Stroke Symptoms As a Surrogate in Stroke Primary Prevention Trials: The CREST Experience

Backgroundand Purpose: The use of surrogate endpoints can decrease sample size while maintaining statistical power. This report considers incident stroke symptoms as a surrogate endpoint in a post-hoc analysis of asymptomatic patients from the multicenter, randomized Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST).Methods:CREST assessed stroke symptoms using the Questionnaire for Verifying Stroke-free Status (QVSS) at baseline and follow-up. While the primary analysis of CREST defined “asymptomatic” as having been free of stroke/TIA for 180 days, herein the population was further restricted by requiring no stroke symptoms at baseline. Incident adjudicated stroke was defined the same as for the primary analysis; incident stroke symptoms was defined as developing ≥1 stroke symptom in follow-up. Treatment differences between stenting (CAS) and endarterectomy (CEA) were assessed for three endpoints: adjudicated stroke, stroke symptoms, and adjudicated stroke or stroke symptoms.Results:The cohort included 826 of the 1181 asymptomatic patients in CREST. Adjudicated stroke events occurred in 44 patients and incident stroke symptoms occurred in 183. Analysis of adjudicated stroke endpoints demonstrated a non-significant hazard ratio (HR) for CAS compared to CEA of 1.02 (95% confidence interval [CI], 0.57-1.85). The corresponding HR for the incident stroke symptoms outcome was 1.54 (95% CI, 1.15-2.08), and the HR for the composite outcome of adjudicated stroke or incident symptoms was 1.38 (95% CI, 1.04-1.83), both significant.Conclusions:The low stroke event rates in asymptomatic patients challenges the assessment of CAS-versus-CEA treatment differences. Incorporating incident stroke symptoms as a surrogate outcome increased the number of events by over 4-fold. The analysis demonstrated a previously unreported significant difference in cerebrovascular risk with CAS compared to CEA. We propose that broadening the endpoints of primary stroke prevention trials to include surrogate events like incident stroke symptoms could make trials more feasible.