Timing of S. aureus-related mortality in a large randomized clinical trial: Implications for future study design
Background: Longer follow-up periods in clinical trials for S. aureus bacteremia (SAB) may capture unrelated deaths, adding random noise that risks biasing trial results towards the null. Objective: To evaluate the timing and infection-relatedness of deaths within a large SAB clinical trial platform. Design: Blinded duplicate adjudication of trial deaths using a modified 7-point Likert-Scale. A third reviewer settled disagreements. Setting: 37 Canadian hospitals participating in the S. aureus Network Adaptive Platform (SNAP) Trial. Participants: 1515 adult patients recruited to SNAP between February 2022 and May 2026. Measurements: Timing and relatedness of 90-day deaths categorized as at least possibly SAB-related not likely to be SAB-related. Optimal follow-up cut-off was determined using Youden's index and graphically. Results: 247 deaths occurred; 97 (39.3%) were adjudicated as at least possibly SAB-related and 150 (60.7%) as not likely related. For probably/definitely related deaths, interrater agreement was 85.0% (Gwet's AC 0.73, substantial); for at least possibly related, it was 77.3% (Gwet's AC 0.55, moderate). Median survival was significantly shorter for SAB-related deaths (12 vs. 30.5 days; difference: 19 days earlier, 95% CI: 12-26, p