It is yet uncertain how vericiguat will affect sequential levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) or how this might affect clinical consequences. Researchers in this study looked at how changes in NT-proBNP correlated with the primary outcome (cardiovascular mortality or heart failure hospitalization) and how vericiguat affected those changes. The levels of NT-proBNP were assessed in 4,805 out of 5,050 patients at baseline, 16, 32, 48, and 96 weeks. A correlation analysis was performed between the NT-proBNP change at week 16 and the primary outcome. Joint modeling and mediation analysis were used to evaluate the association between NT-proBNP alterations and the primary outcome by treatment group. Both groups’ NT-proBNP levels decreased significantly and persistently after therapy. After 16 weeks, vericiguat was associated with a greater reduction in NT-proBNP levels than placebo (any reduction: decreased (OR [95% CI]: 1.45 [95% CI: 1.28-1.65]; P<0.001;  ≥50%) (OR [95% CI]: 1.27 [95% CI: 1.10-1.47]; P=0.001) and increased (OR [95% CI]: 0.68 [95% CI: 0.59-0.78]; P<0.001; increased ≥20% OR: 0.68 [95% CI: 0.59-0.78]; P<0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P<0.001). The average level of mediation of the composite outcome related to NT-proBNP was 45%; the treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16 and HR: 0.90 (95% CI: 0.85-0.96) at week 48. The levels of NT-proBNP were considerably lower in vericiguat-treated patients with deteriorating HFrEF compared to placebo. According to the data, this modification was linked to a small relative improvement in the primary outcome (cardiovascular mortality or heart failure hospitalization). The Vericiguat International Congestive Heart Failure Trial.