Methodological Appraisal of Ongoing Trial of Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Younger Patients: From Incentives to Guideline-Informing Evidence.

OBJECTIVES

To critically appraise the design of the ongoing multicentre, randomized START YOUNG trial comparing transcatheter aortic valve implantation (TAVI) with bioprosthetic surgical aortic valve replacement (SAVR) in patients aged 65-75 years with symptomatic severe aortic stenosis (AS).

METHODS

Publicly available trial information (ClinicalTrials.gov: NCT06861361) was reviewed, and the design was benchmarked against the minimum expected methodological standards for generating practice-changing evidence in patients with very long life expectancy (LE) following SAVR. The appraisal domains included objectives and study endpoints; selected non-inferiority (NI) margins; adequacy of follow-up for late events; statistical analysis plans and handling of crossovers/missing data; consistency of surgical comparators; and prespecified sub-groups.

RESULTS

Several major concerns were identified: (1) co-primary safety/efficacy composites mix hard adverse events (death, stroke) with softer outcomes, with rehospitalization likely to dominate; (2) limited duration primary follow-up (30 days/1 year), with only optional survaillance beyond 5 years, inadequate for durability and late hazards; (3) wide NI margins (7%-8%) that could accept clinically meaningful inferiority; (4) an unclear statistical analysis plan; (5) a device-specific TAVI arm versus heterogeneous SAVR comparator; and (6) up to 25% bicuspid anatomy without stratified randomization or powered analyses. Collectively, these choices markedly increase the risks of type I error, and misinterpretation in a population with likely crossing hazard curves and a long median LE comparable to that of the age-matched general population after SAVR.

CONCLUSIONS

In order to generate guideline-informing evidence for extending TAVI to younger patients with severe AS, the trial should prioritise hard adverse endpoints, tighten NI margins, mandate extended follow-up, standardise the surgical comparator, and adequately power the bicuspid subgroup. Without these revisions, continuing the study under the current protocol risks yielding biased, non-guideline informative results.