依洛尤单抗与阿利西尤单抗对缺血性脑卒中的预防作用及用药安全性的Meta分析

Prevention and safety of evolocumab and alirocumab in ischemic stroke:a Meta analysis

目的评价依洛尤单抗与阿利西尤单抗对高脂血症和动脉粥样硬化性高危心血管病患者缺血性脑卒中发生的预防作用及其用药安全性。方法应用计算机检索PubMed、Embase、Web of Science、Cochrane图书馆、万方、中国知网中自建库起至2023年3月收录的关于依洛尤单抗或阿利西尤单抗(试验组)治疗高脂血症和动脉粥样硬化性高危心血管病患者的随机对照试验研究(对照组使用安慰剂或常规治疗),按照预先设定的纳入与排除标准筛选文献、提取资料,有效性指标为缺血性脑卒中发生率,安全性指标包括心血管死亡、认知功能损害、转氨酶升高3倍以上、肌酸激酶升高3倍以上发生率。使用Cochrane Reviewer Handbook风险评估标准2.0进行文献质量评价,使用Stata软件进行Meta合并分析。结果共纳入11篇文献,包含12项研究,总计53666例患者。Meta合并分析显示:与对照组相比,试验组缺血性脑卒中发生率明显降低,差异有统计学意义[(风险差异(RD)=-0.004,95%CI:-0.005~-0.002,P<0.001];试验组心血管死亡、认知功能损害、转氨酶升高3倍以上、肌酸激酶升高3倍以上发生率的差异均无统计学意义(RD=-0.001,95%CI:-0.004~0.001,P=0.401;RD=0.000,95%CI:-0.003~0.002,P=0.638;RD=-0.001,95%CI:-0.004~0.002,P=0.443;RD=-0.001,95%CI:-0.003~0.000,P=0.137)。按药物不同分组的亚组分析显示:与对照组相比,依洛尤单抗组、阿利西尤单抗组缺血性脑卒中发生率均明显降低,差异均有统计学意义(RD=-0.004,95%CI:-0.007~-0.001,P=0.006;RD=-0.003,95%CI:-0.006~0.000,P=0.024);依洛尤单抗组、阿利西尤单抗组心血管死亡发生率(RD=0.001,95%CI:-0.002~0.004,P=0.619;RD=-0.003,95%CI:-0.007~0.001,P=0.100)、认知功能损害发生率(RD=0.001,95%CI:-0.002~0.004,P=0.463;RD=-0.002,95%CI:-0.005~0.001,P=0.145)、转氨酶升高3倍以上发生率(RD=0.000,95%CI:-0.003~0.003,P=0.888;RD=-0.002,95%CI:-0.007~0.003,P=0.392)、肌酸激酶升高3倍以上发生率(RD=0.000,95%CI:-0.002~0.002,P=0.668;RD=-0.002,95%CI:-0.005~0.000,P=0.106)的差异均无统计学意义。按用药时长不同分组的亚组分析显示:与对照组相比,<1年、1~2年组、>2年组心血管死亡发生率(RD=0.000,95%CI:-0.022~0.022,P=1.000;RD=-0.003,95%CI:-0.009~0.002,P=0.193;RD=-0.001,95%CI:-0.004~0.002,P=0.521)、认知功能损害发生率(RD=-0.003,95%CI:-0.014~0.008,P=0.569;RD=-0.001,95%CI:-0.006~0.004,P=0.696;RD=0.000,95%CI:-0.003~0.002,P=0.735)、转氨酶升高3倍以上发生率(RD=-0.002,95%CI:-0.016~0.012,P=0.749;RD=-0.002,95%CI:-0.013~0.010,P=0.773;RD=-0.001,95%CI:-0.004~0.002,P=0.489)、肌酸激酶升高3倍以上发生率(RD=-0.015,95%CI:-0.032~0.003,P=0.099;RD=-0.011,95%CI:-0.025~0.002,P=0.104;RD=0.000,95%CI:-0.002~0.001,P=0.722)的差异均无统计学意义。结论依洛尤单抗与阿利西尤单抗均能有效预防高脂血症和动脉粥样硬化性高危心血管病患者缺血性脑卒中的发生,且安全性好。

