Objective: To assess outcome, safety and possible mechanism of loading dose clopidogrel in patients with transient ischemic attack (TIA) and minor stroke. Methods: We reviewed patients with confirmed TIA and minor stroke admitted between July 2016 and December 2017 into the First Affiliated Hospital of Soochow University. Loss-of-function allele carriers of CYP2C19 were included and randomly divided into loading dose group (first dose of 300 mg clopidogrel) and standard dose group (first dose of 75 mg clopidogrel), 100 mg aspirin was gave at the same time, followed by aspirin 100 mg/d plus clopidogrel 75 mg/d maintaining for 20 days. Platelet aggregation (maximum aggregation ratio, MAR) induced by Adenosine diphosphate (ADP) was examined before and 3 days after administration. The National Institutes of Health Stroke Scale (NIHSS) score method was employed to assess the NIHSS scores before and after treatment in each group of patients; the modified Rankin Scale (mRS) was used to assess the 3-month functional outcome. Results: There was no significant difference in baseline data between the two groups (P>0.05).The proportion of early neurological function improvement in the two groups was 75.0% and 54.8%, and the difference was statistically significant (χ(2)=4.498, P=0.034). The 3-month prognosis was 79.5% and 61.3%, and the difference was statistically significant (χ(2)=4.000, P=0.045). Adverse events: 1 case in the loading dose group, 1 case in the standard dose group, the difference was not statistically significant (2.3% vs 1.6%, χ(2)=0.061, P=0.806). After 3 days of antiplatelet therapy, the MAR of the loading dose group decreased (11%±8%), and the MAR of the standard dose group decreased (9%±4%), the difference was statistically significant (P=0.013).In the loading dose group, there were 32 (72.7%)CYP2C19*2 carriers and 42 (95.5%)CYP2C19*2+*3 carriers; early neurological function improvement in 33 cases, accounting for 93.8% and 76.2%, respectively, and the difference was statistically significant (χ(2)=4.122, P=0.042). There were 35 patients with good prognosis in 3 months, accounting for 96.9% and 81.0%, respectively. The difference was statistically significant (χ(2)=4.310, P=0.038); MAR of CYP2C19*2 carrier was decreased (15%±5%), and MAR of CYP2C19*2+*3 carrier was decreased (12%±8%). The difference was statistically significant (P=0.039). Conclusions: Loading dose clopidogrel can improve the clinical prognosis of minor stroke/TIA without increasing the risk of bleeding. Loading dose clopidogrel may improve the prognosis of minor stroke/TIA by decreasing MAR of CYP2C19*2 carriers.
目的： 探讨负荷剂量氯吡格雷治疗轻型缺血性脑卒中/短暂性脑缺血发作的有效性、安全性及可能的机制。 方法： 连续纳入2016年7月至2017年12月于苏州大学附属第一医院神经内科治疗的轻型缺血性脑卒中/TIA患者，入组CYP2C19功能丧失性等位基因（LOF）携带者，采用完全随机化方法随机将患者分为负荷剂量组（首剂300 mg氯吡格雷）和标准剂量组（首剂75 mg氯吡格雷），首剂氯吡格雷给药同时给予阿司匹林100 mg，继以阿司匹林100 mg/d+氯吡格雷75 mg/d维持20 d。以腺苷二磷酸（ADP）作为诱导剂分别检测服药前、服药后3 d的血小板最大聚集率（MAR）水平。应用美国国立卫生研究院卒中量表（NIHSS）评分法评定各组患者治疗前及治疗后7 d NIHSS评分；采用改良Rankin量表（mRS）评估3个月功能结局。 结果： 两组基线资料相互比较差异无统计学意义（P>0.05）。早期神经功能改善比例分别是75.0%、54.8%，差异有统计学意义（χ(2)=4.498，P=0.034）；3个月预后良好比例分别是79.5%、61.3%，差异有统计学意义（χ(2)=4.000，P=0.045）。两组不良事件各1例，差异无统计学意义（2.3%比1.6%，χ(2)=0.061，P=0.806）。抗血小板治疗3 d后，负荷剂量组MAR降低（11%±8%），标准剂量组MAR降低（9%±4%），差异有统计学意义（P=0.013）。负荷剂量组CYP2C19*2携带者32例（72.7%）和CYP2C19*2+*3携带者42例（95.5%）；早期神经功能改善比例分别是93.8%、76.2%，差异有统计学意义（χ(2)=4.122，P=0.042）；3个月预后良好比例分别是96.9%、81.0%，差异有统计学意义（χ(2)=4.310，P=0.038）；CYP2C19*2携带者MAR降低（15%±5%），CYP2C19*2+*3携带者MAR降低（12%±8%），差异有统计学意义（P=0.039）。 结论： 负荷剂量氯吡格雷能够改善轻型缺血性脑卒中/TIA患者临床预后，不增加出血风险；负荷剂量氯吡格雷可能通过降低CYP2C19*2携带者血小板聚集率改善轻型缺血性脑卒中/TIA患者临床预后。.
Keywords: CYP2C19 gene; Clopidogrel; Minor stroke; Platelet maximal aggregation rate; Transient ischemic attack.