Abstract WP175: The “Clinical Trial Effect” in Randomized Controlled Secondary Stroke Prevention Clinical Trials: A Systematic Review

Introduction: 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 evaluated whether outcomes in the “standard-of-care” control arm of stroke randomized controlled trials outperformed historical standard of care clinical outcomes. Methods: We searched for secondary stroke prevention randomized controlled trials (RCTs) between 2000-2025 in NEJM, Lancet, JAMA, Neurology, and Stroke. Trials were identified through PubMed using the MeSH terms “stroke” and “secondary prevention”. Trials were included in our analysis if their primary outcome included stroke recurrence and they utilized observational, registry, or natural history clinical data to inform their estimated control arm event rates. For each included trial, we reviewed the published protocol, statistical analysis plan (SAP), and primary manuscript to identify the expected control arm event rates. Observed event rates in the control arm were obtained from the primary publication. Expected-to-observed (E/O) outcome ratios were calculated and displayed in a forest-style plot to demonstrate the presence or absence of a trial effect (Figure 1). Results: The search yielded 407 results, of which 80 studies were retained after title/abstract screening. An additional 41 studies were excluded because the primary outcome did not include stroke recurrence. A further 30 studies were ineligible because their expected outcome rates were not derived from real-world clinical data. Nine eligible RCTs (>11,000 control patients) were identified. Primary outcomes across trials included recurrent ischemic stroke, short-term 90-day stroke or vascular composite outcomes (stroke, systemic embolism or MI). Expected control arm event rates ranged from 1.8-24.7%; observed rates ranged from 0.9-14%. In 8 of 9 trials, observed outcomes were lower than expected (E/O 1.05-2.93), with NAVIGATE-ESUS as the only exception (E/O 0.81). The largest trial effects (E/O > 2.0) were identified in SPS3, VIST, RESPECT PFO, and POINT (see Figure 1). Conclusion: 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.