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利奈唑胺致血小板减少危险因素的Meta分析

作者:未知

  摘 要 目的:系统评价利奈唑胺致血小板减少的危险因素,为临床合理用药提供参考。方法:计算机检索PubMed、Embase、Cochrane图书馆、Web of Science、中国生物医学文献数据库、中国知网和万方数据,检索时限均为建库起至2018年10月,收集利奈唑胺致血小板减少危险因素的临床研究,对符合标准的文献进行资料提取,并采用纽卡斯尔-渥太华质量评估量表(NOS)对纳入文献进行质量评价后,采用Rev Man 5.3软件进行Meta分析。结果:共纳入16项临床研究,合计2 264例患者。Meta分析结果显示,日公斤剂量高[SMD=0.62,95%CI(0.29,0.95),P=0.000 2]、用药前血小板计数低[SMD=-0.90,95%CI(-1.62,-0.18),P=0.01]、肌酐清除率低 [SMD=-0.65,95%CI(-1.10,-0.19),P=0.005]、疗程长 [SMD=0.45,95%CI(0.18,0.71),P=0.000 9]、体质量低 [SMD=-0.36,95%CI(-0.60,-0.11),P=0.005]对血小板减少的发生均有显著影响。结论:血小板基础值低、肌酐清除率低、体质量低,用药疗程长和日公斤剂量高是利奈唑胺致血小板减少的危险因素。
  关键词 利奈唑胺;血小板减少;危险因素;Meta分析
  Meta-analysis of Risk Factors of Linezolid-induced Thrombocytopenia
  BAI Hao1,SUN Pu2,CHEN Kaijie3(1.Dept. of Pharmacy, the Affiliated Cancer Hospital of Chongqing University, Chongqing 400030, China;2.Dept. of Scientific Education, the Affiliated Cancer Hospital of Chongqing University, Chongqing 400030, China;3.Dept. of Medical Administration, the Affiliated Cancer Hospital of Chongqing University, Chongqing 400030, China)
  ABSTRACT OBJECTIVE: To evaluate risk factors of linezolid-induced thrombocytopenia systematically, and to provide reference for rational drug use in clinic. METHODS: Retrieved from PubMed, Embase, Cochrane library, Web of Science, CBM, CNKI and Wanfang database, during database establishment to Oct. 2018, clinical studies about risk factors of linezolid-induced thrombocytopenia were collected, and the data of literatures met criteria were collected. After Newcastle-Ottawa scale (NOS) was applied for evaluating the quality of included literatures. Meta-analysis was conducted by using Rev Man 5.3 software. RESULTS: Sixteen clinical studies involving 2 264 patients in total were included. Results of Meta-analysis showed that daily per kg dose (DKPD) [SMD=0.62, 95%CI(0.29,0.95), P=0.000 2], low platelet count before medication [SMD=-0.90, 95%CI(-1.62, -0.18), P=0.01], low creatinine clearance rate [SMD=-0.65, 95%CI(-1.10,-0.19), P=0.005], long treatment course [SMD=0.45, 95%CI(0.18,0.71), P=0.000 9], low body weight [SMD=-0.36, 95%CI(-0.60,-0.11),P=0.005] significantly influenced the occurrence of thrombocytopenia. CONCLUSIONS: The risk factors associated with linezolid-induced thrombocytopenia include low baseline platelet count, low creatinine clearance rate, low body weight, long medication course and high DKPD.
