Nearly four in five patients with moderate aortic stenosis carry features that double their risk of dying or being hospitalized for heart failure within two years, yet current guidelines do not recommend valve replacement until disease reaches the severe threshold. That gap is the central finding of a real-world analysis of more than 53,000 patients published simultaneously in JACC and presented at TCT 2026, and it has direct implications for how trials in structural heart disease define their populations.
The data come from the egnite Registry, which drew on nearly 15 million patients and 6.5 million echocardiograms across 48 U.S. institutions. Among 53,994 patients with moderate or severe AS identified since January 2022, moderate AS outnumbered severe nearly two to one. Of those moderate patients, 78.7% had at least one at-risk feature, including reduced ejection fraction, diastolic dysfunction, atrial fibrillation, or elevated natriuretic peptides. Two-year mortality ran 20.1% in the at-risk group versus 9.0% in those with no such features; heart failure hospitalization was 44.6% versus 21.9%. Critically, 90% of deaths and 86% of heart failure hospitalizations in the moderate-AS group occurred while patients were still classified as moderate, with no documented progression to severe disease beforehand.
That last figure is the design problem for future trials. The current ACC/AHA guideline sets echocardiographic surveillance at every one to two years for moderate AS, deferring intervention until severe criteria are met. In this cohort, only 20% to 23% of moderate-AS patients had valve replacement documented within two years, compared with 50.1% of those with severe disease. Investigators now have registry-level evidence that a meaningful share of moderate-AS patients deteriorate and die without ever crossing the severity threshold that would trigger action under current standards.
Philippe Généreux, MD, of Atlantic Health Morristown Medical Center, announced a prospective follow-on study called ACTIVATE AS, which will enroll approximately 700 patients identified through the CardioCare platform and follow them every six months for up to two years, with core-laboratory echocardiography, natriuretic peptide testing, and CT calcium scoring at each visit. Funded by an unrestricted grant from Edwards Lifesciences and expected to begin enrollment in 2027, the study is designed to test whether structured, multiparametric surveillance changes management decisions for the at-risk moderate-AS population the registry has now quantified. The enrollment threshold that ACTIVATE AS uses to define at-risk phenotypes will be the number worth watching as the protocol is finalized.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
