阿托伐他汀类药物预防冠状动脉造影/经皮冠状动脉介入治疗对比剂肾病:荟萃分析

    殷莹 胡菊萍

    

    

    【摘要】目的 使用META分析方法研究经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)术前强化阿托伐他汀治疗与预防造影剂肾病(CIN)相关性。方法 本文通过系统检索PubMED、Embase、CBM、Cochrane library等数据库公开发表文献,检索时间截止为2017年12月,且这些文献均以CIN发病率为研究终点,经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)术前强化使用阿托伐他汀与造影剂肾病相关性为研究内容的临床试验文献。结果 共纳入11篇研究文献。结果显示,与对照组相比,术前强化使用阿托伐他汀能显著降低CIN发病率,差异有统计学意义(OR=0.45,95%CI=0.34-0.61,P<0.00001),与此同时发现,将高剂量阿托伐他汀进行亚组分析,最终所得结果也具有统计学意义(OR=0.44,95%CI=0.24-0.81,P=0.009)。结论 术前强化阿托伐他汀治疗能显著降低经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)CIN发病风险。但是对于高剂量阿托伐他汀的预防性治疗,仍需更多研究来提供最佳预防性治疗方案。

    【关键词】阿托伐他汀;造影剂肾病;冠状动脉造影;经皮冠状动脉介入治疗;meta分析

    【中图分类号】R969.4 【文献标识码】A 【文章编号】ISSN.2095.6681.2019.28..04

    【Abstract】objective The results of the studies that reported efficacy of atorvastatin pre-treatment for decreasing the incidence of contrast-induced acute kidney injury (CIAK) in patients undergoing coronary angiography(CAG)or percutaneous coronary intervention(PCI)have been controversial.Objective The aim of the study was to perform a meta-analysis to evaluate the efficacy of atorvastatin on contrast induced nephropathy after CAG or PCI treatment.Methods A systematic electronic search of online electronic databases: Pubmed, Embase, Cochrane library updated on December 2017. The meta-analysis was performed including randomized-controlled trials that comparing atorvastatin versus either low-dose statin or placebo pre- treatment for prevention of CIAKI in patients undergoing CAG,of which the main outcomes was the incidence of contrast-induced nephropathy(CIN).Results A total of 11 randomized controlled trials were included in this analysis, The atorvastatin treatment group can significantly reduce the incidence of CIN (OR=0.45,95%CI=0.34-0.61,P<0.00001).The benefit of high-dose statin was consistent in compared with the control group(OR 0.44,95% CI 0.24-0.81, p=0.009).Conclusions This meta-analysis suggests that preoperative atorvastatin significantly reduced renal insufficiency risk of CIN in patients undergoing CAG,and plays as an effective prophylactic approach to prevent CIAKI, especially for the high-dose atorvastatin. Additional studies are needed to identify at-risk patients, provide optimum peri-procedural treatment, and reduce the incidence of contrast-induced nephropathy(CIN).

    【Key words】atorvastatin; contrast-induced acute kidney injury; coronary angiography; percutaneous coronary intervention; meta-analysis

    造影劑所引起的相关急性肾功能损伤,临床上定义为造影剂肾病,被认为与医院获得性肾功能损伤及死亡率具有明显相关性[1]。近年,越来越多的心内科介入医生开始关注介入术后肾功能损伤,然而相关在肾损伤的病理学研究方面却存在一定争议。一些研究显示肾脏受损过程中氧化应激、炎症、肾脏血流动力学改变及造影剂直接引起管状细胞损伤相互作用[2]。其他机制包括血管收缩因子引起迟发性造影剂肾脏细胞受损导致氧化应激损伤和肾小管重吸收造影剂导致肾小管直接损伤[3-4]。

