Abstract Body (Do not enter title and authors here): Background: Vericiguat, a soluble guanylate-cyclase stimulator, has been shown in randomized trials to reduce the composite risk of cardiovascular death or heart-failure hospitalization. Its broader effect on major adverse cardiovascular events (MACE) and arrhythmia in routine practice, however, remains uncertain.

Research Question: Among adults with heart failure with reduced ejection fraction (HFrEF), does initiating vericiguat alter one-year risks of MACE, malignant ventricular arrhythmia, and all-cause mortality compared with standard therapy?

Methods: Using the TriNetX Global Collaborative Network, we identified adults with HFrEF between 2021 and 2024. Patients who received vericiguat formed the exposure cohort; those without vericiguat exposure served as comparators. One-to-one propensity-score matching balanced demographics, comorbidities, concomitant medications (including guideline-directed medical therapies for heart failure), and laboratory values, yielding 1,397 patients per group. Outcomes were assessed from the day after the index date through 12 months of follow-up. The primary endpoint was MACE—a composite of acute myocardial infarction, stroke, pulmonary embolism, cardiac arrest, and acute systolic heart-failure decompensation. Secondary endpoints were incident malignant ventricular arrhythmia (ventricular fibrillation or flutter) and all-cause mortality. Hazard ratios with 95 % confidence intervals were computed.

Results: A total of 2,794 matched patients (1,397 per group) were analyzed. Median follow-up was 357 days in the vericiguat cohort and 321 days in controls. MACE occurred in 23.9 % vs 26.8 % of patients (hazard ratio [HR] 0.83, 95 % confidence interval [CI] 0.71–0.96; p = 0.012). All-cause mortality was 10.5 % vs 10.9 % (HR 0.93, 95 % CI 0.74–1.16; p = 0.50). Malignant ventricular arrhythmia occurred in 1.7 % vs 1.0 % (HR 1.76, 95 % CI 0.89–3.47; p = 0.10).

Conclusion: In this large, real-world, propensity-matched HFrEF cohort, vericiguat initiation was associated with a 17 % relative reduction in the hazard of one-year MACE, without a statistically significant reduction in mortality or malignant ventricular arrythmia. These findings support vericiguat as an effective adjunct to guideline-directed therapy for mitigating composite cardiovascular events in HFrEF and highlight the need for prospective studies to confirm its long-term effectiveness and safety.