Optimal Timing of Vericiguat Therapy in Patients with Heart Failure with Reduced/Mildly Reduced Ejection Fraction for Improving Mortality and Heart Failure Re-Hospitalization Rate

Background: Vericiguat, a soluble guanylate cyclase stimulator, reduces cardiovascular events in patients with heart failure with reduced ejection fraction following clinical deterioration against guideline-directed medical therapy. However, the optimal timing for initiating vericiguat remains unclear. Methods: We retrospectively analyzed heart failure patients with reduced/mild-reduced ejection fraction who received vericiguat between 2021 and 2025 upon optimal guideline-directed medical therapy. The primary outcome was a composite of all-cause mortality and heart failure hospitalization. Patients were stratified by the number of prior heart failure hospitalizations (<2 vs. ≥2), and outcomes were assessed using multivariable Cox regression and biomarker trajectories over 6 months. Results: A total of 43 patients (with a median age of 73 years, 35 were men) were included. Of these, 26 (60%) patients had ≥2 prior hospitalizations. A number of hospitalizations ≥ 2 independently predicted the primary outcome (hazard ratio: 8.43; 95% confidence interval: 1.79–39.7; p = 0.007). Only patients with <2 prior hospitalizations showed significant improvements in plasma B-type natriuretic peptide levels (p = 0.049) and left ventricular ejection fraction (p = 0.016). In contrast, no meaningful biomarker changes were observed in patients with ≥2 hospitalizations. Conclusions: A history of two or more heart failure hospitalizations is a strong predictor of poor outcomes during vericiguat therapy. These findings suggest that initiating vericiguat earlier—before recurrent hospitalizations—may yield greater clinical benefit.