POINT: Platelet-Oriented Inhibition in New TIA

描述（由申请人提供）：短暂性脑缺血发作（TIA）很常见，在美国每年估计发生25万-35万例，发病率约为中风的30-40%。脑缺血的快速恢复是TIA的一个决定性特征，并将其与完全中风区分开来。这种恢复定义了一种独特的病理生理特征，通常表明先前缺血组织仍处于危险之中：这种特征可能导致更大的不稳定性。事实上，大量研究表明，TIA后短期中风的风险很高，尤其是在最初几天，即使是服用阿司匹林（目前的标准治疗方法）的患者。抗血栓治疗可能在这种急性病理生理中起着独特的作用。如果立即开始对TIA患者进行有效的治疗，可以显著减少卒中的总体负担。然而，尚无大规模试验评估TIA患者的急性干预措施。与其他形式的缺血一样，血小板聚集是脑缺血的重要促成因素。抗血小板药物降低缺血性卒中的风险，在各种设置不同的病理生理。有中风或短暂性脑缺血发作史的患者服用阿司匹林可降低随后发生中风的风险。此外，阿司匹林作为中风后的急性干预可以降低死亡和复发性中风的风险。卒中/TIA后氯吡格雷联合阿司匹林的试验表明，联合用药可降低卒中风险，但增加大出血风险。然而，在TIA后的急性期，血栓形成的风险非常高，出血的风险预计比完全中风后的风险低，因此在这种情况下，联合用药可能特别有效且相对安全。更令人信服的是，在392例轻度中风或短暂性脑缺血发作后急性治疗的患者中，氯吡格雷与阿司匹林联合使用比单独使用阿司匹林降低了90天卒中风险36%，并且耐受性良好。抗血小板治疗从未在关键试验中作为TIA后的急性干预进行过测试，具有不同病理生理的环境可能有利于使用这类药物。我们建议在新TIA （POINT）试验中进行血小板导向抑制。这项随机、双盲、多中心临床试验的主要目的是确定在服用阿司匹林50-325 mg/天的TIA患者发病后12小时内口服氯吡格雷75 mg/天是否有效降低90天卒中、心肌梗死和血管性死亡（主要复合结局）的风险。我们计划在4年内在150个中心招募4150名患者。我们将与NINDS神经急救治疗试验（NETT）网络和临床研究协作（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，令人吃惊的是，考虑到这一领域的明显需求，提出这样一项试验仍然是高度创新的。

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. PUBLIC HEALTH RELEVANCE: Transient ischemic attacks (TIAS) are common, with an estimated 250,000-350,000 occurring each year in the US, and the risk of stroke risk is very high soon afterwards in spite of the best available treatments. In this randomized, blinded, multicenter trial, we will evaluate clopidogrel, a drug that blocks blood clotting, as a treatment to reduce risk of stroke and heart attack after TIA in patients also prescribed aspirin. If the trial is positive, treatment with clopidogrel could reduce the stroke burden in the US and substantially reduce costs of care.