Supplementary Material for: Relevance of Collaterals for the Success of Neuroprotective Therapies in Acute Ischemic Stroke: Insights from the Randomized URICO-ICTUS Trial

Background: Collateral circulation may modify the effect of neuroprotective therapies. We report a post hoc analysis of the URICO-ICTUS trial (NCT00860366) assessing the modifying treatment effect of pretreatment collaterals on clinical and radiological outcomes in patients with large-vessel acute ischemic stroke receiving uric acid therapy or placebo. Methods: URICO-ICTUS was a randomized clinical trial where 411 alteplase-treated patients also received uric acid 1,000 mg (n = 211) or placebo (n = 200) before the end of alteplase infusion. Herein, we included a nested study of 84 patients (placebo = 40, uric acid = 44) who had a pretreatment CT-angiography (CTA) showing a proximal arterial occlusion in the carotid territory. Excellent collaterals were defined as 100% collateral supply on pretreatment CTA. Regression models assessed the interaction between therapy (uric acid/placebo) and collaterals on the main outcome (ordinal modified Rankin Scale [mRS] shift at 90 days). Results: Overall, excellent collaterals were associated with improved outcome. There was a significant interaction between therapy and pretreatment collaterals (p interaction = 0.02) for the prediction of improved mRS shift. The largest treatment contrast in favor of uric acid was found in patients with excellent collaterals (adjusted OR 9.2; 95% CI 1.23–68.6; p = 0.03). Conclusions: Collectively, the study found that collaterals were associated with the neuroprotective effect of uric acid therapy highlighting the importance of assessing collateral status in neuroprotection trials.背景：侧支循环可能会改变神经保护治疗的疗效。本研究针对URICO-ICTUS试验（临床试验注册号：NCT00860366）开展事后分析，旨在评估预处理侧支循环对接受尿酸治疗或安慰剂的大血管性急性缺血性卒中患者的临床及影像学结局的调节治疗效应。 方法：URICO-ICTUS是一项随机临床试验，共纳入411例接受阿替普酶治疗的患者，在阿替普酶输注结束前，予患者1000mg尿酸（n=211）或安慰剂（n=200）。本研究纳入其中的84例患者作为嵌套研究对象，其中安慰剂组40例、尿酸组44例，所有患者均完成预处理CT血管造影（CTA），提示颈动脉供血区存在近端动脉闭塞。优质侧支循环定义为预处理CTA显示侧支供血达100%。本研究通过回归模型分析治疗方式（尿酸/安慰剂）与侧支循环对主要结局（90天时改良Rankin量表[mRS]序贯结局偏移）的交互作用。 结果：总体而言，优质侧支循环与更佳的临床结局相关。在预测mRS序贯结局改善方面，治疗方式与预处理侧支循环之间存在显著交互作用（交互p值=0.02）。在优质侧支循环患者中，观察到最有利于尿酸治疗的疗效差异（校正比值比OR=9.2；95%置信区间CI：1.23~68.6；p=0.03）。 结论：综上，本研究发现侧支循环与尿酸治疗的神经保护效应相关，凸显了在神经保护试验中评估侧支循环状态的重要性。