Objective To evaluate the preventive role and safety of evolocumab and alirocumab in ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients.MethodsPubMed,Embase,Web of Science,Cochrane Library,Wanfang,and CNKI databases were searched for randomized controlled trials(RCTs)comparing evolocumab or alirocumab(experimental group)with placebo or usual care(control group)in hyperlipidemia and atherosclerotic high-risk cardiovascular patients from database inception to March 2023.References were screened and data were extracted according to the preset inclusion and exclusion criteria;incidence of ischemic stroke was as the efficacy index,and incidences of cardiovascular death,cognitive impairment,aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times were as the safety index.Cochrane Reviewer Handbook 2.0 was used to evaluate the RCTs literature quality.Meta analysis was performed using Stata software.ResultsA total of 11 articles were included,including 12 studies with a total of 53666 patients.Compared with the control group,the incidence of ischemic stroke in the experimental group was significantly decreased(risk difference[RD]=-0.004,95%CI:-0.005--0.002,P<0.001);there were no significant differences in the incidence of cardiovascular death,cognitive impairment,aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times between the 2 groups(RD=-0.001,95%CI:-0.004-0.001,P=0.401;RD=0.000,95%CI:-0.003-0.002,P=0.638;RD=-0.001,95%CI:-0.004-0.002,P=0.443;RD=-0.001,95%CI:-0.003-0.000,P=0.137).Subgroup analysis was performed according to drugs:compared with the control group,the incidence of ischemic stroke was significantly reduced in the evolocumab group and alirocumab group(RD=-0.004,95%CI:-0.007--0.001,P=0.006;RD=-0.003,95%CI:-0.006-0.000,P=0.024);there were no significant differences in incidences of cardiovascular death(RD=0.001,95%CI:-0.002-0.004,P=0.619;RD=-0.003,95%CI:-0.007-0.001,P=0.100),cognitive impairment(RD=0.001,95%CI:-0.002-0.004,P=0.463;RD=-0.002,95%CI:-0.005-0.001,P=0.145),aminotransferase increased for more than 3 times(RD=0.000,95%CI:-0.003-0.003,P=0.888;RD=-0.002,95%CI:-0.007-0.003,P=0.392)or creatine kinase increased for more than 3 times(RD=0.000,95%CI:-0.002-0.002,P=0.668;RD=-0.002,95%CI:-0.005-0.000,P=0.106)between the evolocumab group and alirocumab group.Subgroup analysis was performed according to the medication duration:compared with the control group,no significant differences in incidences of cardiovascular death(RD=0.000,95%CI:-0.022-0.022,P=1.000;RD=-0.003,95%CI:-0.009-0.002,P=0.193;RD=-0.001,95%CI:-0.004-0.002,P=0.521),cognitive impairment(RD=-0.003,95%CI:-0.014-0.008,P=0.569;RD=-0.001,95%CI:-0.006-0.004,P=0.696;RD=0.000,95%CI:-0.003-0.002,P=0.735),aminotransferase increased for more than 3 times(RD=-0.002,95%CI:-0.016-0.012,P=0.749;RD=-0.002,95%CI:-0.013-0.010,P=0.773;RD=-0.001,95%CI:-0.004-0.002,P=0.489)or creatine kinase increased for more than three times(RD=-0.015,95%CI:-0.032-0.003,P=0.099;RD=-0.011,95%CI:-0.025-0.002,P=0.104;RD=0.000,95%CI:-0.002-0.001,P=0.722)were noted among medication duration<1 year group,medication duration of 1-2 years group and medication duration>2 years group.ConclusionBoth evolocumab and alirocumab can reduce the incidence of ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients,with good safety.