Abstract:

Objective To assess clopidogrel resistance through CYP2C19 gene detection and platelet aggregation rate, to guide the rational drugs use for patients with recurrent cerebral infarction. Methods This prospective study consecutively enrolled recurrent cerebral infarction patients who underwent CYP2C19 gene sequencing from the Second Hospital of Jiaxing from January 2018 to October 2018. According to the gene detection results, 30 patients with fast, medium and slow metabolism genotype were collected, respectively. All three groups were given clopidogrel 75 mg/d, and the platelet aggregation rate was measured before and 7 days after taking clopidogrel.The incidence of clopidogrel resistance was compared among the three groups. Clopidogrel resistance was determined according to the inhibition rate of platelet aggregation. Patients who were resistant to clopidogrel (inhibition rate <10%) switched to cilotazole 100 mg twice a day, and those who were half responsive or sensitive to clopidogrel continued to take clopidogrel 75 mg/d. The relationship between CYP2C19 genotype and clopidogrel resistance were analyzed. The platelet aggregation rate was measured again at 3 months, and endpoint events were observed during 3-month folllow-up (main endpoints: recurrent cerebral infarction; secondary endpoints: cerebral hemorrhage and death). Results Finally, 90 patients were enrolled, with 49 males (54.4%) and an average age of 68.27±10.14 years old (aged 40-89 years old). Clopidogrel resistance occurred in 22 patients (24.4%), and the rest 68 patients (75.6%) were non-resistant to clopidogrel. The rate of clopidogrel resistance in slow metabolism group was higher than that of fast metabolism group (P <0.001)and medium metabolism group (P =0.06). Logistic regression analysis showed that smoking (OR 7.792, 95%CI 1.899-31.968, P =0.004), diabetes (OR 4.466, 95%CI 1.122-17.778, P =0.034) and CYP2C19 slow metabolism genotype (OR 13.713, 95%CI 2.352-79.959, P =0.004) were independent risk factors for clopidogrel resistance. The mean platelet aggregation rate in clopidogrel non-resistance group (49.51%±4.33% vs 63.73%±7.84%, P <0.001) at 3 months was lower than that at 7 days, and so did the clopidogrel resistance group (55.42%±6.63% vs 76.95%±7.42%, P <0.001). The platelet aggregation inhibition rate was higher in clopidogrel resistance group than clopidogrel nonresistance group at 3 months (21.53%±4.30% vs 14.23%±6.90%, P <0.001). No endpoint event occurred in all the patients during the 3-month follow-up. Conclusions Smoking, diabetes mellitus and CYP2C19 slow metabolism genotype were independent risk factors for clopidogrel resistance in patients with recurrent cerebral infarction. Cilostazol can effectively inhibit platelet aggregation and can be used as an alternative drug in clopidogrel resistance patients with recurrent cerebral infarction.

Key words: CYP2C19 gene; Platelet aggregation rate; Clopidogrel resistance; Recurrent cerebral infarction

摘要：

目的 通过CYP2C19基因检测及血小板聚集率综合评估氯吡格雷抵抗，指导复发性脑梗死患者合 理用药。 方法 对2018年1-10月就诊于嘉兴市第二医院神经内科，诊断为复发性脑梗死的患者进行CYP2C19 基因测序，分别收集氯吡格雷快代谢、中代谢、慢代谢基因型患者各30例，比较3组患者年龄、性别、 BMI、吸烟、高血压、糖尿病及高脂血症等一般临床资料。3组均给予常规剂量氯吡格雷75 mg/d治疗， 检测患者使用氯吡格雷前及使用7 d后的血小板聚集率。根据血小板聚集抑制率判断氯吡格雷抵抗 情况，分析CYP2C19基因型与患者氯吡格雷抵抗的关系。筛选出氯吡格雷抵抗者（血小板聚集抑制率 ＜10%）分至氯吡格雷抵抗组，改用西洛他唑100 mg 2次/日，氯吡格雷半反应（10%≤血小板聚集抑 制率＜30%）及氯吡格雷敏感（血小板聚集抑制率≥30%）者分至非氯吡格雷抵抗组，继续氯吡格雷 75 mg/d治疗。3个月后再次检测血小板聚集率，比较不同药物的血小板聚集抑制情况，并观察终点 事件发生情况（主要终点：再发脑梗死；次要终点：脑出血和死亡）。 结果 最终入组患者90例，其中男性49例（54.4%），年龄40～89岁，平均年龄68.27±10.14岁。快、 中、慢代谢3组糖尿病（P =0.036）和氯吡格雷抵抗发生率（P＜0.001）差异均有统计学意义，其中 慢代谢组合并糖尿病比率高于中代谢组（P =0.010），慢代谢组氯吡格雷抵抗发生率高于快代谢 组（P＜0.001）及中代谢组（P =0.006）。氯吡格雷抵抗组患者22例（24.4%），非氯吡格雷抵抗组患 者68例（75.6%）。Logistic回归分析提示，吸烟（OR 7.792，95%CI 1.899～31.968，P =0.004）、糖尿病 （OR 4.466，95%CI 1.122～17.778，P =0.034）及CYP2C19基因慢代谢（OR 13.713，95%CI 2.352～79.959， P =0.004）是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。非氯吡格雷抵抗组（49.51%±4.33% vs 63.73%±7.84%，P＜0.001）和氯吡格雷抵抗组（55.42%±6.63% vs 76.95%±7.42%，P＜0.001）患 者3个月后的血小板平均聚集率较7 d时均下降，差异有统计学意义。3个月后较非氯吡格雷抵抗组， 氯吡格雷抵抗组血小板聚集抑制率更高（21.53%±4.30% vs 14.23%±6.90%，P＜0.001）。入组患者 随访3个月均无终点事件发生。 结论 吸烟、合并糖尿病及CYP2C19 慢代谢基因型是复发性脑梗死患者氯吡格雷抵抗的独立危险 因素。西洛他唑能有效抑制血小板聚集，可以作为氯吡格雷抵抗的复发性脑梗死患者的替代性用药。

关键词: CYP2C19基因; 血小板聚集率; 氯吡格雷抵抗; 复发性脑梗死