不同他汀类药物对肝功能影响的网状Meta分析

Network Meta-analysis of Effects of Different Statins on Liver Function

背景他汀类药物(简称他汀)是目前最为常用的药物之一,而他汀的不良反应尤其是肝毒性也越来越引起人们的关注,但目前关于不同他汀对肝功能影响的评价不一。目的系统评价不同他汀对肝功能的影响。方法计算机检索Cochrane Library、PubMed、EMBase、Medline,检索干预措施为他汀、不良反应涉及肝功能异常的随机对照试验(RCTs),检索时限为建库至2020-09-10。由2位研究者进行筛选文献、提取资料、评价纳入文献的偏倚风险,采用Stata 14软件进行网状Meta分析。结果共纳入46篇RCTs,54499例患者,包含6种药物:阿托伐他汀(21篇)、瑞舒伐他汀(10篇)、辛伐他汀(10篇)、普伐他汀(7篇)、洛伐他汀(4篇)、匹伐他汀(3篇)。网状Meta分析结果显示,阿托伐他汀肝功能异常发生率高于瑞舒伐他汀、普伐他汀,阿托伐他汀、瑞舒伐他汀肝功能异常发生率高于安慰剂(P<0.05)。累积排序曲线(SUCRA)对不同他汀的排序结果为安慰剂(77.2%)>匹伐他汀(70.9%)>普伐他汀(64.1%)>辛伐他汀(60.7%)>瑞舒伐他汀(40.4%)>洛伐他汀(31.6%)>阿托伐他汀(5.1%)。通过细胞色素P450氧化酶(CYP450酶)进行代谢的他汀肝功能异常发生率高于安慰剂(P<0.05)。SUCRA对不同代谢途径他汀的排序结果为安慰剂(95.6%)>不通过CYP450酶进行代谢的他汀(51.9%)>通过CYP450酶进行代谢的他汀(2.6%)。脂溶性他汀肝功能异常发生率高于安慰剂(P<0.05)。SUCRA对不同性质他汀的排序结果为安慰剂(97.4%)>水溶性他汀(48.7%)>脂溶性他汀(3.9%)。高强度阿托伐他汀肝功能异常发生率高于中强度匹伐他汀、中强度普伐他汀、中强度辛伐他汀、高强度瑞舒伐他汀、中强度瑞舒伐他汀,高强度阿托伐他汀、高强度瑞舒伐他汀肝功能异常发生率高于安慰剂(P<0.05)。SUCRA对不同剂量他汀的排序结果为中强度瑞舒伐他汀(76.4%)>中强度匹伐他汀(71.6%)>安慰剂(69.1%)>中强度辛伐他汀(67.5%)>中强度普伐他汀(55.1%)>低强度普伐他汀(41.7%)>高强度瑞舒伐他汀(40.9%)>中强度阿托伐他汀(37.9%)>低强度洛伐他汀(31.0%)>高强度阿托伐他汀(8.8%)。结论脂溶性他汀、通过CYP450酶进行代谢的他汀、高剂量他汀肝功能异常发生率较高。本研究纳入文献较多且总体质量尚可,对临床用药具有一定的指导意义,但部分文献质量不高,仍需开展更多高质量的RCTs对本研究结果进行验证。

Background As one of the most commonly used drugs,statins’adverse reactions,especially hepatotoxicity,have become a growing concern.However,the assessment of the effects of different statins on liver function still varies at present.Objective To systematically review the effects of different statins on liver function.Methods We searched electronic databases,including Cochrane Library,PubMed,EMBase and Medline to collect randomized controlled trials(RCTs)about abnormal liver function associated with statins as the intervention from inception to September 10th 2020.Literature review,data extraction,and risk of bias evaluation were performed by two researchers.Stata 14 was used for network metaanalysis.Results All in all,46 RCTs were included,containing 6 types of Statins as interventions for 54499 cases,including 21 with atorvastatin,10 with rosuvastatin,10 with simvastatin,7 with pitavastatin,4 with lovastatin,and 3 with pitavastatin.The results of network meta-analysis were as follows:the incidence of liver dysfunction induced by atorvastatin was higher than that caused by rosuvastatin or pravastatin.The incidence of liver dysfunction induced by atorvastatin was higher than that by placebo,so did that induced by rosuvastatin(P<0.05).The SUCRA value for Statins and placebo ranked from highest to lowest were:placebo(77.2%)>pitavastatin(70.9%)>pravastatin(64.1%)>simvastatin(60.7%)>rosuvastatin(40.4%)>lovastatin(31.6%)>atorvastatin(5.1%).The incidence of liver dysfunction caused by statins metabolized by CYP450 enzyme was higher than that by placebo(P<0.05).The ranking results of statins with different metabolic pathways and placebo by SUCRA were:placebo(95.6%)>statins not metabolized by CYP450 enzyme(51.9%)>statins metabolized by CYP450 enzyme(2.6%).The incidence of liver dysfunction caused by liposoluble statins was higher than that by placebo(P<0.05).The ranking results of statins with different solubilities and placebo by SUCRA were:placebo(97.4%)>hydrosoluble statins(48.7%)>liposoluble statins(3.9%).The incidence of liver dysfunction induced by high-intensity atorvastatin was higher than that by medium-intensity pitavastatin,medium-intensity pravastatin,medium-intensity simvastatin,high-intensity rosuvastatin or medium-intensity rosuvastatin(P<0.05).The incidence of liver dysfunction caused by high-intensity atorvastatin or high-intensity rosuvastatin was higher than that by placebo(P<0.05).The ranking results of different doses of statins and placebo by SUCRA were:medium-intensity rosuvastatin(76.4%)>medium-intensity pitavastatin(71.6%)>placebo(69.1%)>medium-intensity simvastatin(67.5%)>medium-intensity pravastatin(55.1%)>low-intensity pravastatin(41.7%)>high-intensity rosuvastatin(40.9%)>mediumintensity atorvastatin(37.9%)>low-intensity lovastatin(31.0%)>high-intensity atorvastatin(8.8%).Conclusion Liposoluble statins,statins metabolized by CYP450 enzymes and high-dose statins tend to lead to a higher incidence of liver dysfunction.With an analysis of the reports of many fair-quality RCTs,this study may be used as guidance for clinical medication.However,due to some eligible RCTs with low quality,more high-quality RCTs are needed to verify our conclusion.