Research Article: Real-world safety of vericiguat as a fifth-line agent in heart failure: a pharmacovigilance study of quintuple therapy

Abstract:
Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is indicated for high-risk worsening heart failure (HF). However, its real-world reporting profile when added to contemporary quadruple guideline-directed medical therapy (GDMT)—effectively creating a “quintuple” regimen—remains largely unexplored, particularly regarding cardiorenal and hematologic adverse-event reporting patterns. We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database (2021 Q1–2025 Q4). HF reports were strictly stratified into an expanded quadruple GDMT cohort [renin–angiotensin system inhibitor?+?beta-blocker?+?mineralocorticoid receptor antagonist [MRA]?+?sodium–glucose cotransporter-2 inhibitor [SGLT2i]] and a quintuple cohort (GDMT?+?vericiguat). Disproportionality analysis utilized a dual-algorithm approach: the frequentist Reporting Odds Ratio (ROR) and the Bayesian Information Component (IC) derived from the Bayesian Confidence Propagation Neural Network (BCPNN). SGLT2i-stratified analyses and formal interaction testing were also performed. The final cohort comprised 5,524 reports (5,459 quadruple; 65 quintuple). No ROR signals were identified for hypotension (ROR?=?1.66, 95% CI: 0.90–3.06), syncope (ROR?=?0.85, 95% CI: 0.21–3.49), or acute kidney injury (ROR?=?0.61, 95% CI: 0.26–1.41). Anemia met the frequentist ROR signal criterion (ROR?=?2.61, 95% CI: 1.03–6.58), but not the BCPNN criterion (IC?=?0.96, IC?2SD?=??0.29). The anemia ROR was 2.61 (95% CI: 1.03–6.58) with an SGLT2i background and 1.82 (95% CI: 0.42–7.88) without an SGLT2i background; formal interaction testing did not demonstrate significant effect modification ( P for interaction?=?0.683). No statistically significant differences were detected in reported serious outcomes between groups. In this FAERS analysis, no robust reporting signals were identified for hypotension, syncope, or acute kidney injury after vericiguat was added to contemporary quadruple GDMT. Although anemia met the frequentist ROR criterion, the finding was not supported by Bayesian signal detection, and formal analyses did not demonstrate significant effect modification by background SGLT2i use. Given the small vericiguat-exposed cohort, these findings should be considered hypothesis-generating and require confirmation in larger longitudinal studies.

Introduction:
Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is indicated for high-risk worsening heart failure (HF). However, its real-world reporting profile when added to contemporary quadruple guideline-directed medical therapy (GDMT)—effectively creating a “quintuple” regimen—remains largely unexplored, particularly regarding cardiorenal and hematologic adverse-event reporting patterns.

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