  KEYWORDS Linezolid; Thrombocytopenia; Risk factors; Meta-analysis
  利奈唑胺是美國FDA批准用于临床使用的首个全合成唑烷酮类抗菌药物,为一种可逆的单胺氧化酶抑制剂[1]。该药说明书批准的适应证有耐万古霉素屎肠球菌引起的感染、由金黄色葡萄球菌或肺炎链球菌引起的医院获得性肺炎或社区获得性肺炎、复杂性皮肤和皮肤软组织感染、非复杂性皮肤和皮肤软组织感染。在既往临床试验中发现,该药可导致血小板计数异常,一项回顾性分析显示利奈唑胺诱导的血小板减少会致使重症患者死亡率升高[2]。文献报道利奈唑胺引起血小板减少与多种因素相关[3-5],截至目前,笔者检索的相关文献发现,能够影响利奈唑胺血小板减少的危险因素主要有血药谷浓度、体质量、肾功能不全、血小板基础值、疗程等,研究多为单中心临床试验和小样本试验结果。本研究运用Meta分析方法,对利奈唑胺引起血小板减少的危险因素进行系统评价和统计分析,以期为临床合理用药提供决策依据。   1 资料与方法
  1.1 文献检索策略
  计算机检索PubMed、Embase、Cochrane图书馆、Web of Science、中国生物医学文献数据库、中国知网和万方数据,同时辅以手工检索及追溯纳入文献的参考文献,检索时间范围为建库起至2018年10月。检索采用主题词与自由词相结合的方式,并根据各数据库的特点对检索式进行调整。中文检索词包括“利奈唑胺”“血小板减少”“剂量调整”“治疗药物浓度监测”。英文检索词包括“Linezolid”“Thrombocytopenia”“Dosage strategy”“TDM”。
  1.2 纳入与排除标准
  利奈唑胺相关血小板减少的定义:排除其余原发或继发血小板减少因素,在应用利奈唑胺治疗后出现血小板计数<100×109 L-1或者低于基线值的75%。纳入标准:(1)研究类型为病例对照研究;(2)研究对象是使用利奈唑胺抗感染治疗的患者;(3)确诊为应用利奈唑胺相关的血小板减少不良事件;(4)比较使用利奈唑胺抗感染治疗后发生血小板减少(Thrombocytopenia,TP)与未发生血小板减少(Normal platlet count,NPC)患者的各项指标[年龄、日公斤剂量(DKPD)、体质量、血小板基础值、肌酐清除率、利奈唑胺血药谷浓度、疗程]。排除标准:非利奈唑胺相关的血小板减少研究;重复发表文献;综述或个案报道、专家评论、编辑意见、产品说明、新闻报道、会议征文等;仅以摘要发表的文献;原始数据无法使用,联系原文作者也不能获得有意义数据的文献。
  1.3 文献筛选、资料提取与质量评价
  由两位评价者各自独立检索和阅读文献,独立摘录相关信息,按照纳入与排除标准独立筛选文献、提取资料和评价纳入研究的质量,如遇分歧,则讨论解决或交由第三方协助裁定。文献资料质量评定参照纽卡斯尔-渥太华质量评估量表(Newcastle-Ottawa scale,NOS)文献质量评估量表[6],该标准包括3个方面的评价:病例组与对照组选择方法;病例组与对照组的可比性;接触暴露评估方法。NOS满分为10分,其中研究对象选择为4分,可比性2分,暴露评估方法4分,NOS>5分的研究可被纳入分析,NOS≥7分的为高质量文献。
  1.4 统计学处理
  采用 Rev Man 5.3 软件对入选文献进行Meta分析,对各研究进行异质性检验。当异质性检验结果为P>0.10,I 2<50%,表明各研究间不存在异质性,采用固定效应模型时进行Meta分析;若异质性检验结果为P≤0.1和/或I 2≥50%,提示各研究结果间存在异质性,则采用随机效应模型进行Meta分析。连续性变量采用标准均数差(Standard mean difference,SMD)为效应分析统计量,区间估计采用 95%置信区间(CI)。P<0.05表示差异具有统计学意义。
  2 结果
  2.1 文献检索结果与质量评价
  初次检索共得到6 243篇文献,其中英文文献6 070篇,中文文献173篇,通过阅读文献题目与摘要,排除明显不相关者得到49篇文献,阅读全文后经NOS质量评价筛选最终纳入16篇文献。16篇文献中3篇为前瞻性研究,13篇为回顾性研究。
  16篇文献均为英文文献[7-22],涉及患者2 264例,所有患者均用利奈唑胺600 mg,q12 h给予抗感染治疗,其中TP组 732例,NPC组1 532例。纳入研究的基本特征以及质量评价结果见表1,由于符合条件纳入的文献关于利奈唑胺谷浓度分析的仅有1篇[19],因此未对谷浓度进行Meta分析。
  2.2 Meta分析结果
  Meta分析结果见图1。
  2.2.1 DKPD 5项研究[7-11](668例患者)报道了利奈唑胺DKPD,各研究间有统计学异质性(P=0.01,I 2=75%),排除临床异质性来源采用随机效应模型合并效应量进行分析。Meta分析结果显示,TP组利奈唑胺DKPD显著高于NPC组,差异有统计学意义[SMD=0.62,95%CI(0.29,0.95),P=0.000 2],详见图1A。
  2.2.2 疗程 11项研究[7,9,11-18,20](1 945例患者)报道应用利奈唑胺的疗程,各研究间有统计学异质性(P<0.001,I 2=82%),排除临床异质性来源采用随机效应模型合并效应量进行分析。Meta分析结果显示,TP组应用利奈唑胺的疗程显著长于NPC组,差异有统计学意义[SMD=0.45,95%CI(0.18,0.71),P=0.000 9],详见图1B。
