In patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF>40%), there is limited evidence on the benefits of sacubitril/valsartan vs broader renin-angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life. In patients with chronic heart failure and an LVEF of more than 40%, the objective was to evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life was compared to background medication–based personalized comparators. A randomized, double-blind, parallel-group clinical experiment lasted 24 weeks (August 2017-October 2019). 2,572 patients with heart failure, LVEF of more than 40%, increased NT-proBNP levels, structural heart disease, and poor quality of life were enrolled from 4,632 patients screened at 396 facilities in 32 countries (last follow-up, October 28, 2019). Patients were randomly assigned to one of two groups: sacubitril/valsartan (n=1,286) or a background medication–based individualized comparator (n=1,286), i.e., enalapril, valsartan, or placebo, stratified by prior use of a renin-angiotensin system inhibitor. Changes in plasma NT-proBNP levels at week 12 and the 6-minute walk distance at week 24 were the primary end objectives. Change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks were secondary end goals. 2,240 (87.1%) of the 2,572 randomised patients (mean age 72.6 years [SD, 8.5 years]; 1,301 women [50.7%]) completed the trial. The sacubitril/valsartan group had 786 pg/mL NT-proBNP levels at baseline, while the comparative group had 760 pg/mL. Patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL), with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P<.001) after 12 weeks. The mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% Confidence interval, 0.93 to 1.97) or improvement in NYHA class did not differ significantly across groups (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). Hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia were the most common adverse events in the sacubitril/valsartan group vs the comparator group (11.6% vs 10.9%). Sacubitril/valsartan treatment, compared to standard renin-angiotensin system inhibitor treatment or placebo, resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks in patients with heart failure and a left ventricular ejection factor of greater than 40%. For a study, more research is needed to determine if sacubitril/valsartan has any clinical benefits in the patients.