remodeling (PROVE-HF; NCT02887183).

Background Compared to angiotensin-converting enzyme inhibition alone, angiotensin receptor-neprilysin inhibition reduces cardiovascular mortality and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF). The pathophysiologic mechanisms responsible for these clinical benefits remain unclear but may be related to effects on central hemodynamics and cardiac structure and function. We sought to determine whether treatment of HFrEF with sacubitril/valsartan improves central aortic stiffness, cardiac remodeling, biomarkers of wall stress and injury, and quality of life compared with enalapril. Methods EVALUATE-HF was a prospective, randomized, multicenter, double-blind, double-dummy clinical trial of patients aged 50 or older with chronic HF, NYHA I-III symptoms, and EF of 40% or less. Participants were randomized 1:1 to treatment with sacubitril/valsartan (target dose 97/103 mg twice daily) versus enalapril (target dose 10 mg twice daily) for 12 weeks followed by open-label sacubitril/valsartan for 12 weeks (Figure). The primary study outcome was between group difference in change from baseline to week 12 in aortic characteristic impedance (Zc). Other prespecified outcomes included change from baseline to week 12 in levels of cardiac biomarkers and echocardiographic measures of cardiac structure and function as well as change in health-related quality of life assessed by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results Between August 17, 2016 and January 26, 2019 we randomized 464 participants at 85 sites in the United States, of whom 231 were randomly assigned to sacubitril/valsartan and 233 to enalapril. For the overall population, mean age was 67.3 +/- 9.1 years, mean EF was 34 +/- 10%, median NTproBNP was 584 [IQR 244, 1467], 109 (23.5%) were female, 115 (24.8%) were black, 313 (67.4%) reported NYHA Class 2, and 391 (84.3%) were previously treated with an ACEi or ARB. We will present the primary results of the EVALUATE-HF study as initially submitted to the 2019 European Society of Cardiology Scientific Sessions, including the effects of sacubitril/valsartan compared with enalapril on change from baseline in central aortic stiffness, cardiac biomarkers, cardiac structure and function. We will also present new data regarding the time course and magnitude of changes in quality of life in both treatment groups during study follow up as well as the relationship of these changes to changes in cardiac structure, function, and biomarkers. Conclusions EVALUATE-HF will provide important mechanistic insights into established clinical benefits of sacubitril/valsartan in HFrEF. We will present detailed quality of life outcomes for the first time at HFSA 2019.