  2.2.3 血小板基础值 12项研究[7-12,14-17,20-21](1 189例患者)报道应用利奈唑胺前的血小板基础值,各研究间有统计学异质性(P<0.001,I 2=97%),排除临床异质性来源采用随机效应模型合并效应量进行分析。Meta分析结果显示,TP组应用利奈唑胺前的血小板基础值低于NPC组,差异有统计学意义[SMD=-0.90,95%CI(-1.62,-0.18),P=0.01],详见图1C。
  2.2.4 肌酐清除率 6项研究[7,9-12,17](692例患者)報道患者肌酐清除率,各研究间有统计学异质性(P<0.001,I 2=84%),排除临床异质性来源采用随机效应模型合并效应量进行分析。Meta分析结果显示,TP组给药前肌酐清除率显著低于NPC组,差异有统计学意义[SMD=-0.65,95%CI(-1.10,-0.19),P=0.005],详见图1D。
  2.2.5 体质量 11项研究[7-12,14-15,18,20,22](1 291例患者)报道患者体质量,各研究间有统计学异质性(P=0.000 1, I 2=72%),排除临床异质性来源采用随机效应模型合并效应量进行分析。Meta分析结果显示,TP组体质量显著低于NPC组,差异有统计学意义[SMD=-0.36,95%CI(-0.60,-0.11),P=0.005],详见图1E。   2.2.6 年齡 15项研究[7-18,20-22](2 258例患者)报道患者年龄,各研究间有统计学异质性(P<0.000 01,I 2=81%),排除临床异质性来源采用随机效应模型合并效应量进行分析。Meta分析结果显示,TP组与NPC组年龄的差异无统计学意义[SMD=0.10,95%CI(-0.13,0.34),P=0.39],详见图1F。
  2.3 发表偏倚
  以年龄为指标绘制倒漏斗图,结果倒漏斗图结果显示样本主要分布于中线周围且分布对称,说明本研究纳入的文献发表偏倚较低,详见图2。
  3 讨论
  利奈唑胺作为唑烷酮类药物,能与核糖体50S亚基肽基转移酶中心可逆结合起到抗菌作用。其结构具有分子量小、脂溶性高的特点,具有良好的组织穿透性,给药后血药浓度>4 μg/mL的时间在9~10 h,口服给药生物利用度100%,非肾脏清除率为65%,具有良好的药动学和药效学性质,在抗革兰氏阳性菌感染中广泛使用[23-24]。多例临床研究报道在应用利奈唑胺的过程中患者出现血小板减少的不良事件,对长期应用利奈唑胺后进行的安全性评价的研究发现,血小板减少是利奈唑胺最主要的严重不良反应[25]。
  本文采用Meta分析方法,对利奈唑胺引起血小板减少的危险因素进行了系统评价,结果显示TP组患者的体质量、肌酐清除率和用药前血小板计数低于NPC组;而TP组的疗程长于NPC组,TP组DKPD高于NPC组;而两组的年龄的差异无统计学意义。
  文献报道利奈唑胺引起血小板减少的危险因素具体包括疗程≥14 d[12]、肌酐清除率<50 mL/min[18]、DKPD>22 mg/(kg·d)[9]、体质量<55 kg[10]。另有研究表明,上述危险因素与利奈唑胺谷浓度存在一定的联系,长期应用利奈唑胺进行TDM的成年患者中发现,当利奈唑胺血药谷浓度ctrough>7 mg/L或AUC>300 mg/(L·h)时血小板下降的风险>50%[25];Dong YH等[26]研究了利奈唑胺谷浓度与血小板减少和疗效的关系,发现当ctrough>2 mg/L时细菌清除的概率>80%,当ctrough>6.3 mg/L时发生血小板减少的概率>50%,认为给药剂量及体质量与血药谷浓度密切相关。随着利奈唑胺用药时间的延长,血药谷浓度逐渐上升,而血小板计数逐渐下降[25];Matsumoto K等[23]运用群体药动学模型发现给药剂量、肌酐清除率与血药谷浓度密切相关;Nukui Y等[24]研究发现在肾功能不全患者中,发生血小板减少患者的利奈唑胺谷浓度平均值为13.4 mg/L,未发生血小板减少患者为4.3 mg/L。但是由于研究中符合纳入条件的样本量较少(n=1)[19],无法对谷浓度进行有意义的Meta分析,因此对于谷浓度是否作为利奈唑胺血小板减少的影响因素可能还需进一步的研究。
  本研究发现DKPD与利奈唑胺诱导血小板减少直接相关,提示可通过调整利奈唑胺DKPD来降低血小板下降风险;分析显示发生利奈唑胺诱发血小板减少的患者存在体质量较轻、肌酐清除率低、血小板基础值较低或者给药疗程长等个体因素,因此在调整给药剂量时需要参考上述个体化因素。
  综上所述,本次Meta分析结果发现患者的血小板基础值、肌酐清除率、体质量和用药疗程是影响利奈唑胺诱发血小板减少的重要因素,患者应用利奈唑胺的DKPD与血小板减少直接相关。笔者认为需要根据患者的血小板基础值、肌酐清除率、疗程、体质量等因素通过调整日给药剂量来降低利奈唑胺诱发血小板减少发生风险。由于研究符合纳入条件的样本文献较少,导致无法对谷浓度进行Meta分析,但根据作者检索的大量文献结果,笔者仍然建议患者监测利奈唑胺血药谷浓度以防止可能的利奈唑胺诱导血小板减少。
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  (收稿日期:2018-10-11 修回日期:2019-01-14)
  (編辑:刘明伟)
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