SECONDARY PREVENTION OF SMALL SUBCORTICAL STROKES (SPSS)

总体目标 小型皮质下卒中二级预防（SPS 3）项目的目的是 确定有效的治疗方法，以预防复发性卒中和认知功能下降的患者， 皮质下卒中（S3）（a.k.a.腔隙性梗塞）。美国近200万S3幸存者面临高风险 复发性中风和发展为血管性痴呆。此外，"无症状"（更准确地说， S3存在于约20%的65岁以上的人中。虽然S3可以由许多类型的 脑血管疾病，大多数是由于颅内脑小动脉疾病。最佳抗血小板药物 S3患者的治疗和抗高血压管理，以减少卒中复发和认知能力下降 还没有被定义，可能会产生重要的健康益处。虽然MRI定义的症状性S3在 没有可手术的颈动脉狭窄和主要危险的心源性栓塞是指标 参与SPS3的事件和复发性卒中是主要结局，SPS3的目标更广泛， 范围，包括评估和预防血管性痴呆。以前的临床试验没有解决 尤其是S3患者。SPS3将确定最佳治疗，以防止复发 无动脉内膜切除术或抗凝治疗指征的S3患者的卒中和认知能力下降。 S3在西班牙裔中特别常见，是最常见的中风亚型之一。 是否S3的预后和积极控制血压和加强 抗血小板治疗在西班牙裔中的重要差异也是未知的，这些问题将在 由SPS3处理。 SPS 3旨在通过两个同时有效地解决几个重要的临床和科学问题， 临床试验加上对可能影响预后的特征进行仔细的前瞻性分析， 对干预措施的回应。由于高血压是S3最普遍和最有力的风险因素， 抗血小板治疗是二级预防的标准治疗， 血压控制和抗血小板治疗最好一起进行。 具体目的：确定预防卒中复发和认知功能下降的有效疗法 有症状的S3患者。SPS3的核心包括两项随机临床试验，涉及2500名 有症状的S3参与者在析因设计中随机接受两种干预措施。 主要目标： A）确定阿司匹林（325 mg/d）加氯吡格雷的联合抗血小板治疗是否 (75在减少卒中复发（主要终点）、认知功能恢复（主要终点）方面优于阿司匹林（325 mg/d）。 下降和主要血管事件。 B）确定将血压"强化"降低到特定目标范围是否优于"常规" 高血压管理，以减少复发性卒中、认知能力下降和主要血管事件。 次要目的： 比较联合抗血小板治疗与阿司匹林的绝对获益差异， 西班牙裔参与者与非西班牙裔参与者之间的"强化"血压降低与"常规控制" 白色参与者。 你好西班牙裔将从联合抗血小板药物中获得更大的获益（绝对风险降低） 治疗和从"强化"血压控制预防中风复发比非西班牙裔 白人，因为他们中风复发率更高。 此外，纳入20%的西班牙裔参与者将有助于描述该人群中的S3， 包括卒中复发率和风险因素、认知能力下降的发生率和风险因素、 抗血小板干预和对血压控制干预的反应。 SPS的重要性/相关性3.美国每年至少发生20万起S3，近两个 100万S3幸存者存在复发性卒中和血管性痴呆的高风险。目前尚不清楚如何以最佳方式 预防S3幸存者的卒中复发和认知障碍。没有临床试验专门针对 这个重要的常见中风亚型没有二级预防中风的研究测试不同的目标 中风幸存者的血压控制水平，尽管高血压作为最重要的 卒中的常见独立危险因素，尤其是S3。以前的中风研究都没有关注 西班牙裔; S3是这个增长最快的美国少数民族中最常见的中风亚型之一。额外 数百万美国人患有与大脑小动脉相关的"亚临床" S3和认知障碍 疾病; SPS3的结果也可能影响其管理。

OVERALL AIM The aim of the Secondary Prevention of Small Subcortical Strokes (SPS3) project is to define efficacious therapies for prevention of recurrent stroke and cognitive decline in patients with small subcortical strokes (S3) (a.k.a. lacunar infarcts). Nearly two million survivors of S3 in U.S. are at high risk for recurrent stroke and for developing vascular dementia. Additionally, "asymptomatic" (more accurately termed "subclinical") S3 are present in about 20% of people over age 65. While S3 can be caused by many types of cerebrovascular disorders, most are due to intracranial cerebral small artery disease. Optimal antiplatelet therapy and antihypertensive management of S3 patients to reduce stroke recurrence and cognitive decline has not been defined and is likely to yield important health benefits. Although MRI-defined symptomatic S3 in the absence of surgically amenable cervical carotid stenosis and major-risk cardioembolic sources is the index event for participation in SPS3 and recurrent stroke is the primary outcome, the goals of SPS3 are broader in scope and include assessment and prevention of vascular dementia. No previous clinical trials have addressed these important issues specifically in S3 patients. SPS3 will define optimal treatment to prevent recurrent stroke and cognitive decline for S3 patients without an indication for endarterectomy or anticoagulation. S3s are particularly frequent in Hispanics, in whom they are one of the most common stroke subtypes. Whether the prognosis of S3 and the benefits of aggressive blood pressure control and of enhanced antiplatelet therapy are importantly different in Hispanic are