See related article, p 1190

Acute ischemic strokes and transient ischemic attacks (TIA) pose a high risk for recurrent stroke at 90 days. Prior studies have estimated this risk to be between 10% and 20%.^1,2 Antiplatelet therapy has been the mainstay of treatment for secondary prevention of noncardioembolic ischemic stroke in this cohort of patients. In recent years, 2 large randomized clinical trials conducted in diverse populations have demonstrated clinical benefit in prescribing dual antiplatelet therapy for the first 3 weeks after a minor stroke (National Institutes of Health Stroke Scale [NIHSS] <3) or TIA, specifically in selected patients with strokes not caused by atrial fibrillation or large artery extracranial atherosclerosis with planned carotid intervention.^3,4 Anticoagulation has previously been explored in patients with less severe noncardioembolic stroke to reduce early recurrence but has not been deemed safe due to high intracranial and systemic bleeding risks.^5,6

In this issue of Stroke, Butcher et al⁷ present the results of the DATAS II (Dabigatran Treatment of Non-Acute Cardioembolic Ischemic Stroke Trial), a phase II prospective, randomized, open label, blinded outcome trial comparing early use of dabigatran versus aspirin in patients with TIA or minor ischemic stroke, defined as NIHSS <9 and infarct volume <25 mL. A total of 305 adult patients were randomized to aspirin or dabigatran within 72 hours of stroke onset. The dose of dabigatran was adjusted according to renal function, and dabigatran was administered for 30 days followed by aspirin thereafter. This was a safety study, and the primary outcome was the development of a symptomatic hemorrhagic transformation within 37 days of randomization. Secondary outcomes included asymptomatic hemorrhagic transformation, asymptomatic progressive ischemic strokes observed on the day 30 magnetic resonance imaging, systemic bleeding, or the clinical presentation of a recurrent infarct.

It is important to note the inclusion and exclusion criteria for the trial. The index event for inclusion in the trial was ischemic stroke in 79% of patients, and the remainder were TIA. Baseline infarct volume was small at 3.2±6.5 mL and hence these patients were likely to have a low risk for hemorrhagic transformation. Patients with known atrial fibrillation or an indication for anticoagulation, as well as those who received a mechanical thrombectomy, or those needing imminent carotid revascularization were excluded from the study. Although the remainder of stroke patients are at risk for recurrent events, the risk is likely lower in this population except for those patients who might have undiagnosed paroxysmal atrial fibrillation.

Interestingly, although not surprisingly, there was no symptomatic hemorrhagic transformation observed in either arm. Even those with known cerebral microbleeds at baseline (10.1%, n=31) were not noted to have any hemorrhagic conversion. Asymptomatic hemorrhages (graded as hemorrhagic infarct 1) were seen more frequently on the day 30 magnetic resonance imaging scan in the dabigatran arm as compared with the aspirin arm (7.8% versus 3.5%). This finding is consistent with prior anticoagulant studies in ischemic stroke. The rate of recurrent clinical strokes were low in both groups at 30 days (3.9% dabigatran, 2.7% aspirin). Only 4 patients had documented atrial fibrillation during follow-up. Incidental asymptomatic infarcts, although low in number, seemed to be higher in volume in the dabigatran arm as compared with the aspirin arm. It is unclear why there is a difference in stroke volume, and the authors do not offer any plausible explanations.

Overall it may appear that dabigatran is safe to use in the early period (30 days) after a minor stroke or TIA. However, several cautionary points are worth noting. First, the results cannot be extrapolated to stroke types beyond minor strokes or TIAs as the median NIHSS was low (1, 0–2), and stroke volumes were extremely small. Second, although dabigatran did not result in an increased frequency of symptomatic hemorrhages, the risk for asymptomatic hemorrhages was doubled in the dabigatran arm as compared with aspirin alone. Third, this is a safety trial and does not speak to the efficacy of dabigatran in minor stroke and TIA. Fourth, clinicians around the world have likely made a transition in their practice after the POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) and CHANCE (Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events) trials were published and are using dual antiplatelet therapy in the first 21 days for patients with minor strokes (NIHSS <3) and TIA. It would be interesting to see how dabigatran fares in comparison to dual antiplatelet therapy and if the 2 therapies are relevant for 2 different sub populations within minor stroke and TIA. It is possible that those who benefit from dabigatran may have cortical, embolic appearing strokes of unknown source.

What is the take-home message? Dabigatran may be safe to use for minor stroke and TIA patients, with low NIHSS and stroke volumes <10 mL within the first 30 days after stroke onset. However, further studies that include patients with a broader spectrum of baseline deficits and infarct size are essential to determine if it is ready for prime time. Whether early anticoagulation offers any additional benefits beyond that of dual antiplatelet therapy needs to be established by further trials.

