Blood Pressure and Safety Events With Vericiguat in the VICTORIA Trial

Abstract

Background Although safety and tolerability of vericiguat were established in the VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial in patients with heart failure with reduced ejection fraction, some subgroups may be more susceptible to symptomatic hypotension, such as older patients, those with lower baseline systolic blood pressure (SBP), or those concurrently taking angiotensin receptor neprilysin inhibitors. We described the SBP trajectories over time and compared the occurrence of symptomatic hypotension or syncope by treatment arm in potentially vulnerable subgroups in VICTORIA. We also evaluated the relation between the efficacy of vericiguat and baseline SBP. Methods and Results Among patients receiving at least 1 dose of the study drug (n=5034), potentially vulnerable subgroups were those >75 years old (n=1395), those with baseline SBP 100-110 mm Hg (n=1344), and those taking angiotensin receptor neprilysin inhibitors (n=730). SBP trajectory was plotted as mean change from baseline over time. The treatment effect on time to symptomatic hypotension or syncope was evaluated overall and by subgroup, and the primary efficacy composite outcome (heart failure hospitalization or cardiovascular death) across baseline SBP was examined using Cox proportional hazards models. SBP trajectories showed a small initial decline in SBP with vericiguat in those >75 years old (versus younger patients), as well as those receiving angiotensin receptor neprilysin inhibitors (versus none), with SBP returning to baseline thereafter. Patients with SBP <110 mm Hg at baseline showed a trend to increasing SBP over time, which was similar in both treatment arms. Safety event rates were generally low and similar between treatment arms within each subgroup. In Cox proportional hazards analysis, there were similar numbers of safety events with vericiguat versus placebo (adjusted hazard ratio [HR], 1.18; 95% CI, 0.99-1.39; P=0.059). No difference existed between treatment arms in landmark analysis beginning after the titration phase (ie, post 4 weeks) (adjusted HR, 1.14; 95% CI, 0.93-1.38; P=0.20). The benefit of vericiguat compared with placebo on the primary composite efficacy outcome was similar across the spectrum of baseline SBP (P for interaction=0.32). Conclusions These data demonstrate the safety of vericiguat in a broad population of patients with worsening heart failure with reduced ejection fraction, even among those predisposed to hypotension. Vericiguat's efficacy persisted regardless of baseline SBP. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.

Keywords: blood pressure; heart failure; heart failure with reduced ejection fraction; safety events; vericiguat.

Figures

Figure 1. SBP trajectory (mean ±1 SE) over time in the entire VICTORIA population (A), and by subgroups of age below (B) or above (C) 75 years; SBP above (D) or below (E) 110 mm Hg; and those not receiving (F) or receiving (G) ARNI at baseline.

ARNI indicates angiotensin receptor neprilysin inhibitors; SBP: systolic blood pressure; and VICTORIA: Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction.

Figure 2. Kaplan‐Meier event curves for time from randomization to (A) symptomatic hypotension or syncope, (B) symptomatic hypotension alone, and (C) syncope alone, and (D) landmark analysis in the post‐titration phase (ie, after 4 weeks) of time to symptomatic hypotension or syncope, (E) symptomatic hypotension alone, (F) and syncope alone. aHR indicates adjusted hazard ratio.

Figure 3. Treatment effect of vericiguat compared with placebo on the primary composite end point (first heart failure hospitalization or cardiovascular death) according to baseline systolic blood pressure.