Efficacy and safety of vericiguat in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan: insights from the VICTORIA trial

Aim We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post‐randomization drop‐in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat. Methods and results The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all‐cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71–1.19) versus 0.89 (0.80–0.98), 0.71 (0.45–1.12) versus 0.95 (0.82–1.11), and 0.98 (0.74–1.29) versus 0.87 (0.78–0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p‐values for interaction: 0.81, 0.23 and 0.47, respectively). Post‐randomization, more drop‐in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm. Conclusions Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat. Clinical Trial Registration: ClinicalTrials.gov NCT02861534. Time to initiation of drop‐in therapy with sacubitril/valsartan according to treatment group among sacubitril/valsartan naïve patients at randomization. Significantly more patients in the placebo group (n = 238/2148 [11.1%]) had sacubitril/valsartan added than vericiguat (n = 187/2161 [8.7%]; p = 0.007). This difference in