From the Department of Emergency Medicine, Washington University, St. Louis (O.A., P.P., S.P.); the Departments of Neurology and Rehabilitation Medicine (J.B., I.D., S.D., M.H., P.K.), Emergency Medicine (A.P.), and Radiology (A.V.), University of Cincinnati, and the Department of Pharmacy, University of Cincinnati Medical Center (N.S.) - both in Cincinnati; the Department of Radiology, University of Virginia, Charlottesville (C.P.D.); the Clinical Institute for Research and Innovation, Memorial Hermann Hospital (J.C.G.), the Department of Neuroradiology, University of Texas M.D. Anderson Cancer Center (M.W.), and the Department of Neurology, University of Texas Health Science Center (A.D.B.), Houston, Berry Consultants, Austin (S.B., T.G.), and the Texas Stroke Institute, Medical City Healthcare, Dallas (A.J.Y.) - all in Texas; the Department of Emergency Medicine, University of Michigan, Ann Arbor (W.B.), and the Department of Neurology, McLaren Flint, Flint (A.M.) - both in Michigan; the Department of Neurology, University of Minnesota, Minneapolis (O.B., C.S.); the Department of Neurology, Sarasota Memorial Hospital, Intercoastal Medical Group, Sarasota (M.C.), and the Department of Neurology, Mayo Clinic, Jacksonville (J.H.) - both in Florida; the Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.E., J.I.), and the Department of Medicine (Neurology), Prisma Health-Upstate, University of South Carolina Greenville School of Medicine, Greenville (S.S.); the Department of Emergency Medicine, Temple University, Philadelphia (N.G.); the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (S.J.); the Department of Neurology, Yale University, New Haven, CT (A.S.J.); the Departments of Neurology and Emergency Medicine, State University of New York, New York (S.R.L.); the Department of Neurology, Wake Forest University, Winston-Salem, NC (T.R.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.W.).
N Engl J Med. 2024 Sep 5;391(9):810-820. doi: 10.1056/NEJMoa2314779.
BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).
背景：静脉溶栓是急性缺血性脑卒中的标准治疗方法。联合使用静脉溶栓药物阿加曲班（一种抗凝剂）或依替巴肽（一种抗血小板药物）的疗效和安全性尚不清楚。
方法：我们在美国 57 个地点进行了一项 3 期、3 组、适应性、单盲、随机、对照临床试验。发病后 3 小时内接受静脉溶栓的急性缺血性脑卒中患者，在溶栓开始后 75 分钟内被分配接受静脉注射阿加曲班、依替巴肽或安慰剂。主要疗效终点为使用集中评估的效用加权 90 天改良 Rankin 量表评分（范围 0 至 10，得分越高代表结果越好）。主要安全性终点为随机分组后 36 小时内出现症状性颅内出血。
结果：共有 514 例患者被分配接受阿加曲班（59 例）、依替巴肽（227 例）或安慰剂（228 例）治疗。所有患者均接受静脉溶栓治疗（70%接受阿替普酶，30%接受替奈普酶），225 例（44%）患者接受血管内血栓切除术。90 天时，阿加曲班组的平均（±SD）效用加权改良 Rankin 量表评分（mRS）为 5.2±3.7，依替巴肽组为 6.3±3.2，安慰剂组为 6.8±3.0。阿加曲班优于安慰剂的后验概率为 0.002（后验平均差异为 1.51±0.51），依替巴肽优于安慰剂的后验概率为 0.041（后验平均差异为 0.50±0.29）。三组症状性颅内出血发生率相似（阿加曲班组 4%，依替巴肽组 3%，安慰剂组 2%）。阿加曲班组（24%）和依替巴肽组（12%）90 天死亡率高于安慰剂组（8%）。
结论：在发病后 3 小时内接受静脉溶栓治疗的急性缺血性脑卒中患者中，联合应用静脉阿加曲班或依替巴肽不能降低卒中后残疾程度，反而与死亡率升高相关。（由美国国立神经病学与卒中研究所资助；MOST ClinicalTrials.gov 编号，NCT03735979）。
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