In clinical practice, efficacy and safety of Sacubitril/Valsartan (S/V) treatment in patients with acute decompensated heart failure (ADHF) and reduced ejection fraction compared with angiotensin converting enzyme inhibitor (ACEI)/Angiotensin receptor blocker (ARB). Methods From May 2018 to October 2019, according to the inclusion and exclusion standards, patients with ADHF and reduced ejection fraction were successively enrolled in 4 research cardiology centres. The patients were divided into the S/V or ACEI/ARB group according to the clinical prescribing information. During hospitalization and after discharge, the doctor titrated the drug dose according to the patient's condition and blood pressure, followed up to 12 months after discharge. The primary endpoint was the composite of death from cardiovascular causes and rehospitalization for heart failure, and the secondary efficacy endpoint was the composite of death from any causes and rehospitalization for any causes. The safety endpoint was a composite of worsening renal function, hyperkalaemia, cough, angioneurotic oedema, and symptomatic hypotension. Results A total of 758 patients were included during the screening period, of which 127 were excluded according to the inclusion criteria, 631 were included for propensity score matching, and 502 patients were included in the data analysis. In total, 251 patients who received S/V and 251 patients who received an ACEI/ARB had similar propensity scores and were included and compared. In the S/V group and ACEI/ARB group, the incidences of the primary endpoints (cardiovascular causes and rehospitalization for HF) were 23.5% and 32.3%, respectively (HR:0.687;95% CI:0.493～0.958; P=0.027), the incidences of cardiovascular death were 4.8% and 10.4%, respectively (HR:0.444; 95% CI:0.235～0.840; P=0.017), and the incidences of rehospitalization for heart failure were 18.7% and 21.9% (HR:0.845; 95% CI:0.573～1.247; P=0.398). The incidences of the secondary endpoints (death from any causes and rehospitalization for any causes) were 35.1% and 38.2%, respectively (HR:0.891; 95% CI:0.668～1.191; P=0.437). The incidences of death from any causes were 4.8% and 11.6%, respectively (HR:0.396; 95% CI:0.214～0.731; P=0.0005), and the incidences of rehospitalization for any causes were 30.3% and 26.7% (HR:1.168; 95% CI:0.841～1.622; P=0.352); The safety end point did not differ significantly between the two groups. Conclusion In clinical practice, among patients hospitalized with ADHF and a reduced left ventricular ejection fraction, S/V therapy led to a reduction in the number of deaths from cardiovascular causes and rehospitalizations for heart failure compared to ACEI/ARB therapy alone, and the safety is similar.