also not known, and these issues will be addressed by SPS3. SPS3 seeks to efficiently address several important clinical and scientific questions through two simultaneous clinical trials coupled with careful, prospective analysis of features potentially influencing prognosis and response to interventions. Since hypertension is the most prevalent and powerful risk factor for S3, and antiplatelet therapy is the standard of care for secondary prevention, definition of the efficacy and safety of blood pressure control and antiplatelet therapy should optimally be tested together. SPECIFIC AIM: To define efficacious therapies for prevention of stroke recurrence and cognitive de-cline in patients with symptomatic S3. The core of SPS3 consists of two randomized clinical trials involving 2500 participants with symptomatic S3 randomized to two interventions in a factorial design. Primary Aims: A) To determine whether combination antiplatelet therapy consisting of aspirin (325 mg/d) plus clopidogrel (75 mg/d) is superior to aspirin (325 mg/d) for reducing stroke recurrence (the primary endpoint), cognitive decline and major vascular events. B) To determine whether "intensive" blood pressure lowering to a specific target range is superior to "usual" hypertension management for reducing recurrent stroke, cognitive decline and major vascular events. Secondary Aim: To compare the differences in absolute benefit of combination antiplatelet therapy vs. aspirin and of "intensive" blood pressure lowering vs. "usual control" between Hispanic participants vs. non-Hispanic white participants. Rationale'. Hispanics will have larger benefits (absolute risk reductions) from combination antiplatelet therapy and from "intensive" blood pressure control for prevention of stroke recurrence than non-Hispanic whites, based on their higher rate of recurrent stroke. In addition, the inclusion of 20% of Hispanic participants will serve to characterize S3 in this population, including stroke recurrence rate and risk factors, rate and risk factors for cognitive decline, response to antiplatelet intervention, and response to blood pressure control intervention. IMPORTANCE/RELEVANCE OF SPS3. At least 200,000 S3s occur annually in the U.S., with nearly two million S3 survivors at high risk for recurrent stroke and vascular dementia. It remains unclear how to optimally prevent stroke recurrence and cognitive impairment in S3 survivors. No clinical trials have specifically focused on this important, common stroke subtype. No secondary stroke prevention study has tested different target levels of blood pressure control in stroke survivors, despite the importance of hypertension as the most common independent risk factor for stroke, and particularly for S3. No previous stroke study has focused on Hispanics; S3 is one the most frequent stroke subtype among this fastest growing U.S. minority. Additional millions of Americans have "subclinical" S3 and cognitive impairment associated with cerebral small artery disease; the results of SPS3 will likely impact their management as well.