Dr Chaturvedi has received previous funding from Boehringer-Ingelheim for the ADIOS study (Arrhythmia Detection in Obstructive Sleep Apnea). The other author reports no conflicts.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Guest Editor for this article was Pooja Khatri, MD, MSc.

请参阅相关文章，第1190页

急性缺血性中风和短暂性脑缺血发作（TIA）在90天后复发性中风的风险很高。先前的研究估计这种风险在10％到20％之间。^1,2抗血小板疗法一直是该人群中非心脏栓塞性缺血性卒中二级预防的主要治疗手段。近年来，在不同人群中进行的2项大型随机临床试验表明，在轻度卒中（美国国立卫生研究院卒中量表[NIHSS] <3）或TIA（特别是在选定的人群中）后的前3周内开具双重抗血小板治疗的临床益处并非由房颤或大动脉颅外动脉粥样硬化引起的中风，并计划进行颈动脉介入治疗。^3,4先前已经在较轻的非心脏栓塞性卒中患者中进行了抗凝治疗，以减少早期复发，但由于颅内和全身出血的风险较高，因此尚未被认为是安全的。^5,6

在本期《中风》中，Butcher等人⁷给出了DATAS II（达比加群治疗非急性心脏栓塞性缺血性卒中试验）的结果，该研究为II期前瞻性，随机，开放标签，盲法试验，比较了达比加群和阿司匹林在TIA或轻度缺血性卒中患者中的早期使用，定义因为NIHSS <9和梗死体积<25 mL。共有305名成年患者在卒中发作后72小时内随机接受阿司匹林或达比加群治疗。达比加群的剂量根据肾功能进行调整，达比加群给药30天，随后服用阿司匹林。这是一项安全性研究，其主要结果是在随机分配的37天内出现了有症状的出血性转化。次要结果包括无症状的出血性转化，

重要的是要注意试验的纳入和排除标准。该试验纳入的指标事件是79％的患者发生缺血性卒中，其余为TIA。基线梗塞体积较小，为3.2±6.5 mL，因此这些患者出血转化的风险很低。有已知房颤或抗凝适应症的患者，以及接受机械血栓切除术的患者，或需要即将进行颈动脉血运重建的患者均排除在研究范围之外。尽管其余卒中患者有复发事件的风险，但该人群中的风险可能较低，除了那些可能未被诊断为阵发性房颤的患者。

有趣的是，尽管不足为奇，但在任何一方均未观察到症状性出血性转化。即使那些基线已知脑微出血的患者（10.1％，n = 31）也未发现有出血性转化。与阿司匹林组相比，达比加群组在第30天磁共振成像扫描中发现无症状出血（分级为出血性梗死1）的频率更高（7.8％比3.5％）。这一发现与先前在缺血性卒中中的抗凝研究一致。两组在30天时的复发性中风发生率均较低（达比加群3.9％，阿司匹林2.7％）。随访期间仅4例患者记录了房颤。偶发的无症状梗塞虽然数量较少，但与阿司匹林组相比，达比加群组的发生率似乎更高。

总体而言，达比加群似乎在轻度中风或TIA后的早期（30天）内可以安全使用。但是，有几点警告要注意。首先，由于中位NIHSS低（1、0–2）且中风量极小，因此无法将结果外推至中风或TIA以外的中风类型。其次，尽管达比加群并没有导致症状性出血的发生率增加，但与单独使用阿司匹林相比，达比加群组无症状性出血的风险增加了一倍。第三，这是一项安全性试验，并未说明达比加群在轻度卒中和TIA中的疗效。第四，在发表并发表了POINT（在新的TIA和轻度缺血性卒中中以血小板为导向的抑制作用）和CHANCE（在患有急性非致残性脑血管事件的高危患者中使用氯吡格雷）试验之后，世界各地的临床医生可能已在实践中进行了转变。对于轻度卒中（NIHSS <3）和TIA的患者，在头21天使用双重抗血小板治疗。有趣的是，观察达比加群与双重抗血小板治疗相比的情况如何，以及这两种疗法是否与轻度卒中和TIA内的两个不同亚人群相关。受益于达比加群的患者可能患有未知来源的皮质栓塞样中风。

带回家的消息是什么？达比加群对于卒中发作后最初30天内NIHSS低且卒中量<10 mL的轻度卒中和TIA患者可能是安全的。但是，包括基线缺陷和梗塞范围更广的患者在内的进一步研究对于确定是否准备好迎接黄金时段至关重要。早期抗凝治疗是否能提供双重抗血小板治疗以外的其他益处，还需要进一步的试验来确定。

Chaturvedi博士先前已获得勃林格殷格翰公司的ADIOS研究（阻塞性睡眠呼吸暂停中的心律失常检测）资助。另一位作者报告没有冲突。

本文表达的观点不一定是编辑者或美国心脏协会的观点。

本文的客座编辑是医学博士Pooja Khatri。