Effect of Vericiguat on Total Heart Failure Events in Compensated Outpatients With HFrEF

BACKGROUND: In the VICTOR (Vericiguat Global Study in Participants With Chronic Heart Failure) trial, in a contemporary ambulatory cohort with heart failure and reduced ejection fraction (HFrEF) and no recent hospitalization, the primary outcome of hospitalization for heart failure (HHF) and cardiovascular death was not statistically significantly reduced with vericiguat. Vericiguat reduced risk of mortality but not HHF. In this ambulatory compensated cohort, time to first HHF may underestimate the overall worsening HF burden by failing to consider the high proportion of outpatient worsening HF events. OBJECTIVES: This study aimed to determine the effect of vericiguat on the overall risk of worsening HF by incorporating the entire patient experience of worsening outpatient and inpatient HF episodes. METHODS: VICTOR was a phase 3, double-blind, placebo-controlled trial testing the effect of vericiguat in ambulatory patients with HFrEF who had not experienced recent worsening (defined as HHF admission within 6 months or outpatient intravenous diuretic use within 3 months) and were on a background of high use of contemporary guideline therapy. The primary endpoint was a composite of cardiovascular death or HHF. The current analysis provides detailed effects of vericiguat on overall worsening HF in both the inpatient and outpatient settings, including urgent care visits for intravenous diuretics or outpatient oral diuretic initiation or intensification. RESULTS: A total of 6,105 participants were randomized. Outpatient worsening HF was more common as the first worsening HF event (n = 851, 59.3%), compared with HHF (n = 507, 35.4%) or urgent HF visits (n = 76, 5.3%). Outpatient oral diuretic initiation or intensification was associated with increased mortality (RR: 1.69; 95% CI: 1.47-1.94; P < 0.001). Overall worsening HF occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.8%) in the placebo group (HR: 0.90; 95% CI: 0.81-1.00; P = 0.047). The composite of all-cause death and overall worsening HF occurred in 917 participants (30.0%) in the vericiguat group and 1,004 participants (32.9%) in the placebo group (HR: 0.90; 95% CI: 0.82-0.98; P = 0.016). CONCLUSIONS: In compensated patients with HFrEF on contemporary guideline therapy, worsening HF in outpatients was more common than HHF and was associated with higher risk of mortality. Exploratory analyses suggested a potential reduction in overall worsening HF events when both inpatient and outpatient settings were considered.