PCSK9抑制剂对动脉粥样硬化性心血管疾病有效性及安全性的meta分析

doi:10.3969/j.issn.1004-583X.2022.12.002

摘要/Abstract

摘要：

目的系统评价PCSK9抑制剂对动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease,ASCVD)患者的有效性及安全性。方法计算机检索PubMed、Embase、Cochrane图书馆和临床试验注册平台Clinical Trails.gov,检索年限从建库至2022年5月。筛选并纳入PCSK9抑制剂治疗ASCVD患者的随机对照试验(randomized controlled trials,RCTs),应用Review Manager 5.4软件对符合标准的RCTs进行meta分析。结果共纳入10项随机对照试验,共计54 472例患者。有效性分析结果显示:与对照组相比,PCSK9抑制剂可降低ASCVD患者低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平49.26%(95% CI:-54.00~-44.52,P<0.01),并显著降低了其他5项血脂水平;PCSK9抑制剂组动脉粥样硬化斑块体积百分比(percent atheroma volume,PAV)降低1.1%(95%CI:-1.48~-0.73,P<0.01),最小纤维帽厚度(fibrous cap thickness,FCT)增加31.32%(95%CI:15.82~-46.82,P<0.01);PCSK9抑制剂并没有降低心血管死亡风险(RR=0.97,95%CI0.86~1.10,P>0.05),但可降低心肌梗死风险(RR=0.73,95%CI:0.65~0.81,P<0.01)和卒中风险(RR=0.78,95%CI:0.68~0.90,P<0.01)。安全性分析结果显示:PCSK9抑制剂组与对照组严重不良反应事件(serious adverse events,SAEs)发生率相似(RR=0.97,95%CI:0.95~1.00,P>0.05); 注射部位反应,PCSK9抑制剂组较对照组发生率高(RR=1.57,95%CI:1.40~1.76,P<0.01)。而肌痛、神经认知反应、新发糖尿病发生率与对照组相比差异无统计学意义(P>0.05)。结论 PCSK9抑制剂可显著降低LDL-C水平,降低心肌梗死、卒中发生率,无严重不良反应。

关键词: 心血管疾病, 动脉粥样硬化, PCSK9抑制剂, meta分析

Abstract:

Objective To systematically evaluate the efficacy and safety of proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors on atherosclerotic cardiovascular disease (ASCVD). Methods PubMed, Embase, Cochrane Library and Clinical Trails.gov were subject to the computer retrieval from the data of database construction to May 2022. The randomized controlled trials (RCTs) of PCSK9 inhibitors for ASCVD patients were screened and incorporated, and the meta analysis on conforming RCTs was performed with Review Manager 5.4 software. Results A total of 10 RCTs comprising 54 472 patients were enrolled. Efficacy analysis results showed that PCSK9 inhibitors could reduce the level of low-density lipoprotein cholesterol (LDL-C) by 49.26%(95%CI: -54.00 to -44.52, P<0.01) and significantly reduced the other five lipid levels compared with the control group. Percent atheroma volume (PAV) reduced by 1.1% (95%CI: -1.48 to 0.73, P<0.01) and the minimum fibrous cap thickness (FCT) increased by 31.32%(95%CI: 15.82 to -46.82, P<0.01) in the PCSK9 inhibitors group. PCSK9 inhibitors did not reduce the risk of cardiovascular death (RR=0.97, 95%CI: 0.86 to 1.10, P>0.05), and reduced the risk of myocardial infarction (RR=0.73, 95%CI 0.65 to 0.81, P<0.01) and stroke (RR=0.78, 95%CI 0.68 to 0.90, P<0.01). The incidence of serious adverse events (SAEs) between the PCSK9 inhibitors group and control group was similar (RR=0.97, 95%CI 0.95 to 1.00, P>0.05). The incidence of injection site reaction in the PCSK9 inhibitor group was higher (RR=1.57, 95%CI: 1.40 to 1.76, P<0.01). Differences in myalgia, neurocognitive reaction and incidence new-onset diabetes weren't statistically significant when compared to such indexes in the control group (P>0.05). Conclusion PCSK9 inhibitors is capable of significantly reducing the level of LDL-C, incidence of myocardial infarction and stroke without serious adverse reactions.

Key words: cardiovascular diseases, atherosclerosis, PCSK9 inhibitors, meta-analysis

中图分类号:

R543.5

张磊, 娄海东, 智昱, 亓树莹. PCSK9抑制剂对动脉粥样硬化性心血管疾病有效性及安全性的meta分析[J]. 临床荟萃, 2022, 37(12): 1074-1080.

Zhang Lei, Lou Haidong, Zhi Yu, Qi Shuying. Efficacy and safety of PCSK9 inhibitors on atherosclerotic cardiovascular disease: A meta-analysis[J]. Clinical Focus, 2022, 37(12): 1074-1080.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2022.12.002

https://huicui.hebmu.edu.cn/CN/Y2022/V37/I12/1074

图/表 15

表1 患者基线资料汇总

纳入研究	研究分组	纳入标准	样本量 (例)	给药方案	高强度他汀(%)		年龄(岁)		男性(%)		基线LDL-C 水平(mg/dl)		随访时间
纳入研究	研究分组	纳入标准	样本量 (例)	给药方案	干预组	对照组	干预组	对照组	干预组	对照组	干预组	对照组	随访时间
ODYSSEY COMBO I 2015^[3]	Ali vs安慰剂	ASCVD或ASCVD等危	316	75 mg Q2W(若8周时LDL-C≥70 mg/dl,12周时给予150 mg q2w)	61.7	64.5	63	63	62.7	72	94.8	100.2	52周
ODYSSEY COMBO II 2015^[4]	Ali vs依折麦布	CHD或CHD等危	720	75 mg Q2W(若8周时LDL-C≥70 mg/dl,12周时给予150 mg q2w)	66.8	66.4	61.7	61.3	75.2	70.5	108.3	104	52周
ODYSSEY LONG TERM 2015^[5]	Ali vs安慰剂	杂合子FH或CHD或CHD等危	2341	150 mg q2w	46.8	46.7	60.4	60.6	63.3	60.2	122.7	121.9	78周
ODYSSEY OUTCOMES 2018^[6]	Ali vs安慰剂	ACS	18, 924	75 mg q2w	88.6	89.1	58.5	58.6	74.7	74.9	92	92	2.8年
PACMAN-AMI 2022^[7]	Ali vs安慰剂	AMI,适合冠状动脉腔内成像	300	150 mg q2w 瑞舒伐他汀20 mg qd	7.4	5.9	58.4	58.6	83.8	78.3	154.8	150.9	52周
GLAGOV 2016^[8]	Evo vs安慰剂	冠状动脉造影证实冠状动脉狭窄	968	420 mg q4w	57.9	59.9	59.8	59.8	72.1	72.3	92.6	92.4	78周
FOURIER 2017^[9]	Evo vs安慰剂	ASCVD	27, 564	140 mg q2w或420 mg q4w	69.5	69.1	62.5	62.5	75.4	75.5	92	92	2.2年
HUYGENS 2022^[10]	Evo vs安慰剂	NSTEMI,适合冠状动脉腔内成像	161	420 mg q4w	82.7	78.8	60.9	60.2	75	67.9	140.4	142.1	52周
ORION-10 2020^[11]	Inc vs安慰剂	ASCVD	1561	284 mg,第1天、第90天,然后每6个月	67.2	68.8	66.4	65.7	68.5	70.3	104.5	104.8	540天
ORION-11 2020^[11]	Inc vs安慰剂	ASCVD或ASCVD等危	1617	284 mg,第1天、第90天,然后每6个月	79.0	78.2	64.8	64.8	71.5	72	107.2	103.7	540天

图1 纳入RCT的质量评价

图2 LDL-C降低百分比森林图

图3 TC降低百分比森林图

图4 Non-HDL-C降低百分比森林图

图5 AproB降低百分比森林图

图6 Lp(a)降低百分比森林图

图7 TG降低百分比森林图

图8 PAV降低森林图

图9 最小FCT增加百分比森林图

图10 心血管死亡风险森林图

图11 心肌梗死风险森林图

图12 冠状动脉血运重建森林图

图13 卒中风险森林图

表2 药物不良反应meta分析

评价指标	纳入文献	样本量		异质性检验		效应模型	合并效应值
评价指标	纳入文献	PCSK9i	对照组	$I 2$	P值	效应模型	$R R$	95%CI	P值
严重不良反应	[3-6, 8, 9, 11]	26751	25623	0	0.63	固定	0.97	0.95,1.00	0.10
注射部位反应	[3-11]	26948	25829	15%	0.31	固定	1.57	1.40,1.76	<0.01
肌痛	[3-5, 8-11]	17380	16261	18%	0.29	固定	1.07	0.97,1.18	0.17
神经认知反应	[3-9]	26087	24970	24%	0.25	固定	1.00	0.87,1.15	0.96
新发糖尿病	[5, 6, 8, 9, 11]	17398	16914	0	0.44	固定	1.01	0.95,1.08	0.75
ALT>3ULN	[4-6, 11]	12964	11942	0	0.74	固定	0.94	0.79,1.12	0.50
AST>3ULN	[5, 6, 11]	12492	11699	0	0.52	固定	0.91	0.74,1.11	0.33
CK>3ULN或 5UL或10ULN	[4-6, 8, 9, 11]	26962	25934	0	0.94	固定	0.93	0.78,1.12	0.47

表2 药物不良反应meta分析

评价指标	纳入文献	样本量		异质性检验		效应模型	合并效应值
评价指标	纳入文献	PCSK9i	对照组	$I 2$	P值	效应模型	$R R$	95%CI	P值
严重不良反应	[3-6, 8, 9, 11]	26751	25623	0	0.63	固定	0.97	0.95,1.00	0.10
注射部位反应	[3-11]	26948	25829	15%	0.31	固定	1.57	1.40,1.76	<0.01
肌痛	[3-5, 8-11]	17380	16261	18%	0.29	固定	1.07	0.97,1.18	0.17
神经认知反应	[3-9]	26087	24970	24%	0.25	固定	1.00	0.87,1.15	0.96
新发糖尿病	[5, 6, 8, 9, 11]	17398	16914	0	0.44	固定	1.01	0.95,1.08	0.75
ALT>3ULN	[4-6, 11]	12964	11942	0	0.74	固定	0.94	0.79,1.12	0.50
AST>3ULN	[5, 6, 11]	12492	11699	0	0.52	固定	0.91	0.74,1.11	0.33
CK>3ULN或 5UL或10ULN	[4-6, 8, 9, 11]	26962	25934	0	0.94	固定	0.93	0.78,1.12	0.47

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