AbstractStudy ObjectiveTo assess the effectiveness of sacubitril/valsartan versus angiotensin receptor antagonist therapy for prevention of heart failure (HF)‐related hospitalization and all‐cause hospitalization in a large cohort of patients with heart failure with reduced ejection fraction (HFrEF).DesignRetrospective cohort study.Data SourceIBM^® MarketScan^® research databases (2014–2018).PatientsPatients aged 18 years or older with their first HFrEF hospitalization on or after January 1, 2015, who initiated sacubitril/valsartan or angiotensin receptor antagonist after hospital discharge.InterventionSacubitril/Valsartan versus Angiotensin receptor antagonist.Measurements and Main ResultsThe index date was the first sacubitril/valsartan or angiotensin receptor antagonist fill date. After 1 up to 3 propensity score matching, Cox proportional hazards regression was used with robust variance estimators to compare HF‐related and all‐cause hospitalizations between treatments. Subgroup and sensitivity analyses were conducted to assess the robustness of the main analysis. After propensity score matching, 1,088 sacubitril/valsartan and 2,839 angiotensin receptor antagonist new users were included. The crude incidence of HF‐related hospitalization was 13 per 100 person‐years for sacubitril/valsartan users and 18 per 100 person‐years for angiotensin receptor antagonist users. Compared with angiotensin receptor antagonist use, sacubitril/valsartan use was associated with 27% lower risk of HF‐related hospitalization (adjusted hazard ratio, 0.73; 95% confidence interval, 0.58–0.91; p = 0.006) and 31% lower risk of all‐cause hospitalization (adjusted hazard ratio, 0.69; 95% confidence interval, 0.61–0.79; p < 0.001). Subgroup analyses revealed no significant heterogeneity, including subpopulations with chronic kidney disease or coronary artery disease.ConclusionsCompared with angiotensin receptor antagonists, sacubitril/valsartan was associated with lower risk of HF‐related and all‐cause hospitalizations. Our data suggest that, when added sequentially, sacubitril/valsartan should be the preferred initial agent over angiotensin receptor antagonists.