Vericiguat for heart failure with reduced ejection fraction on quadruple therapy without recent worsening heart failure: an exploratory real-world cohort study

Background: Heart failure with reduced ejection fraction (HFrEF) patients remain at substantial risk despite quadruple guideline-directed medical therapy (GDMT [ARNI + SGLT2 inhibitor + β-blocker + MRA]). Data on vericiguat in stable HFrEF patients without recent worsening heart failure receiving contemporary quadruple GDMT are limited. This observational study aimed to explore the efficacy and safety of vericiguat in this population. Methods: A total of 450 adult patients with LVEF < 45% were enrolled (200 received quadruple GDMT plus vericiguat, 250 received quadruple GDMT alone). After 1:1 propensity score matching (PSM), 144 well-matched pairs were identified. The primary outcome was the composite of cardiovascular death or first HF hospitalization within 12 months. Secondary outcomes included changes in NYHA functional class, KCCQ-12 scores, and occurrence of hypotension. Due to the non-randomized design, all efficacy findings except the primary composite endpoint are considered exploratory. Trial Registration: ChiCTR, ChiCTR2500095278. Registered 4 January 2025. Retrospectively registered. Results: Over 12 months, the primary composite endpoint occurred in 5.56% of the vericiguat group versus 9.03% of the control group (P = 0.365; HR 0.616, 95% CI 0.255–1.486). No statistically significant differences were observed for cardiovascular death or all-cause mortality. Exploratory analyses showed that the vericiguat group had higher KCCQ-12 Overall Summary Scores (91.61 ± 9.56 vs. 87.93 ± 11.25, P = 0.003) and a greater proportion achieving a ≥ 5-point improvement (94.44% vs. 81.25%, P = 0.001). NYHA functional class distribution also differed between groups (P = 0.029). Hypotension rates were similar between groups. Conclusion: Among HFrEF patients without recent worsening, vericiguat did not significantly reduce the primary composite endpoint at 12 months. Exploratory observations suggest potential associations with improved quality of life and functional class without increased hypotension risk. These hypothesis‑generating findings require confirmation in adequately powered randomized controlled trials.