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)

<i>Background:</i> 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. <i>Methods:</i> PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. Patients ≧50 years presenting with an ischemic stroke &lt;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. <i>Results:</i> 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. <i>Conclusions:</i> 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.

<i>背景:</i> 短暂性脑缺血发作(transient ischemic attack, TIA)与缺血性脑卒中(ischemic stroke)患者面临较高的卒中复发及死亡风险。尽管乙酰水杨酸(acetylsalicylic acid, ASA，又名阿司匹林)已被证实并认可为该类患者的标准治疗方案，但近期多项临床试验表明，联合应用ASA与双嘧达莫(dipyridamole, DP)或氯吡格雷(clopidogrel)的疗效可能优于单用ASA。通过血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitors, ACEI)或血管紧张素Ⅱ受体拮抗剂(angiotensin Ⅱ receptor blockers, ARB)阻断肾素-血管紧张素系统(renin-angiotensin system, RAS)，同样可降低卒中复发风险。正在开展的有效预防第二次卒中方案(Prevention Regimen for Effectively Avoiding Second Strokes, PRoFESS)试验旨在评估两个核心问题：其一，ASA联合缓释型双嘧达莫对比氯吡格雷的疗效差异；其二，在常规治疗基础上加用替米沙坦(telmisartan)能否降低卒中患者的后续卒中风险。
<i>方法:</i> PRoFESS试验为一项多中心、随机双盲临床试验，覆盖全球35个国家或地区的695个研究中心。入组标准为年龄≥50岁、距缺血性卒中发作时间<120天且病情稳定的患者，按随机化原则分组。本试验的主要终点为卒中复发，采用时间-事件分析法(time-to-event analysis)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。其余次要终点包括上述复合终点联合充血性心力衰竭(congestive heart failure)、新发糖尿病(new-onset diabetes)、其他指定的闭塞性血管事件（肺栓塞(pulmonary embolism)、深静脉血栓形成(deep-vein thrombosis)、外周动脉闭塞(peripheral arterial occlusion)、短暂性脑缺血发作、未归类为卒中的脑静脉血栓形成(cerebral venous thrombosis)或视网膜血管意外(retinal vascular accident)）、任何原因的死亡、按TOAST分型标准(TOAST criteria)划分的卒中亚型以及简易精神状态检查表(Mini Mental State Examination, MMSE)评分。安全性通过评估重大出血事件(major hemorrhagic events)的发生风险进行评价。ASA+DP与氯吡格雷的比较将首先开展非劣效性(noninferiority)初步评估，随后进行优效性(superiority)检验；而替米沙坦与安慰剂(placebo)的对比则直接评估其优效性。
<i>结果:</i> 本试验共纳入超20000例随机化患者，采用2×2析因设计(2 × 2 factorial design)，是迄今为止规模最大的旨在探索卒中二级预防的临床试验。入组患者的平均年龄为66.1±8.6岁，其中女性占比36.0%。从合格事件到随机分组的中位时间为15天，39.9%的患者在事件发生后10天内完成随机分组。依据TOAST分型标准，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。
<i>结论:</i> 有效预防第二次卒中方案(PRoFESS)试验是迄今为止规模最大的卒中二级预防临床试验，将直接对比两种抗血小板治疗方案的疗效，并评估替米沙坦对比安慰剂的临床获益。