The “clinical trial effect” proposes that clinical trial participants experience improved outcomes compared to similarly treated patients not enrolled in a clinical trial. Evidence for the clinical trial effect remains mixed. We assessed whether control-arm outcomes in secondary stroke prevention trials outperform expectations based on real-world data.

We identified secondary stroke prevention RCTs published between 2000-2025 in NEJM, Lancet, JAMA, Neurology, and Stroke. Trials were included if their primary otucome was recurrant stroke and if their estimated control-arm event rates were based on observational, registry, or natural-history data. Expected event rates were obtained from trial protocols or statistical analysis plans; observed rates were extracted from the primary publications. For each study, expected-to-observed (E/O) event-rate ratios were calculated, with E/O>1.0 indicating fewer observed events than predicted.

In this exploratory analysis, secondary stroke prevention trial participants consistently had less recurrent stroke than expected based upon real-world clinical data. Our findings may support the presence of a clinical trial effect, but should be interpreted cautiously due to non-contemporaneous control bias.