Emerging concepts in heart failure management and treatment: focus on vericiguat

Abstract

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is dysregulated in patients with heart failure (HF) resulting in myocardial and vascular dysfunction that contributes to its progression. Vericiguat is a novel direct sGC stimulator that targets in at least two ways the NO-sGC-cGMP pathway with the subsequent restoration of cGMP activity. The VICTORIA trial assessed the effects of vericiguat (versus placebo) in 5050 patients with chronic HF (NYHA class II-IV), left ventricular ejection fraction (LVEF) <45%, elevated natriuretic peptide levels and a recent HF decompensation (hospitalized or outpatient intravenous diuretics). After a median follow-up of 10.8 months, a lower risk (10% reduction) of the primary combined outcome (cardiovascular death or HF hospitalization) was achieved (HR 0.90, 95% CI 0.83-0.98; p=0.02). The composite endpoint was driven by HF hospitalizations (HR 0.9, 95% CI 0.81-1.00; p=0.048) whilst CV death reduction was not statistically significant on its own. The target dose was achieved in 89% of patients treated with vericiguat, and no significant differences were observed in the rates of syncope or hypotension. The VICTORIA trial showed that vericiguat was safe, well tolerated and without need of laboratory testing. The aim of this review is to provide comprehensive information about vericiguat in terms of its differential mechanism of action and clinical data particularly focused on the VICTORIA trial. A comparison is also made with DAPA-HF and EMPEROR-Reduced considering that, in all these contemporary trials, a new study medication was added to the standard triple HF therapy. This is a relevant issue because the VICTORIA trial had a significant but less powerful effect than DAPA-HF and EMPEROR-Reduced on HF outcomes in a setting of more severe disease, higher event rate and shorter follow-up. In addition, relevant data on other previous studies are also provided in both HF with reduced LVEF (SOCRATES-Reduced) and HF with preserved LVEF (SOCRATES-Preserved and VITALITY-Preserved). This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.

Keywords: VICTORIA trial; guanylate cyclase stimulators; heart failure; vericiguat.

Figure 1. Cardiovascular effects of vericiguat

In a heart failure setting, an increased oxidative stress, inflammation and endothelial dysfunction reduce nitric oxide (NO) bioavailability, which results in soluble guanylate cyclase (sGC) deficiency with a subsequent reduction in cyclic guanosine monophosphate (cGMP) synthesis (orange arrows). A lower sGC activity is associated with coronary microvascular dysfunction, altered diastolic relaxation, inflammation, fibrosis, hypertrophy and apoptosis of cardiomyocytes in response to cardiac injury.– Vericiguat directly stimulates sGC (independent of NO involvement) and it also sensitizes this enzyme to endogenous NO by the stabilization of its binding site. Consequently, by restoring cGMP deficiency (green arrows), myocardial function and vascular tone improve. Vericiguat is a poorly soluble and highly permeable agent that, once ingested, requires a median time of <2.5 hours to reach its maximum plasma concentration (half-life 18–22 hours). It is approximately 98% bound to plasma proteins (essentially albumin) and is not affected by renal or hepatic insufficiency. In healthy subjects, 53.1% and 45.2% of the administered dose is excreted in the urine and faeces, respectively. eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate.