Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Neurology, Weihai Wendeng District People's Hospital, Shandong, China.
JAMA Netw Open. 2024 Sep 3;7(9):e2431938. doi: 10.1001/jamanetworkopen.2024.31938.
Prior trials showed that dual antiplatelet therapy could reduce the risk of early new stroke in patients with acute mild ischemic stroke or transient ischemic attack (TIA) within 24 hours of symptom onset. However, it is currently uncertain whether dual antiplatelet therapy can reduce the risk of early new stroke in patients with a more delayed initiation time window.
To evaluate the efficacy and safety of clopidogrel and aspirin among patients with mild ischemic stroke or TIA when initiated within 24 hours, from more than 24 hours to 48 hours, and from more than 48 hours to 72 hours.
DESIGN, SETTING, AND PARTICIPANTS: The Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis randomized clinical trial was a double-blind, placebo-controlled, multicenter, 2-by-2 factorial randomized clinical trial conducted at 222 hospitals in China from September 17, 2018, to October 15, 2022. All patients with acute mild ischemic stroke and TIA were included in this subgroup analysis and categorized into 3 groups according to time from symptom onset to randomization (group 1: ≤24 hours; group 2: >24 to ≤48 hours; and group 3: >48 to 72 hours). Patients were followed up for 90 days.
All patients received clopidogrel combined with aspirin (clopidogrel 300 mg loading dose on day 1, followed by 75 mg daily on days 2 to 90, and aspirin 100 to 300 mg on the first day and then 100 mg daily for days 2 to 90) or aspirin alone (100 to 300 mg on day 1 and then 100 mg daily for days 2 to 90) within 72 hours after symptom onset.
The primary outcome was new stroke (ischemic or hemorrhagic) within 90 days. The primary safety outcome was moderate-to-severe bleeding, according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria.
This analysis included a total of 6100 patients (3050 in the clopidogrel-aspirin group and 3050 in the aspirin group). The median age was 65 years (IQR, 57-71 years), and 3915 patients (64.2%) were male. In the population with time to randomization of 24 hours or less, stroke occurred in the next 90 days in 97 of 783 patients (12.4%); among those randomized from more than 24 hours to 48 hours, in 211 of 2552 patients (8.3%) among those randomized from more than 24 hours to 48 hours, and in 193 of 2765 patients (7.0%). The clopidogrel-aspirin group had a lower risk of new stroke within 90 days compared with the aspirin alone group both in patients with time to randomization of from 48 to 72 hours (5.8% vs 8.2%; hazard ratio [HR], 0.70 [95% CI, 0.53-0.94]), of more than 24 to 48 hours (7.6% vs 8.9%; HR, 0.85 [95% CI, 0.65-1.12]), and of 24 hours or less (11.5% vs 13.4%; HR, 0.83 [95% CI, 0.55-1.25]) (P = .38 for interaction). Among those with time to randomization of more than 48 to 72 hours, moderate-to-severe bleeding occurred in 12 patients (0.9%) in the clopidogrel-aspirin group and in 6 patients (0.4%) in the aspirin-alone group (HR, 2.00 [95% CI, 0.73-5.43]), while moderate-to-severe bleeding in those with time to randomization of more than 24 hours to 48 hours occurred in 9 patients (0.7%) in the clopidogrel-aspirin group and in 4 patients (0.3%) in the aspirin-alone group (HR, 2.25 [95% CI, 0.68-7.39]) and in those with time to randomization of within 24 hours, occurred in 6 patients (1.5%) in the clopidogrel-aspirin group and in 3 patients (0.8%) in the aspirin-alone group (HR, 1.57 [95% CI, 0.36-6.83]) (P = .92 for interaction).
In this randomized clinical trial of antiplatelet therapy in China, patients with mild ischemic stroke or TIA had consistent benefit from dual antiplatelet therapy with clopidogrel and aspirin vs aspirin alone when initiated within 72 hours after symptom onset, with a similar increase in the risk of moderate-to-severe bleeding. Patients should receive dual antiplatelet therapy with clopidogrel and aspirin within 72 hours after symptom onset.
