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，估计在美国每年发生250，000 - 350，000例，发病率约为中风的30-40%。脑缺血的快速恢复是TIA的定义特征，并将其与完全性卒中区分开来。这种恢复定义了一个独特的病理生理学特征，通常表明先前缺血组织的存在仍然处于危险之中：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后的短期中风风险很高，特别是在最初几天，即使在使用阿司匹林（目前的标准治疗）治疗的患者中。抗血栓治疗可能在这种急性病理生理学中发挥独特的作用。如果立即开始，TIA患者的有效治疗可以显著降低卒中的总体负担。然而，没有大规模的试验评估了TIA患者的急性干预。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。抗血小板药物可降低各种不同病理生理条件下缺血性卒中的风险。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，阿司匹林作为中风后的急性干预措施，可降低死亡和复发性中风的风险。中风/短暂性脑缺血发作后氯吡格雷联合阿司匹林的试验表明，联合用药可降低中风风险，但增加大出血风险。然而，TIA后急性期血栓形成的风险极高，预计出血风险低于完全卒中后，因此该组合在这种情况下可能特别有效且相对安全。更令人信服的是，在一项对392例轻微卒中或TIA后接受急性治疗的患者进行的初步试验中，与阿司匹林单药相比，氯吡格雷联合阿司匹林使90天卒中风险降低了36%，并且耐受性良好。抗血小板治疗从未在关键性试验中作为TIA后的急性干预进行过测试，TIA具有独特的病理生理学，可能有利于使用此类药物。我们正在提议新TIA中的血小板导向抑制（POINT）试验。这项随机、双盲、多中心临床试验的主要具体目的是确定在接受阿司匹林50-325 mg/天的患者中，在TIA发作12小时内开始给予负荷剂量600 mg后口服氯吡格雷75 mg/天是否能有效降低卒中、心肌梗死和血管性死亡（主要复合结局）的90天风险。我们计划在4年内在150个中心招募4150例患者。我们将与NINDS神经系统紧急情况治疗试验（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，对此没有进行关键的随机试验。事实上，考虑到这一领域的明显需要，提出这样一项试验仍然具有很高的创新性，这令人吃惊。 公共卫生相关性：短暂性脑缺血发作（TIAS）很常见，在美国每年估计发生250，000 - 350，000例，尽管有最好的治疗方法，但卒中风险很快就会很高。在这项随机、盲法、多中心试验中，我们将评估氯吡格雷（一种阻断血液凝固的药物）作为一种治疗方法，以降低TIA后中风和心脏病发作的风险。如果试验结果呈阳性，氯吡格雷治疗可以减轻美国的中风负担，并大幅降低护理成本。

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.