Vericiguat, Reduced NT

Vericiguat significantly decreases N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with placebo and may be associated with a modest decrease in cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF), according to a study in JACC: Heart Failure.

In an analysis of the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA; ClinicalTrials.gov Identifier: NCT02861534), investigators evaluated the relationship between sequential changes in NT-proBNP and the primary composite outcome of cardiovascular death or HF hospitalization and its components, the impact of vericiguat vs placebo on changes in NT-proBNP, and the association between the clinical efficacy of vericiguat and changes in NT-proBNP.

Study participants had recent worsening chronic HFrEF with elevated NT-proBNP levels (>1000 pg/mL in sinus rhythm and >1600 pg/mL in atrial fibrillation) and were randomly assigned to receive vericiguat or placebo. All patients with NT-proBNP samples available at randomization were included (n=4805; mean age, 68 [60-76] years; 24.1% women). Of these patients, 2414 received vericiguat and 2391 received placebo. Additional samples were measured at weeks 16, 32, 48, and 96.

The median NT-proBNP level at randomization was 2816 pg/mL, and the relationship between relative changes of ±20% in NT-proBNP levels at week 16 and the primary composite outcome for all patients from week 16 was then assessed. Patients with NT-proBNP levels of 2816 pg/mL or less at randomization and decreases of 20% or more have the lowest cumulative incidence of the composite outcome. For the 2 groups with decreases in NT-proBNP levels of less than 20%, the composite outcome incidence progressively increases, with the highest composite event rate occurring in patients with randomization NT-proBNP levels higher than 2816 pg/mL with less than 20% reduction (P <.001 across all 4 groups).

NT-proBNP levels significantly decrease at 16 weeks in both treatment groups, with further decreases occurring through 96 weeks. Participants who received vericiguat compared with placebo have a significantly greater decrease in NT-proBNP levels at week 16 (median reduction, 450 pg/mL vs 200 pg/mL; P <.001). This decrease was less overall throughout the study.

Participants who received vericiguat are 45% more likely to have any reduction in NT-proBNP levels and 30% less likely to have their NT-proBNP levels increase vs those who received placebo. A consistent pattern of decreased levels with vericiguat (relative 27%-42% reduction) and increased levels with placebo (relative 70%-79% increase) is found when more granular relative reductions in NT-proBNP levels were assessed in the range from 10% to 50%.

At week 16, a relative (approximately 4%) but significant treatment effect related to serial NT-proBNP on the composite outcome and its components was observed (hazard ratio [HR] 0.96; 95% CI, 0.95-0.99). These effects increase progressively to a 10% or more relative reduction to week 48 (HR 0.90; 95% CI, 0.85-0.96). The estimated overall treatment effect is statistically significant at 30 to 35 weeks for the composite endpoint and HF hospitalization but not for cardiovascular death.

The extent of mediation ranges from 40% to 78% across the composite endpoint and its components when the repeated measures of NT-proBNP as a mediator are taken into account.

Study limitations include the potential for residual survival bias. Also, some samples were missing, and attribution of some of vericiguat's treatment to changes in NT-proBNP cannot be proven definitively.

"Patients treated with vericiguat compared with placebo had significantly greater declines and lesser increments in sequential measures of NT-proBNP, and these changes appear related to the modest relative clinical benefit of vericiguat therapy," the investigators wrote.

Disclosure: The VICTORIA trial was funded by Merck Sharp & Dohme Corporation, a subsidiary of Merck & Co, Inc, and Bayer AG. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Armstrong PW, Zheng Y, Troughton RW, et al. Sequential evaluation of NT-proBNP in heart failure: insights into clinical outcomes and efficacy of vericiguat. JACC: Heart Fail. Published online July 6, 2022. doi.org/10.1016/j.jchf.2022.04.015