The Effect of Vericiguat on Endothelial Function in Patients With Heart Failure With Reduced Ejection Fraction: A Pilot Randomized Study

Vericiguat is a soluble guanylate cyclase stimulator previously shown to improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying mechanisms remain incompletely understood. To evaluate the feasibility of assessing the effects of vericiguat on endothelial function, we conducted a pilot, randomized, double-blind, placebo-controlled trial of vericiguat in patients with HFrEF. Feasibility and efficacy outcomes were assessed at baseline and at 12 weeks on treatment. The primary efficacy outcome was brachial artery flow-mediated vasodilation. Secondary efficacy outcomes included N-terminal pro-brain natriuretic peptide, inflammatory markers, functional capacity, and health-related quality of life. An analysis of covariance model was used for continuous and Mantel-Haenszel tests for discretized outcomes. We enrolled 26 participants (median age 67 years, 84% male), with 25 completing 12-week follow-up, 13 in the active and 12 in the control arm. Feasibility objectives were successfully met, including enrollment, retention, drug titration, and completeness of data collection for all endpoints. In exploratory analyses, treatment with vericiguat resulted in flow-mediated dilation mean difference of 0.7%, (95% confidence interval: -1.1% to 2.5%, p = 0.40) and a nominally significant reduction of log NTproBNP of -0.42 (95% confidence interval: -0.81 to -0.04, p = 0.03). No significant differences in inflammatory biomarkers, functional capacity, or health-related quality of life were observed. We demonstrated the feasibility of assessing endothelial function in patients with HFrEF treated with vericiguat. While the pilot study size did not provide sufficient precision to confirm a treatment effect, our findings support future larger and longer studies to evaluate the therapeutic potential of soluble guanylate cyclase stimulation on endothelial function in HFrEF.