Efficacy of Sodium-glucose co-Transporter 2 inhibitors in slOwing Progression of Aortic Valve Stenosis. (STOP-AVS)
Description: Background: Aortic valve stenosis is the leading cause of death from valvular heart disease in high-income countries. As populations age in the context of the demographic transition, aortic stenosis places a considerable strain on healthcare resources. In the absence of effective strategies for the prevention of disease progression, the only available treatment option for severe stenosis is to alleviate mechanical obstruction through surgical or transcatheter valve replacement.Rationale: Key pathophysiological pathways involved in aortic valve degeneration include oxidative stress, disruption of endothelial integrity, and inflammatory processes. By reducing oxidative stress, modulating nitric oxide signaling, and suppressing pro-inflammatory cytokine production, sodium-glucose co-transporter 2 (SGLT2) inhibitors may mitigate the calcific remodeling of the aortic valve. Furthermore, SGLT2 inhibitors have a well-established safety profile in patients with diabetes, all types of heart failure and chronic kidney disease, supporting their potential suitability for long-term administration in patients with established cardiovascular disease. Objective: The STOP-AVS trial aims to evaluate the efficacy of a daily therapy with an SGLT2 inhibitor in slowing the progression of aortic valve stenosis in patients with mild to moderate aortic valve stenosis.Methods: This is an investigator-initiated, phase IIb, randomized, double-blind, placebo-controlled clinical trial. A total of 746 patients aged >50 years with mild to moderate aortic stenosis, defined by a mean transvalvular gradient of 10-39 mmHg and an aortic valve area between 1.0 and 1.99 cm², will be enrolled at 4 sites in Switzerland. Participants will be randomized in a 1:1 ratio to receive either SGLT2 inhibitor or placebo for a duration of 3 years. Randomization will be stratified by the severity of aortic stenosis (mild vs. moderate) to ensure balanced groups. The primary endpoint is a composite of all-cause death, heart failure hospitalization and aortic valve replacement (AVR) at maximum follow-up. Secondary endpoints include change in transvalvular aortic valve mean gradient as assessed by transthoracic echocardiography, Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score, extent of secondary cardiac damage according to the classification proposed by Généreux and colleagues, and incremental cost-effectiveness ratio. Safety endpoints include ketoacidosis, worsening renal function, orthostatic syncope, and genitourinary infections. Echocardiographic, laboratory and KCCQ assessments will be performed at baseline and every 6 months until the end of the study. Observational data indicates that treatment with SGLT-2 inhibitors reduce the risk of progression to severe aortic stenosis by approximately 40% over three years, indicating a 40% relative risk reduction for the need of AVR. The sample size calculation employs a superiority design with two groups (treatment and control) and an equal 1:1 allocation ratio. The primary outcome is defined as a time-to-event outcome, assessed using an unweighted log-rank test. The sample size calculation encompasses nine 6-month intervals, with an anticipated cumulative incidence of the primary outcome at 33.8% within the control group. Participant recruitment is phased across three 6-month periods, with proportional allocations of 40%, 30%, and 30%, respectively, and an annual attrition rate of 2%. The analysis is powered at 80% to detect a hazard ratio of 0.65 favoring the treatment group, with a two-sided significance level of 0.05. This design necessitates a total sample size of 746 participants, equally distributed between the two groups (373 per group), anticipating 173 primary outcome events. All analyses will adhere to the intention-to-treat principle.Expected Impact: This study aims to provide robust evidence on the potential of SGLT2 inhibitors to slow the progression of aortic stenosis, potentially offering a novel and readily available pharmacological treatment for this common and serious condition.
Amount: CHF 4,850
Funding type: research
Funder scheme: IICT - PPI Preparatory Grant
Start date: 2025-07-01
End date: 2025-10-31
Investigator: Pilgrim, Thomas
Institution: University of Berne – BE
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 238553
OpenAlex ID: G5568636942