Supplementary Material for: Rationale, Design and Baseline Data of a Randomized, Double-Blind, Controlled Trial Comparing Two Antithrombotic Regimens (a Fixed-Dose Combination of Extended-Release Dipyridamole plus ASA with Clopidogrel) and Telmisartan versus Placebo in Patients with Strokes: The Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS)

Background: Individuals with transient ischemic attack and ischemic stroke have a high risk of recurrent stroke and death. While acetylsalicylic acid (ASA, aspirin) is proven and accepted as standard therapy in these patients, recent trials demonstrate that a combination of ASA and dipyridamole (DP) or clopidogrel may be superior to ASA. Blocking the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may also reduce recurrent stroke. The ongoing PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial is designed to evaluate whether ASA + extended-release DP compared to clopidogrel, and whether telmisartan in addition to usual care in individuals after a stroke, will reduce the risk of further strokes. Methods: PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. Patients ≧50 years presenting with an ischemic stroke <120 days who were stable were randomized. The primary outcome for the trial is recurrent stroke, using a time-to-event analysis. The most important secondary outcome is the composite of stroke, myocardial infarction or vascular death. Other secondary outcomes include this composite + congestive heart failure, new-onset diabetes, other designated occlusive vascular events (pulmonary embolism, deep-vein thrombosis, peripheral arterial occlusion, transient ischemic attack, cerebral venous thrombosis or retinal vascular accident not classified as stroke), any death, stroke subtype by TOAST criteria and Mini Mental State Examination score. Safety is evaluated by assessing the risk of major hemorrhagic events. The comparison between ASA + DP and clopidogrel is based on an initial assessment of noninferiority, followed by evaluation of superiority, while for telmisartan, we will assess its superiority over placebo. Results: With over 20,000 patients randomized, and utilizing a 2 × 2 factorial design, PRoFESS is the largest stroke trial to investigate the prevention of recurrent stroke. The mean age was 66.1 ± 8.6 years, and 36.0% of the patients were females. The median time from qualifying event to randomization was 15 days with 39.9% of patients randomized within 10 days. According to the TOAST criteria, 28.5% of the strokes were due to large-vessel disease, 52.1% to small-vessel disease, 1.8% to cardioembolism, and 2.0% to other determined etiologies and 15.5% were of undetermined etiology. Conclusions: PRoFESS is the largest secondary stroke prevention trial to date and will directly compare two antiplatelet regimens as well as the benefit of telmisartan versus placebo.

背景：短暂性脑缺血发作与缺血性脑卒中患者存在较高的卒中复发及死亡风险。尽管乙酰水杨酸（acetylsalicylic acid, ASA，即阿司匹林）已被证实并公认作为此类患者的标准治疗方案，但近期临床试验表明，乙酰水杨酸与双嘧达莫（dipyridamole, DP）联合或乙酰水杨酸与氯吡格雷联合的治疗方案可能优于单用乙酰水杨酸。通过血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂阻断肾素-血管紧张素系统，同样可降低卒中复发风险。正在进行中的PRoFESS试验（全称：Prevention Regimen for Effectively Avoiding Second Strokes，有效避免二次卒中预防方案）旨在评估两个核心问题：其一，相较于氯吡格雷，乙酰水杨酸+缓释型双嘧达莫的方案效果如何；其二，卒中患者在常规治疗基础上加用替米沙坦（telmisartan）能否降低进一步卒中的风险。方法：PRoFESS是一项多中心、随机双盲试验，覆盖35个国家或地区的695个研究中心。纳入年龄≥50岁、发病于120天内且病情稳定的缺血性脑卒中患者进行随机分组。试验的主要终点为卒中复发，采用时间-事件分析方法进行评估。最关键的次要终点为卒中、心肌梗死或血管性死亡的复合终点。其他次要终点包括上述复合终点加充血性心力衰竭、新发糖尿病、其他指定的闭塞性血管事件（肺栓塞、深静脉血栓形成、外周动脉闭塞、短暂性脑缺血发作、脑静脉血栓形成或未归类为卒中的视网膜血管意外）、全因死亡、按TOAST标准分型的卒中亚型，以及简易精神状态检查（Mini Mental State Examination, MMSE）评分。安全性通过评估重大出血事件的发生风险进行评价。乙酰水杨酸+双嘧达莫与氯吡格雷的比较将首先进行非劣效性初步评估，随后开展优效性分析；而对于替米沙坦，将评估其相较于安慰剂的优效性。结果：PRoFESS试验共纳入超20000名随机分组患者，采用2×2析因设计，是目前规模最大的卒中复发预防相关临床试验。受试者平均年龄为66.1±8.6岁，女性占比36.0%。从确诊卒中到随机分组的中位时间为15天，39.9%的患者在发病后10天内完成随机分组。按TOAST标准分型，28.5%的卒中为大血管病变所致，52.1%为小血管病变所致，1.8%为心源性栓塞所致，2.0%为其他明确病因所致，另有15.5%的卒中病因未明确。结论：PRoFESS是截至目前规模最大的继发性卒中预防试验，将直接对比两种抗血小板治疗方案的效果，并评估替米沙坦相较于安慰剂的临床获益。