    因他汀类药物具有调脂作用,因而常被用于治疗心血管相关疾病。随着对他汀类研究的不断深入,越来越多研究发现他汀类药物还具有抗炎、抗氧化和改善内皮功能等作用[5]。目前有些研究发现短期使用他汀类药物可以预防性降低CIN发病率,但有些研究结果却与之相反[6]。

    本研究主要使用Meta分析的方法,对此类相关研究结果进行综合系统评价,探讨研究经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)强化阿托伐他汀与预防造影剂肾病相关性,来对这一结论的争议性进行分析。

    1 资料与方法

    1.1 纳入标准

    所纳入研究试验组为阿托伐他汀,对照组为安慰剂,均为随机对照试验;检索文献研究终点为造影剂肾病发生率;纳入研究患者接受了冠状动脉造影和/或经皮冠状动脉介入治疗术;仅纳入英文文献。

    排除标准:同时使用其他他汀类药物预防性治疗;研究终点未用CIN发病率作为疗效评价指标;仅抽象的,缺乏全文文献等,不能获得足够的原始数据的文献;重复出版和报告。

    1.2 检索

    策略系统性检索2017年12月之前公开发表的文献,在Cochrane library、PubMED、Embase、CBM等数据库中检索数据, 以“造影剂肾病”“阿托伐他汀”等为检索关键词进行检索。阅读文献的参考文献,必要时进行扩大检索,纳入符合纳入标准文献。

    1.3 质量评估

    所选择的文献的质量是使用纽卡斯尔渥太华量表评价[7]。数据提取即是对文献中的每个评价指标进行评价。满足1项予以1分。如果所有所选文献的8个指标都满足,给予9分;如果获得6点以上,质量被认为是好的。

    1.4 资料提取

    由2名研究员对数据进行搜集,有分歧时进行讨论,必要时第三方参与讨论解决。所提取的数据主要包括:(1)一般信息:标题,作者,发布日期和文献来源;(2)文献中的方法的信息;(3)研究特征:各组患者的基本数据;(4)成果指标。高剂量阿托伐他汀定义为每天至少80mg;低剂量阿托伐他汀定义为每天少于8 0mg。

    1.5 统计学方法

    本文采用Cochrane协作网提供的RevMan5.3软件进行统计。计数资料采用比值比(OR)为效应量,各效应量均以95﹪CI表示。各纳入研究结果间的异质性采用I2检验[8],若无统计学异质性(P>0.1,I2<50﹪),采用固定效应模型;若有统计学异质性(P>0.1,I2>50﹪),需分析异质性来源,确定是否能采用随机效应模型[9]。

    2 结 果

    2.1 入选文献质量评价

    根据文献入选和排除标准,348篇相关文章可以检索到,阅读的问题和摘要的阅读,331篇不符合纳入标准被排除在外,和17篇最初包括在内。阅读全文后,其中6不符合纳入标准。最后,11篇文章被包括在本研究[10-20],并且所选择的文献的质量得分均高于6分。见表1,且搜索过程在图1中示出。

    2.2 阿托伐他汀与经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)造影剂肾病相关性

    共纳入11篇研究文献(图2),结果显与对照组相比,强化阿托伐他汀显著降低CIN发病率共纳入11篇研究文献(图2),结果显与对照组相比,强化阿托伐他汀显著降低CIN发病,差异有统计学意义(OR=0.45,95%CI=0.34-0.61,P<0.00001)。

    2.3 高剂量阿托伐他汀与经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)造影剂肾病相关性

    高剂量阿托伐他汀与对照组相比,其亚组分析也具有统计学意义(OR=0.44,95%CI=0.24-0.81,P=0.009),显著降低CIN发病率(图3)。

    3 讨 论

    造影剂肾病(CIN)是冠状动脉介入治疗常见术后并发症,会导致死亡率、心血管事件的发生率、院内获得性肾衰竭的风险增加,住院时间延长[21]。因此,预防CIN的发生可以提高临床疗效的获益。

