Timing of S. aureus -related mortality in a large randomized clinical trial: Implications for future study design
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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<0.0001). Nearly 80% of SAB-related deaths occurred by day 30, whereas 50% of unrelated deaths occurred between days 30 and 90. Youden’s index optimized follow-up at 20.5 days.
Limitations
Potential for cause-of-death misclassification and data limited to Canadian sites.
Conclusion
Deaths considered attributable to SAB cluster rapidly within the first month, while later deaths are predominantly unrelated. A 30-day all-cause mortality window may be more appropriate than 90 days for primary mortality outcomes in trials evaluating acute SAB therapies with longer follow up reserved for metastatic infection and recurrence.
