Vericiguat outcomes by pre-randomisation worsening heart failure events: a post-hoc recurrent events analysis of the VICTOR trial

Background History of worsening HF (WHF) events is a traditional enrichment selection criterion in HF trials. Complementing VICTORIA where all patients with HFrEF had a recent WHF, VICTOR investigated stable ambulatory patients with or without a non-recent prior WHF episode. VICTOR found that vericiguat, on top of GDMT, improved survival but had neutral effects on the primary composite of CV death or hospitalisation for HF (HFH), with no treatment modification on the primary composite in those with vs without a WHF event prior to randomisation. Purpose To assess whether treatment effects on other endpoints in VICTOR differed between those with vs without a WHF event prior to randomisation. Methods This post-hoc analysis defined prior WHF event as HFH (> 6 months before randomisation) or an urgent outpatient visit requiring intravenous (IV) diuretics (>3 months prior randomisation). The endpoint assessed was time to CV death plus total (first and recurrent) WHF events. Other key endpoints included total WHF events, CV deaths, and all-cause deaths. Andersen–Gill models adjusted for NYHA class were used to determine HRs with 95% CIs and to test for treatment-by-stratum interactions. Results In the VICTOR ITT population (N=6105), 53% had, and 47% did not have, a documented WHF event prior to randomisation. Patients with a prior WHF event were slightly younger but had a higher baseline comorbidity and symptom burden than patients without WHF (Table 1). Background HF therapy in VICTOR was excellent overall. Treatment was similarly distributed in subgroups, except for more loop diuretic use in patients with a prior WHF event vs those without (77% vs 61%). In patients with a prior WHF event, vericiguat reduced the outcome of time to CV death plus total (first and recurrent) WHF events vs placebo over a median follow-up of 18 months (HR 0.81; 95% CI 0.72–0.90; Figure 1). This group also showed lower total WHF events with vericiguat (HR 0.82; 95% CI 0.72–0.93) and fewer all-cause deaths or WHF events (HR 0.81; 95% CI 0.73–0.91) vs placebo. In contrast, among patients without prior WHF, no respective benefits were seen (all HRs were neutral). Of note, all treatment-by-stratum interactions were significant for all recurrent event endpoints (Pinteraction ranged from 0.003 to 0.008). Safety profiles were similar between vericiguat and placebo, regardless of history of WHF. Among participants with prior WHF, SAEs occurred in 27% (vericiguat) vs 28% (placebo) and serious drug-related events in 1.0% vs 1.1%, respectively. Conclusions In stable patients with HFrEF and a history of WHF (HFH or urgent outpatient IV diuretics), vericiguat markedly reduced CV death and recurrent WHF outcomes. These results suggest that the clinical value of vericiguat may be greater in patients with a history of WHF event despite clinical stability at trial entry, which highlights the opportunity for risk-stratified use in HF management.