即时检测CYP2C19基因型精准指导下高危非致残性缺血性脑血管事件的抗血小板治疗

Efficacy analysis of anti-platelet in the treatment of high-risk non-disabling ischemic cerebrovascular events guided by point-of-care testing of CYP2C19 gene

目的探讨在即时检测CYP2C19基因型的精准指导下,不同双重抗血小板方案治疗高危非致残性缺血性脑血管事件(HR-NICE)的有效性及安全性。方法采用单中心、前瞻性、随机、开放标签、终点盲法设计。连续收集2020年7月至2022年1月于徐州市中心医院脑卒中绿色通道及神经内科病房收治的HR-NICE患者,对所有患者无创刮取颊黏膜行即时检测,筛选CYP2C19功能缺失等位基因CYP2C19*2和CYP2C19*3的携带者,携带1个功能缺失等位基因为CYP2C19中代谢,携带2个功能缺失等位基因为CYP2C19慢代谢,使用全自动医用PCR分析仪进行即时检测CYP2C19基因型,将检测周转时间缩短至1 h。将CYP2C19基因型为中慢代谢的患者按照随机数字表法分为常规治疗组(氯吡格雷75 mg,1次/d)、替格瑞洛组(替格瑞洛90 mg,2次/d)和强化剂量组(氯吡格雷150 mg,1次/d),分别联合阿司匹林100 mg,1次/d双重抗血小板治疗21 d。收集3组患者的一般基线资料、急性卒中Org10172治疗试验分型及90 d改良Rankin量表(mRS)评分、不良事件及严重不良事件发生等情况。主要疗效结局为90 d内新发卒中,主要安全结局为90 d内严重或中度出血。结果共纳入716例HR-NICE患者,常规治疗组240例、替格瑞洛组240例、强化剂量组236例,3组患者基线资料差异均无统计学意义(均P>0.05)。90 d新发卒中患者常规治疗组26例(10.8%),替格瑞洛组11例(4.6%),强化剂量组4例(1.7%),3组间差异具有统计学意义(χ^(2)=19.28,P<0.05)。其中常规治疗组与替格瑞洛组(χ^(2)=6.59,P=0.010)、常规治疗组与强化剂量组(χ^(2)=16.83,P<0.001)差异均具有统计学意义,而替格瑞洛组与强化剂量组差异无统计学意义(P>0.05)。90 d中重度出血患者常规治疗组1例(0.4%),替格瑞洛组6例(2.5%),强化剂量组0例,3组间差异具有统计学意义(χ^(2)=7.23,P<0.05),其中替格瑞洛组与强化剂量组差异具有统计学意义(P=0.030)。CYP2C19基因检测为中代谢的患者中,90 d卒中复发者常规治疗组13例(13/158,8.2%),替格瑞洛组4例(4/153,2.6%),强化剂量组0例(0/159),3组间差异具有统计学意义(χ^(2)=16.04,P<0.001),其中强化剂量组与常规治疗组(χ^(2)=13.64,P<0.001)差异有统计学意义,强化剂量组与替格瑞洛组差异无统计学意义(P>0.05)。在强化剂量组90 d卒中复发患者中,CYP2C19中代谢0例(0/159),CYP2C19慢代谢4例(4/77,5.2%),差异有统计学意义(P=0.011),在常规剂量组和替格瑞洛组差异无统计学意义(P>0.05)。结论通过即时检测筛选CYP2C19功能缺失等位基因的携带者,可快速精准指导非心源性HR-NICE的抗血小板治疗。强化氯吡格雷剂量(150 mg,1次/d)联合阿司匹林治疗能够有效减少患者卒中复发及出血和不良事件的发生,且CYP2C19中代谢者可能为强化氯吡格雷剂量的最佳获益人群。

Objective To explore the efficacy and safety of different anti-platelet regimens in the treatment of high-risk non-disabling ischemic cerebrovascular events(HR-NICE)guided by point-of-care testing of CYP2C19 gene.Methods A single-centre,prospective,randomised,open-label,and blinded endpoint design was uesd in the study.From July 2020 to January 2022,HR-NICE patients were enrolled in the Stroke Green Channel and Department of Neurology of Xuzhou Central Hospital,and all patients were scraped the buccal mucosa for screening for CYP2C19 loss-of-function allele carriers by point-of-care testing.Patients with intermediate metabolism were defined as those who carried 1 loss-of-function allele and patients with poor metabolism were those who carried 2 loss-of-function alleles.This study reduced the test turnaround time to 1 hour by using a fully automated medical polymerase chain reaction analyzer for a point-of-care test of CYP2C19 genotype.CYP2C19 loss-of-function allele carriers were divided according to the random number table method into the conventional treatment group(clopidogrel 75 mg,once a day),the ticagrelor group(ticagrelor 90 mg,twice a day)and the intensive dose group(clopidogrel 150 mg,once a day)separately combined with aspirin(100 mg,once a day)dual antiplatelet for 21 days.Baseline information,Acute Stroke Org 10172 Treatment Trial staging,90-day modified Rankin Scale score,occurrence of adverse events and severe adverse events were collected for all the 3 groups.The primary efficacy outcome was new stroke within 90 days,and the primary safety outcome was severe or moderate bleeding within 90 days.Results A total of 716 patients were included:240 in the conventional treatment group,240 in the ticagrelor group and 236 in the intensive dose group.There was no statistically significant difference between the 3 groups at baseline(all P>0.05).There were 26 cases(10.8%)with new stroke events in the conventional treatment group,11 cases(4.6%)in the ticagrelor group and 4 cases(1.7%)in the intensive dose group,with statistically significant differences among the 3 groups(χ^(2)=19.28,P<0.05),and the differences between the conventional treatment group and the ticagrelor group(χ^(2)=6.59,P=0.010)and between the conventional treatment group and the intensive dose group(χ^(2)=16.83,P<0.001)were statistically significant,whereas the difference between the ticagrelor group and the intensive dose group was not statistically significant(P>0.05).In the 3 groups,there was 1 case(0.4%)of severe bleeding in the conventional treatment group,6 cases(2.5%)in the ticagrelor group and none in the intensive dose group,which showed statistically significant differences(χ^(2)=7.23,P<0.05),and there was statistically significant difference between the ticagrelor group and the intensive dose group(P=0.030).Among the patients with intermediate CYP2C19 metabolism,there were 13 cases(13/158,8.2%)with 90-day recurrent stroke in the conventional treatment group,4 cases(4/153,2.6%)in the ticagrelor group,and 0 case(0/159)in the intensive dose group,with statistically significant difference(χ^(2)=16.04,P<0.001),and the differences between the intensive dose group and the conventional treatment group were statistically significant(χ^(2)=13.64,P<0.001),whereas there was no statistically significant difference between the intensive dose group and the ticagrelor group(P>0.05).In the patients with 90-day recurrent stroke in the intensive dose group,there was 0 case(0/159)with intermediate metabolism and 4 cases(4/77,5.2%)with poor metabolism,with statistically significant differences(P=0.011),whereas there were no statistically significant differences in the conventional treatment group and the ticagrelor group(P>0.05).Conclusions Screening carriers of CYP2C19 loss-of-function alleles by point-of-care testing can quickly and precisely guide the treatment of patients with non-cardiogenic HR-NICE.An intensive clopidogrel dose of 150 mg,once a day combined with aspirin was effective in reducing stroke recurrence with less occurrence of any bleeding and adverse events,and patients with intermediate CYP2C19 metabolism may be the best population to benefit.