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Aims Sacubitril/valsartan, dapagliflozin and vericiguat have shown a prognostic benefit in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). Assessing their relative efficacy is an important goal. Methods and results We assessed the relative efficacy of dapagliflozin, sacubitril/valsartan and vericiguat, by comparing the treatment arms with the respective control arms (standard of care) through a network meta-analysis. The phase 3 trials (PARADIGM-HF, DAPA-HF, VICTORIA), the HFrEF subgroup of DECLARE-TIMI 58, and a phase 2 trial on vericiguat were evaluated. Dapagliflozin was associated with a non-significant reduction in the risk of cardiovascular (CV) death or HF hospitalization compared to sacubitril/valsartan (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.64 to 1.22) and vericiguat (HR 0.82, 95% CI 0.6 to 1.12). The risk of CV death did not differ significantly between patients on dapagliflozin or sacubitril/valsartan (HR 0.90, 95% CI 0.51 to 1.58), and between patients on dapagliflozin or vericiguat (HR 0.77, 95% CI 0.44 to 1.37). As for HF hospitalization, dapagliflozin conferred a significant benefit over vericiguat (HR 0.77, 95% CI 0.63 to 0.93), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.72 to 1.06). Dapagliflozin was ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat. Conclusion Based on an indirect comparison, dapagliflozin is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on dapagliflozin or sacubitril/valsartan, while dapagliflozin is superior to vericiguat. Registration number PROSPERO ID 186351.

66 Relative efficacy of sacubitril/valsartan, dapagliflozin and vericiguat: a systematic review and network meta-analysis