强化剂量与标准剂量霉酚酸类药物用于成年肾移植受者有效性与安全性比较的Meta分析

Comparison of the Effectiveness and Safety of Intensified Dose and Standard Dose of Mycophenolic Acids for Adult Renal Transplant Recipients:A Meta-analysis

目的:比较强化剂量与标准剂量霉酚酸类药物用于成年肾移植受者的有效性与安全性,为临床合理用药提供循证参考。方法:计算机检索Embase、PubMed、Cochrane图书馆、Clinical trials.gov、中国知识资源总库、万方数据、中国生物医学文献数据库,检索时限均为各数据库建库起至2020年3月,收集霉酚酸类药物[吗替麦考酚酯(MMF)、麦考酚钠肠溶片(EC-MPS)]强化剂量对比标准剂量用于成年肾移植受者的随机对照试验(RCT)和队列研究;筛选文献、提取资料后,采用Cochrane干预措施系统评价手册(第5版)推荐的偏倚风险评估工具对RCT进行质量评价,采用NOS量表对队列研究进行质量评价;采用Rev Man 5.3软件进行Meta分析,并进行敏感性分析。结果:共纳入8项研究,其中6项为RCT、2项为队列研究,共1637例患者。Meta分析结果显示,强化剂量组患者经活检证实的急性排斥反应(BPAR)发生率[RR=0.65,95%CI(0.48,0.89),P=0.007]、巨细胞病毒(CMV)感染发生率[RR=0.39,95%CI(0.17,0.91),P=0.03]均显著低于对照组。按药物进行的亚组分析结果显示,MMF强化剂量组[RR=0.72,95%CI(0.53,0.99),P=0.04]、EC-MPS强化剂量组[RR=0.19,95%CI(0.04,0.81),P=0.03]患者的BPAR发生率均显著低于标准剂量组;MMF强化剂量组[RR=0.16,95%CI(0.02,1.33),P=0.09]、EC-MPS强化剂量组[RR=0.51,95%CI(0.20,1.30),P=0.16]患者的CMV感染发生率与标准剂量组比较,差异均无统计学意义(P>0.05)。两组患者排斥反应、治疗失败、移植物丢失、终止治疗、病死、总体不良事件、感染(总体)、BK病毒感染、尿路感染、血液系统不良事件(总体)、白细胞减少、贫血、血小板减少、胃肠道不良事件(总体)、恶心、呕吐、腹泻等发生率比较,差异均无统计学意义(P>0.05)。敏感性分析结果显示,排斥反应、CMV感染、白细胞减少发生率的结果稳定性一般。结论:早期强化剂量霉酚酸类药物用于成年肾移植受者的有效性、安全性与标准剂量总体相当,虽然强化剂量可降低BPAR及CMV感染的发生风险,但结合敏感性分析结果,建议应谨慎解读排斥反应、CMV感染、白细胞减少发生率等结果。

OBJECTIVE:To compare the effectiveness and safety of intensified dose and standard dose of mycophenolic acids(MPA)for kidney transplant recipients,and to provide evidence-based reference for clinical use of drugs.METHODS:Retrieved from Embase,PubMed,Cochrane library,Clinical trials,CNKI,Wanfang database and CBM,randomized controlled trial(RCT)and cohort study about intensified dose and standard dose of clinical commonly used Mycophenotate mofetil(MMF)and Mycophenolate sodium enteric-coated tablet(EC-MPS)for adult kidney transplant recipients were collected during the inception to Mar.2020.After literature screening and data extraction,the quality of RCTs were evaluated with bias risk evaluation tool recommended by Cochrane Handbook for Systematic Reviews of Interventions(fifth edition).The quality of cohort study was evaluated by NOS scale.Meta-analysis was performed by using Rev Man 5.3 software,and sensitivity analysis was conducted.RESULTS:A total of 8 studies were included,involving 6 RCTs,2 cohort studies,with 1637 patients involved.Meta-analysis results showed that,the incidence of biopsy-proven acute rejection(BPAR)[RR=0.65,95%CI(0.48,0.89),P=0.007]and cytomegalovirus(CMV)infection[RR=0.39,95%CI(0.17,0.91),P=0.03]in intensified dose group were significantly lower than control group.Subgroup analysis by drug showed that the incidence of BPAR in MMF intensive dose group[RR=0.72,95%CI(0.53,0.99),P=0.04]and EC-MPS intensive dose group[RR=0.19,95%CI(0.04,0.81),P=0.03]was significantly lower than that in standard dose group;there was no statistical significance in the incidence of CMV infection in MMF intensive dose group[RR=0.16,95%CI(0.02,1.33),P=0.09]and EC-MPS intensive dose group[RR=0.51,95%CI(0.20,1.30),P=0.16],compared with standard dose group(P>0.05).There was no significant difference in the incidence of rejection,treatment failure,graft loss,termination of treatment,death,overall adverse events,infection(overall),BK virus infection,urinary tract infection,hematological adverse events(overall),leucopenia,anemia,thrombocytopenia,gastrointestinal adverse events(overall),nausea,vomiting or diarrhea between 2 groups(P>0.05).Sensitivity analysis showed that the incidence of rejection,CMV infection and leukopenia were generally stable.CONCLUSIONS:The efficacy and safety of early intensive dose of MPA in adult renal transplant recipients are generally similar to those of standard dose.Although intensive dose can reduce the risk of BPAR and CMV infection,the incidence of rejection,CMV infection and leucopenia should be carefully interpreted according to results of sensitivity analysis.