Vericiguat for the Inhibition of Calcific Aortic Valve Stenosis Progression
brief summary
Calcific aortic valve stenosis (CAVS) is a condition in which the aortic valve progressively narrows and stiffens due to calcium deposition, eventually impairing blood flow from the heart to the body. No drug therapy has been proven to slow CAVS progression. Individuals with mild-to-moderate CAVS are managed with periodic monitoring until the stenosis becomes severe, at which point surgical or transcatheter valve replacement is the only treatment option. The goal of this clinical trial is to determine whether vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, can slow the progression of mild-to-moderate CAVS. The primary questions this study aims to answer are: Does vericiguat slow the progression of aortic valve calcium accumulation, as measured by the change in aortic valve calcium score from baseline to 24 months, compared to placebo? The study will compare vericiguat against a placebo (an inactive pill that is identical in appearance but contains no active drug). Both participants and the research team will not know which treatment each participant is receiving throughout the study. Participants will: Take vericiguat or placebo orally once daily for 24 months; Begin treatment at 2.5 mg/day and undergo a stepwise dose increase every two weeks to a target dose of 10 mg/day, provided the drug is tolerated; Attend approximately 8 scheduled study visits over two years, during which they will undergo cardiac imaging examinations (transthoracic echocardiography and non-contrast cardiac CT), blood sample collection, physical assessment, and completion of standardized questionnaires on quality of life and heart failure symptoms; Undergo cardiac magnetic resonance imaging (MRI) at the beginning and end of the study, if there are no contraindications. Approximately 238 participants will be enrolled across roughly 19 hospitals in China.
detailed description
BACKGROUND AND UNMET NEED Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease worldwide and a leading cause of heart failure, valve replacement, and cardiovascular death in older adults. In Western populations, the prevalence of CAVS reaches 1-2% among individuals aged ≥65 years and approximately 12% in those aged ≥75 years. In China, prevalence is rising sharply as the population ages. Once the aortic valve peak velocity exceeds 2.5 m/s, the disease typically progresses to severe stenosis within a decade. Among patients with symptomatic severe aortic stenosis who do not undergo intervention, two-year mortality approaches 50%.
Aortic valve replacement-either surgical (SAVR) or transcatheter (TAVI)-is currently the only effective treatment for severe CAVS. However, valve replacement carries substantial procedural risks (stroke, conduction block, paravalvular leak, bleeding, infection) and imposes a heavy economic burden. There is therefore an urgent clinical need for a pharmacological intervention that can slow CAVS progression at the mild-to-moderate stage and thereby reduce the proportion of patients who progress to severe stenosis requiring valve replacement.
Over the past two decades, numerous randomized controlled trials have tested pharmacological strategies for slowing CAVS progression, including intensive statin therapy (SALTIRE, TASS, ASTRONOMER), anti-osteoporotic agents (SALTIRE-2: denosumab and alendronate), vitamin K2 plus vitamin D supplementation, and DPP-4 inhibitors (evogliptin). All have yielded negative results. Recent evidence has reframed CAVS as an active fibro-calcific disease driven by valvular interstitial cell (VIC) osteogenic differentiation, endothelial dysfunction, and inflammatory signaling, rather than a passive degenerative process. The consistent failure of prior trials highlights the need for mechanistically novel therapeutic targets.
RATIONALE FOR TARGETING THE NO-sGC-cGMP PATHWAY Cyclic guanosine monophosphate (cGMP) is a critical second messenger in cardiovascular homeostasis, synthesized from GTP by guanylate cyclases. Soluble guanylate cyclase (sGC)-the principal receptor for nitric oxide (NO)-is widely expressed in valvular endothelial cells and VICs. cGMP activates protein kinase G (PKG), which exerts multiple protective effects including suppression of VIC osteogenic differentiation, preservation of mitochondrial function, and attenuation of oxidative stress.
In calcified aortic valve tissue, the NO-sGC-cGMP signaling axis is markedly impaired despite compensatory upregulation of sGC subunits. The key mechanism involves localized oxidative stress that converts sGC from its active (reduced, heme-containing) form to an oxidized or heme-free form that is insensitive to endogenous NO, thereby limiting cGMP production. Our group has further demonstrated that serum cGMP concentrations are significantly reduced in patients with CAVS and correlate inversely with CT-derived aortic valve calcium (AVC) scores and echocardiographic mean pressure gradients, supporting cGMP-PKG pathway downregulation as a hallmark of CAVS progression.
official title
Vericiguat for the Inhibition of Calcific Aortic Valve Stenosis Progression: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (VERIFICATION Study)