Efficacy and safety of vericiguat in patients with HFrEF treated with sacubitril/valsartan: results from the VICTORIA trial

Abstract

Background: In the VICTORIA trial (n=5050) the reduction in the primary composite endpoint of cardiovascular death (CVD) or heart failure hospitalization (HFH) was similar whether or not patients received sacubitril/ valsartan. The distribution of those patients who received sacubitril/ valsartan after randomization (drop-ins) and the relationship to the efficacy and safety of vericiguat is unknown. Purpose: We assessed the efficacy and safety of vericiguat in patients who were or were not treated with sacubitril/valsartan at baseline in the VICTORIA trial and the implications of post- randomization use of sacubitril/ valsartan. Methods: A total of 5040 patients were analyzed according sacubitril/ valsartan use at randomization or initiated after randomization. The efficacy of vericiguat on the primary composite endpoint and its components, time to first HF hospitalization or all-cause mortality, were assessed according to sacubitril/valsartan use. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalemia. Results: Overall, 731 patients (360 on vericiguat and 371 on placebo) received sacubitril/valsartan at randomization. Patients treated with sacubitril/ valsartan were twice as likely to be from Western Europe or North America, to have a lower ejection fraction and systolic and diastolic blood pressures, were more often on triple therapy (65.9 vs 58.6%), and more likely to have received biventricular pacing (17.9 vs 14.1%) or ICDs (42.3 vs 25.3%). For patients on sacubitril/valsartan at baseline, the adjusted hazard ratios for vericiguat's treatment effect on the primary composite outcome, CVD, and HFH was 0.94 (95% CI 0.74-1.20), 0.81 (95% CI 0.55- 1.20) and 0.99 (95% CI 0.76-1.30), respectively. For those patients not on sacubitril/valsartan (2161 vericiguat; 2148 on placebo), the corresponding adjusted hazard ratios for vericiguat's treatment effect on the primary composite outcome, CVD, and HFH were 0.89 (0.80-0.98), 0.95 (0.82-1.11), and 0,87 (0.78-0.98), respectively. There was no significant interaction on the treatment effect of vericiguat based on the use of sacubitril/valsartan. More placebo patients (n=238) received drop-in use of sacubitril/valsartan than vericiguat group (n=187; p=0.007) post-randomization during followup (Figure). Overall, adverse events in the 992 patients receiving sacubitril/ valsartan (at either baseline or drop-in for at least 3 months) were not significantly different according to those on placebo vs vericiguat for symptomatic hypotension (21.0% vs 23.1), renal dysfunction (8.0 vs 9.0%), and hyperkalemia (10.3 vs 7.9%). Conclusions: Sacubitril/valsartan use was initiated more frequently after randomization in patients on placebo than on vericiguat. Concomitant use of sacubitril/valsartan did not alter the efficacy of vericiguat and was similarly tolerated in both study arms.