ClinicalTrials.gov Identifier: NCT03635749.
先前的试验表明，在症状发作后 24 小时内，双重抗血小板治疗可以降低急性轻度缺血性卒中和短暂性脑缺血发作（TIA）患者的早期新发卒中风险。然而，目前尚不确定在更延迟的起始时间窗内，双重抗血小板治疗是否可以降低早期新发卒中的风险。
评估在症状发作后 24 小时内、24 至 48 小时内和 48 至 72 小时内开始使用氯吡格雷和阿司匹林治疗轻度缺血性卒中和 TIA 患者的疗效和安全性。
设计、地点和参与者：强化他汀类药物和抗血小板治疗急性高颅内或颅外动脉粥样硬化随机临床试验是一项在中国 222 家医院进行的双盲、安慰剂对照、多中心、2x2 析因随机临床试验，于 2018 年 9 月 17 日至 2022 年 10 月 15 日进行。所有急性轻度缺血性卒中和 TIA 患者均纳入本亚组分析，并根据症状发作至随机分组的时间分为 3 组（组 1：≤24 小时；组 2：＞24 至≤48 小时；组 3：＞48 至 72 小时）。患者随访 90 天。
所有患者均在症状发作后 72 小时内接受氯吡格雷联合阿司匹林（氯吡格雷 300mg 负荷剂量，第 1 天，然后第 2 天至第 90 天每天 75mg，第 1 天阿司匹林 100 至 300mg，然后第 2 天至第 90 天每天 100mg）或阿司匹林单药治疗（第 1 天 100 至 300mg，然后第 2 天至第 90 天每天 100mg）。
主要结局为 90 天内新发卒中（缺血性或出血性）。主要安全性结局为根据全球应用链激酶和组织型纤溶酶原激活剂治疗闭塞冠状动脉标准确定的中度至重度出血。
本分析共纳入 6100 例患者（氯吡格雷-阿司匹林组 3050 例，阿司匹林组 3050 例）。中位年龄为 65 岁（IQR，57-71 岁），3915 例（64.2%）为男性。在随机时间为 24 小时或更短的人群中，90 天内有 783 例（12.4%）患者发生新发卒中；在随机时间为 24 至 48 小时的患者中，2552 例中有 211 例（8.3%），在随机时间为 48 至 72 小时的患者中，2765 例中有 193 例（7.0%）。与阿司匹林单药治疗相比，氯吡格雷-阿司匹林组在随机时间为 48 至 72 小时（5.8%比 8.2%；风险比[HR]，0.70[95%CI，0.53-0.94]）、24 至 48 小时（7.6%比 8.9%；HR，0.85[95%CI，0.65-1.12]）和 24 小时或更短（11.5%比 13.4%；HR，0.83[95%CI，0.55-1.25]）时，90 天内新发卒中的风险均较低（交互 P=0.38）。在随机时间为 48 至 72 小时的患者中，氯吡格雷-阿司匹林组有 12 例（0.9%）发生中度至重度出血，阿司匹林组有 6 例（0.4%）（HR，2.00[95%CI，0.73-5.43]），而在随机时间为 24 至 48 小时的患者中，氯吡格雷-阿司匹林组有 9 例（0.7%）发生中度至重度出血，阿司匹林组有 4 例（0.3%）（HR，2.25[95%CI，0.68-7.39]），在随机时间为 24 小时内的患者中，氯吡格雷-阿司匹林组有 6 例（1.5%）发生中度至重度出血，阿司匹林组有 3 例（0.8%）（HR，1.57[95%CI，0.36-6.83]）（交互 P=0.92）。
在这项中国抗血小板治疗的随机临床试验中，轻度缺血性卒中和 TIA 患者在症状发作后 72 小时内接受氯吡格雷和阿司匹林双联抗血小板治疗与阿司匹林单药治疗相比，均具有一致的获益，且中度至重度出血风险增加。患者应在症状发作后 72 小时内接受氯吡格雷和阿司匹林双联抗血小板治疗。
ClinicalTrials.gov 标识符：NCT03635749。
