Sacubitril/valsartan was not a recommended therapy in the American College of Cardiology Practice Guideline for Patients with New York Heart Association Class IV Heart Failure with a Reduced Ejection Fraction because there was little to no clinical evidence in this population. To compare sacubitril/valsartan therapy with valsartan in patients with advanced heart failure and a reduced ejection fraction who presented with recent New York Heart Association class IV symptoms. A double-blind, randomized clinical trial was carried out; a total of 335 patients with advanced heart failure were included.COVID-19 risk necessitated CXL discontinuation on March 23, 2020, just over one year after it started. Patients were assigned to either sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended treatment. The area under the curve (AUC) for comparing N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at baseline to those after 24 weeks of therapy. The majority of the 335 individuals were males (73%), and their average age was 59.4 years old (13.5) (SD). During the short run-in period, 70% of eligible patients (n=72) were unable to tolerate sacubitril/valsartan 100 mg/d, and 49 people (29%) discontinued treatment.The median NT-proBNP AUC for the valsartan treatment arm (n=168) was 1.19 (IQR, 0.91-1.64). In contrast, the sacubitril/valsartan treatment arm had an AUC of 1.08 (IQR, 0.75-The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% confidence interval [CI], 0.84 to 1.08; P=.45). Sacubitril/valsartan did not improve the clinical composite of several days alive, out of the hospital, or free from heart failure events when compared with valsartan. There were no apparent safety issues aside from a significantly higher incidence of non-life-threatening hyperkalemia in the sacubitril/valsartan group (28 [17%] vs 15 [9%]; P=.04). The findings revealed that sacubitril/valsartan and valsartan did not significantly differ in terms of lowering NT-proBNP levels in patients with chronic advanced heart failure with a reduced ejection fraction.