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Background and aim:Heart failure with preserved ejection fraction (HFpEF) is associated with an increased risk of heart failure (HF) hospitalizations and cardiovascular death (CVD). Both dapagliflozin and sacubitril–valsartan have recently shown convincing reductions in the combined risk of CVD and HF hospitalizations in patients with HF and mildly reduced ejection fraction (HFmrEF) or HFpEF. We aimed to investigate the cost-per-outcome implications of dapagliflozin vs sacubitril–valsartan in the treatment of HFmrEF or HFpEF patients.Methods:We compared the annualized cost needed to treat (CNT) to prevent the composite outcome of total HF hospitalizations and CVD with dapagliflozin or sacubitril–valsartan. The CNT was estimated by multiplying the annualized number needed to treat (aNNT) by the annual cost of therapy. The aNNT was calculated based on data collected from the DELIVER trial for dapagliflozin and a pooled analysis of the PARAGLIDE-HF and PARAGON-HF trials for sacubitril–valsartan. Costs were based on 2022 US prices. Scenario analyses were performed to attenuate the differences in the studies’ populations.Results:The aNNT with dapagliflozin in DELIVER was 30 (95% confidence interval [CI]: 21-62) versus 44 (95% CI: 25-311) with sacubitril–valsartan in a pooled analysis of PARAGLIDE-HF and PARAGON-HF, with an annual cost of $4,951 and $5,576, respectively. The corresponding CNTs were $148,547.13 (95% CI: $103,982.99–$306,997.39) for dapagliflozin and $245,346.77 (95% CI: $139,401.58–1,734,155.60) for sacubitril–valsartan for preventing the composite outcome of CVD and HF hospitalizations. The CNT for preventing all-cause mortality was lower for dapagliflozin than sacubitril–valsartan $1,128,958.15 [CI: $401,077.24–∞] vs $2,185,816.71 [CI: $607,790.87–∞].Conclusion:Dapagliflozin provides a better monetary value than sacubitril–valsartan in preventing the composite outcome of total HF hospitalizations and CVD among patients with HFmrEF or HFpEF.