POINT: Platelet-Oriented Inhibition in New TIA

描述(申请人提供)：短暂性脑缺血发作(TIA)很常见，估计每年在美国发生250,000-350,000例，发病率约为中风的30-40%。脑缺血的快速恢复是短暂性脑缺血发作的一个显著特征，它与完全性卒中不同。这种恢复定义了一个独特的病理生理特征，通常表明先前缺血组织的存在仍处于危险之中：这一特征可能导致更大的不稳定性。事实上，许多研究表明，TIA后中风的短期风险很高，特别是在最初的几天，即使是接受阿司匹林治疗的患者也是如此，阿司匹林是目前的治疗标准。抗血栓治疗可能在这一急性病理生理学中起着独特的作用。对于短暂性脑缺血发作患者，如果立即开始有效的治疗，可以显著减轻中风的总体负担。然而，还没有大规模试验对短暂性脑缺血发作患者的急性干预进行评估。与其他形式的脑缺血一样，血小板聚集是脑缺血的一个重要因素。在具有不同病理生理机制的各种环境中，抗血小板药物可降低缺血性中风的风险。给有中风或短暂性脑缺血发作病史的患者服用阿司匹林可降低随后发生中风的风险。此外，阿司匹林在中风后作为一种急性干预措施开始使用，可降低死亡和中风复发的风险。卒中/短暂性脑缺血发作后联合应用氯吡格雷和阿司匹林的试验表明，这种联合治疗降低了中风的风险，但增加了大出血的风险。然而，TIA后急性期血栓形成的风险极高，出血风险预计低于完全中风后，因此在这种情况下，联合治疗可能特别有效和相对安全。更令人信服的是，在一项对392名轻微中风或短暂性脑缺血发作后急性治疗的患者进行的试点试验中，氯吡格雷与阿司匹林联合使用，与单独使用阿司匹林相比，90天的中风风险降低了36%，而且耐受性很好。抗血小板治疗从来没有在关键试验中被测试为TIA后的急性干预，这一环境具有明显的病理生理学，可能有利于这类药物的使用。我们建议在新的TIA(POINT)试验中采用血小板导向抑制。这项随机、双盲、多中心临床试验的主要具体目标是确定在每天服用阿司匹林50-325毫克的患者在短暂性脑缺血发作后12小时内开始服用氯吡格雷75毫克/天后，是否能有效地降低中风、心肌梗死和血管死亡(主要的综合结果)的90天风险。我们计划在4年内在150个中心招募4150名患者。我们将与NINDS神经紧急情况治疗试验(NETT)网络和临床研究合作(CRC)合作，后者将负责现场监测和数据管理。很少有像TIA这样常见和不祥的情况没有进行过关键的随机试验。事实上，考虑到这一领域的明显需求，提出这样一项试验仍然具有高度的创新性，这一点令人震惊。

DESCRIPTION (provided by applicant): Transient ischemic attacks (TIA) are common, with an estimated 250,000-350,000 occurring each year in the US, an incidence about 30-40% that of stroke. Rapid recovery of cerebral ischemia is a defining characteristic of TIA and distinguishes it from completed stroke. This recovery defines a distinct pathophysiologic feature that generally indicates the presence of previously ischemic tissue still at risk: a characteristic that may be responsible for greater instability. In fact, numerous studies have shown that short-term risk of stroke is high after TIA, particularly in the first few days, even in patients treated with aspirin, the current standard of care. Antithrombotic therapy may play a distinct role in this acute pathophysiology. Effective therapies in those with TIA could significantly reduce the overall burden of stroke if initiated immediately. However, no large-scale trial has evaluated an acute intervention in patients with TIA. Platelet aggregation is an important contributing factor in cerebral ischemia, as in other forms of ischemia. Antiplatelet agents reduce the risk of ischemic stroke in a variety of settings with distinct pathophysiologies. Aspirin given to patients with a history of stroke or TIA reduces subsequent risk of stroke. Furthermore, aspirin initiated as an acute intervention after stroke reduces risk of death and recurrent stroke. Trials of clopidogrel in combination with aspirin after stroke/TIA suggest that the combination reduces risk of stroke but increases risk of major hemorrhage. However, the risk of thrombosis is extremely high in the acute period after TIA and risk of hemorrhage is expected to be lower than after a completed stroke, so the combination may be particularly effective and relatively safe in this setting. Even more compelling, clopidogrel in combination with aspirin reduced the 90-day risk of stroke by 36% compared to aspirin alone in a pilot trial of 392 patients treated acutely after minor stroke or TIA, and it was well tolerated. Antiplatelet therapy has never been tested in a pivotal trial as an acute intervention after TIA, a setting with distinct pathophysiology that may favor the use of this class of agents. We are proposing the Platelet-Oriented Inhibition in New TIA (POINT) trial. The Primary Specific Aim of this randomized, double-blind, multicenter clinical trial is to determine whether clopidogrel 75 mg/day by mouth after a loading dose of 600 mg is effective in reducing the 90-day risk of stroke, myocardial infarction, and vascular death (the primary composite outcome) when initiated within 12 hours of TIA onset in patients receiving aspirin 50-325 mg/day. We plan to enroll 4150 patients at 150 centers over 4 years. We will work with the NINDS Neurologic Emergencies Treatment Trials (NETT) network and the Clinical Research Collaboration (CRC), which will be responsible for site monitoring and data management. There are few conditions as common and ominous as TIA for which no pivotal randomized trial has been performed. In fact, it is startling that proposing such a trial remains highly innovative given the obvious need in this area.