From the Department of Neurology (J.F.M., T.G.B.), Mayo Clinic, Jacksonville, FL; Department of Neurology (J.V.), Medical University of South Carolina, Charleston; and Department of Epidemiology (V.J.H.), School of Public Health, and Department of Biostatistics (G.H.), University of Alabama, Birmingham.
Neurology. 2022 Nov 22;99(21):e2378-e2384. doi: 10.1212/WNL.0000000000201188. Epub 2022 Aug 26.
The use of surrogate end points can decrease sample size while maintaining statistical power. This report considers incident stroke symptoms as a surrogate end point in a post hoc analysis of asymptomatic patients from the multicenter, randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST).
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/transient ischemic attack 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 3 end points: adjudicated stroke, stroke symptoms, and adjudicated stroke or stroke symptoms.
The cohort included 826 of the 1,181 asymptomatic patients in CREST. Adjudicated stroke events occurred in 44 patients, and incident stroke symptoms occurred in 183. Analysis of adjudicated stroke end points demonstrated a nonsignificant hazard ratio (HR) for CAS compared with CEA of 1.02 (95% 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.
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 with CEA. We propose that broadening the end points of primary stroke prevention trials to include surrogate events such as incident stroke symptoms could make trials more feasible.
替代终点的使用可以在保持统计效力的同时减少样本量。本报告考虑了多中心随机颈动脉血管重建内膜切除术与支架置入术试验（CREST）中无症状患者的事后分析中以偶发卒中症状作为替代终点。
CREST 使用基线和随访时的验证无卒中状态问卷（QVSS）评估卒中症状。虽然 CREST 的主要分析将“无症状”定义为 180 天内无卒中/短暂性脑缺血发作，但此处人群进一步限制为基线时无卒中症状。经裁决的卒中定义与主要分析相同；偶发卒中症状定义为随访时出现≥1 种卒中症状。评估支架置入术（CAS）和内膜切除术（CEA）之间的 3 个终点的治疗差异：经裁决的卒中、卒中症状和经裁决的卒中或卒中症状。
该队列包括 CREST 中 1181 例无症状患者中的 826 例。44 例患者发生经裁决的卒中事件，183 例患者发生偶发卒中症状。对经裁决的卒中介点进行分析显示，CAS 与 CEA 相比，风险比（HR）无统计学意义（95%CI，0.57-1.85）。偶发卒中症状结局的相应 HR 为 1.54（95%CI，1.15-2.08），经裁决的卒中或偶发症状复合结局的 HR 为 1.38（95%CI，1.04-1.83），均有统计学意义。
无症状患者的低卒中发生率对评估 CAS 与 CEA 治疗差异提出了挑战。将偶发卒中症状作为替代结局纳入后，事件数量增加了 4 倍以上。该分析显示，CAS 与 CEA 相比，脑血管风险存在先前未报道的显著差异。我们建议，将主要卒中预防试验的终点扩大到包括偶发卒中症状等替代事件，可使试验更具可行性。
