SOCRATES 研究（阿司匹林或替格瑞洛治疗的急性卒中和短暂性脑缺血发作以及患者结局）中，短暂性脑缺血发作或急性缺血性卒中患者接受替格瑞洛与阿司匹林治疗后的大出血风险
Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).
机构信息
From Department of Neurology, University of California, San Francisco (J.D.E.); AstraZeneca, Gothenburg, Sweden (M.A., S.B.-S., H.D., P.H., M.J., J.J.); Stanford University Medical Center, Stanford Stroke Center, Palo Alto, CA (G.W.A.); Department of Neurology and Stroke Center, Bichat University Hospital and Medical School, Paris, France (P.A.); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA (S.R.E.); National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (K.M.); Stroke Unit, Hospital Vall d'Hebron, Barcelona, Spain (C.A.M.); Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China (Y.W.); Department of Medicine and Therapeutics, Chinese University of Hong Kong, China (K.S.L.W.); and Dean's Office, Dell Medical School, University of Texas, Austin (S.C.J.).
出版信息
Circulation. 2017 Sep 5;136(10):907-916. doi: 10.1161/CIRCULATIONAHA.117.028566. Epub 2017 Jun 27.
BACKGROUND
Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH).
METHODS
An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population.
RESULTS
A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor.
CONCLUSIONS
Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.
背景
轻度急性缺血性卒中和短暂性脑缺血发作的患者存在随后发生卒中的高风险，需要在急性期使用更强效的抗血小板治疗。然而，必须评估更强烈的抗血小板治疗的潜在益处与大出血风险之间的关系。SOCRATES 试验（急性卒中和短暂性脑缺血发作患者接受阿司匹林或替格瑞洛治疗和患者结局）是首个在急性缺血性卒中和短暂性脑缺血发作患者中使用替格瑞洛的试验，比较了替格瑞洛与阿司匹林的疗效和安全性。主要安全性终点是评估 PLATO（血小板抑制和患者结局）定义的治疗相关主要出血，特别关注颅内出血（ICH）。
方法
一个独立的裁判委员会对出血情况进行了盲法评估，使用了 PLATO、TIMI（心肌梗死溶栓）和 GUSTO（全球应用开放阻塞冠状动脉策略）的定义。ICH 和大出血的定义排除了脑微出血和脑梗死的无症状出血性转化，以便更好地在急性卒中人群中区分重要事件。
结果
共纳入 13199 例随机患者中的 13130 例至少接受了 1 次研究药物治疗，并纳入安全性分析集。替格瑞洛组有 31 例（0.5%）患者发生 PLATO 大出血，阿司匹林组有 38 例（0.6%）患者发生大出血（危险比，0.83；95%置信区间，0.52-1.34）。大出血最常见的部位是颅内和胃肠道。替格瑞洛组有 12 例（0.2%）患者发生 ICH，阿司匹林组有 18 例（0.3%）患者发生 ICH。30 例 ICH 中有 13 例（替格瑞洛 4 例，阿司匹林 9 例）为出血性卒中，4 例（每组 2 例）为脑梗死的症状性出血性转化。ICH 中自发性出血 6 例，创伤性出血 3 例，操作相关出血 3 例。替格瑞洛组共发生 9 例致命性出血，阿司匹林组发生 4 例。ICH 或致命性出血的复合终点包括替格瑞洛组 15 例和阿司匹林组 18 例。独立于出血分类、PLATO、TIMI 或 GUSTO，两种治疗方法在大出血或严重出血方面的相对差异相似。替格瑞洛组非主要出血更为常见。
结论
替格瑞洛治疗急性缺血性卒中和短暂性脑缺血发作患者的抗血小板治疗方案与阿司匹林相比，出血情况相似。ICH 较少见。
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