    尽管许多药物被用来预防PCI术后CIN发生,但是预防CIN最有效的治疗方式仍未达成共识[22-24]。CIN的发病机制具有多样性,其中氧化应激是造影剂肾病的重要发病机制之一,目前多项研究表明造影剂肾病的发生发展可能与使用造影剂后的氧化应激增强有关,氧化应激增强可使氧自由基过量产生,从而引起内皮细胞损害,进一步造成肾小管细胞的损伤甚至细胞坏死。此外,肾血液动力学的改变和肾髓质缺氧,肾小管损害,肾小管阻塞及肾小管上皮细胞的凋亡也是CIN的重要原因[25]。

    本研究纳入近年高质量RCT,进行meta询证分析,研究發现强化阿托伐他汀显著降低经皮冠状动脉介入(PCI)或冠状动脉造影(CAG)CIN发病风险,尤其对于使用高剂量阿托伐他汀预防性治疗,效果更显著。

    本研究存在一定局限性:测试人群,病理特点,造影剂类型和给药方案的异质性的分布可能影响结果的分析;各个研究纳入患者基础肾脏功能有差异,导致CIN的发病率有偏差;仅纳入英文文献,可能潜在增大发表偏移。

    综上所述,与安慰剂对照组对比,强化阿托伐他汀治疗能显著降低冠状动脉造影(CAG)或经皮冠状动脉介入(PCI)CIN发病风险。由于纳入文献存在一定的异质性,尚需更多研究为临床决策提供更多询证医学证据。与此同时,对CIN的发病机制研究,筛选出高危人群,早期临床干预,提高临床疗效,降低死亡风险,还需要更多的研究去证实。

    参考文献

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    [4] Li Hong,Li X,Ma H,et al.Atorvastatin in combination with probucol: a new way to reduce serum uric acid levels during the perioperative period of the interventional procedure.ScientificWorldJournal 2014;2014:565367.

    [5] Farmer,J.A. Pleiotropic effects of statins. Current Atherosclerosis Reports 2,208-217(2000).

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    [7] 603-605:Newcastle-Ottawa scale for non-randomized studies in the quality of meta-analysis [J].Eur? epidemic,2010,25(9) Evaluation of the Stan A. Critical evaluation.

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    [9] Higgins,J.P.T.,Thompson,S.G.,Deeks, J.J.& Altman, D.G. Measuring inconsistency in meta-analyses. Bmj 327,557-560(2003).

    [10] ?zhan, H.et al.Coronary angiography in patients with short-term high-dose atorvastatin for the prevention and treatment of contrast nephropathy. Angiography 61,711-714 (2010).

    [11] Acikel,S.et al.Prevention of contrast damage in renal function by long-term statin therapy in patients with short-term or elective coronary angiography.Blood Coagulation & Fibrinolysis 21,750-757(2010).

    [12] Li,W.et al.Beneficial Effects of High-Dose Atorvastatin Pretreatment on Renal Function in Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention.Cardiology 122,195-202(2012).

    [13] Patti,G.,et al.Short-Term, High-Dose Atorvastatin Pretreatment to Prevent Contrast-Induced Nephropathy in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention(from the ARMYDA-CIN [Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Contrast-Induced Nephropathy] Trial. The American Journal of Cardiology 108,1-7(2011).

    [14] Park,S.H.,et al.Therapeutic effects of combination therapy of statins and N-acetylcysteine ??in emergency percutaneous coronary intervention for ST-segment elevation myocardial infarction in patients with contrast-enhanced nephropathy. International Journal of Cardiology 212,100-106 (2016).

    [15] Quinta Valle,C.,et al.The effect of high loading dose of atorvastatin on contrast agent acute kidney injury. Circulation 126, 3008-3016 (2012).

    [16] Tosso,A,etc.It is useful for the prevention of contrast nephropathy in chronic kidney disease atorvastatin (80 mg).American Journal of Cardiology 105, 288-292 (2010).

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    本文編辑:赵小龙

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