- ackground: The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown in the PARADIGM-HF trial to be superior to enalapril in reducing the risks of cardiovascular (CV) deaths and hospitalizations in heart failure (HF) patients. Although several studies suggested that sacubitril/valsartan is a cost-effective therapy, budget constraints may limit its use. Our objective was to characterize HF sub-populations in which cost per CV death/hospitalization prevented are excessively high in order to assist in treatment prioritization decisions. Methods: Outcome data were retrieved from the published PARADIGM-HF trial reports. Costs were calculated based on current United States prices of sacubitril/valsartan. Results: In the PARADIGM-HF trial, treatment of 4,187 patients with sacubitril/valsartan resulted in prevention of 203 CV deaths or HF hospitalizations (135 CV deaths) during a total of 9,396 patient-years. The estimated additional cost of sacubitril/valsartan during the trial’s follow-up period would have reached $42,089,220. Therefore, the cost of preventing one HF hospitalization or CV death would have been $207,336 and the cost of preventing one CV death would have been $311,772. This figure is significantly higher in sub-groups that presented a lower risk-reduction, as in patients with an ejection fraction >35% ($674,831) and in patients without prior use of HF medical therapy ($2,024,494). Conclusions: In healthcare settings under budget constraints, payers can maximize clinical outcomes in HF patients, by prioritizing sacubitril/valsartan therapy to sub-populations that have demonstrated higher benefit in the PARADIGM-HF trial. Advocating the reduction of sacubitril/valsartan prices could enable wider populations to benefit from this promising therapy.