随机对照试验Meta分析的质量评价

目的了解国内随机对照试验Meta分析的质量,找出问题所在,提高研究质量.资料与方法以检索到的6个国内随机对照试验的Meta分析报告为研究样本,以Sacks等提出的Meta分析质量评价方法为基础,对评分细则稍加调整,作为评价标准.评价标准包含6个方面的23个项目.根据每个项目是否被涉及和规范程度,酌情计予4、2或0分.每个研究的23个项目的总分除以满分(92分),得到一个质量百分数.结果6项研究的平均得分为(40 94±20.92),最高得分为71.74,最低为17.39,这些研究的得分差距非常大.对在此次质量评价中考虑的6个方面的所有23个项目,只有一项Meta分析强调了6个方面的至少1个项目;2项Meta分析强调了5个方面的至少1个项目;一项Meta分析强调了4个方面的至少1个项目;1项Meta分析强调了3个方面的至少1个项目;Meta分析只强调了2个方面的至少1个项目.对所有23个项目,只有4～17个项目被强调.结论急需对Meta分析方法的应用加以规范,既推广,又防止"滥用".     

Zonisamide for Bipolar Depression: A Randomized,Double Blind,Placebo-Controlled,Adjunctive Trial

Objective

This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar depression.

Experimental design

One hundred two patients with bipolar disorder, type I or II in the depressed phase of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases, a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. MADRS score was the primary outcome variable. Secondary outcome measures included the YMRS, CGI-S, CGI-I, Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also evaluated. Side effects were measured using the SAFTEE.

Principal observations

There were no statistically significant differences in response between subjects treated with adjunctive zonisamide vs. placebo controls for the primary or secondary outcome measures. There were also no differences between the groups with regard to response rate or remission rate.

Conclusions

In contrast to preliminary open label studies that suggested a role for zonisamide in bipolar depression, we could not confirm these results in a large double blind controlled study.     

基于Meta分析的葛根素注射剂辅助治疗脑梗死临床评价研究

摘 要 目的：采用Meta分析方法评价葛根素注射剂辅助西医常规治疗脑梗死的有效性及安全性。方法：计算机检索the Cochrane Library、PubMed、Embase、SinoMed、中国期刊全文数据库（CNKI）、中文科技期刊全文数据库（VIP）、万方数据库中有关葛根素注射剂治疗脑梗死的随机对照试验（RCTs）,文献检索年限为各数据库建库至2016年10月22日。采用Cochrane风险评估表评价其偏倚风险,提取资料并通过 RevMan5.3 软件进行数据分析。结果：共纳入18个RCTs,累计1 624名患者。Meta分析结果显示,在西医常规治疗的基础上,联用葛根素注射剂可提高脑梗死患者的临床总有效率（RR=1.21,95%CI：1.15~1.26,P<0.000 01)。此外,联用葛根素注射剂也可改善神经功能缺损情况（MD=-5.03,95%CI：-6.88~ -3.17,P<0.000 01）,影响血液流变学指标等。纳入研究中2个RCTs明确记录未发生明显不良反应,5个RCTs发生了26例不良反应。结论：葛根素射剂辅助西医常规治疗脑梗死具有较好的疗效,但其安全性需进一步探讨。     

A Meta-analysis of Factors Impacting Detection of Antidepressant Efficacy in Clinical Trials: The Importance of Academic Sites

Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant–placebo differences, we conducted a meta-analysis of all relevant phase II–IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D₁₇) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (β=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug–placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug–placebo separation for both HAM-D₁₇ continuous score change (β=2.24, p=0.034) and response rate (β=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.     

骨松宝颗粒治疗骨质疏松随机对照试验的Meta分析

目的:采用循证医学的方法评价骨松宝颗粒自上市后临床使用的有效性和安全性。方法:计算机检索CNKI全文数据库医药卫生专辑、维普资讯网、万方数据库以及美国国立医学图书馆(PubMed)和Cochrane图书馆中的相关内容;手工检索《中国药典》(2005年版)、《中国循证医学杂志》(2001年1月～2009年5月),并查阅相关文献的参考文献,文献检索语种不限,检索起止日期为各资料库的最早起始日期至2009年6月30日。根据Jadad量表评分标准对纳入文献进行质量评定。数据的统计处理应用Meta分析方法。结果:14篇RCT研究符合纳入标准,均为中文发表研究,其中高质量研究10篇,低质量研究4篇,有2篇为骨松宝颗粒与安慰剂对照,采用骨松宝颗粒治疗的患者共842例。结果表明,骨松宝颗粒用于治疗骨质疏松,可以改善骨质疏松中医证候;对提高L2～4骨密度、股骨颈骨密度、Words’三角骨密度、大粗隆骨密度有疗效;治疗组与其它同类药物的不良反应发生率无明显差异;所有纳入试验均未报告严重不良反应。结论:现有证据表明骨松宝颗粒在改善骨质疏松症状、提高骨密度方面疗效确切。然而,由于现有证据存在潜在的发表偏倚和所纳入RCT的随访时间不够长,需进一步长期观察研究以掌握其疗效和安全性。     

依巴斯汀治疗慢性荨麻疹临床疗效的Meta分析

目的:评价依巴斯汀治疗慢性荨麻疹临床疗效及不良反应。方法:计算机检索Cochrane图书馆、PubMed、EMbase、中国知网和万方数据库。检索时间均为建库至2011年2月。收集以依巴斯汀与其他药物对照治疗慢性荨麻疹的随机对照临床试验(RCT)。评价纳入文献的研究质量,提取有效数据,采用RevMan 5.0软件进行Meta分析。结果:共纳入12个研究,包括1567例慢性荨麻疹患者。Meta分析结果显示,依巴斯汀治疗慢性荨麻疹临床疗效较其他抗组胺药高;依巴斯汀联合用药或其他抗组胺药联合用药治疗慢性荨麻疹临床疗效比单一应用依巴斯汀的疗效高,但复发率比较差异无统计学意义;依巴斯汀治疗慢性荨麻疹的不良反应与依巴斯汀联合用药或其他抗组胺药联合用药比较,差异无统计学意义。结论:依巴斯汀能有效治疗慢性荨麻疹,不良反应少。由于慢性荨麻疹病因复杂,且本次研究仍有局限性,还需要更多大样本、设计严格的随机临床对照试验加以证实。     

基于Meta分析的康艾注射液辅助治疗结直肠癌临床评价研究

摘 要 目的：采用Meta分析方法评价康艾注射液联合FOLFOX化疗方案治疗结直肠癌的临床疗效与安全性。方法：通过计算机检索PubMed、the Cochrane Library、Embase、中国期刊全文数据库（CNKI）、中国生物医学文献服务系统（SinoMed）、中文科技期刊数据库（VIP）、万方数据库(Wanfang)中关于康艾注射液联合FOLFOX化疗方案治疗结直肠癌的随机对照试验,检索时间从数据库建库至2016 年10月。由两位研究者独立对纳入研究进行偏倚风险评价,提取资料并通过RevMan 5.3 软件对纳入研究的临床疗效及安全性进行分析。结果：共纳入13项研究,累计患者952例。Meta分析结果显示,康艾注射液联合FOLFOX化疗方案不仅可以提高结直肠癌患者的临床总有效率（RR=1.17,95%CI：1.01~1.35,P=0.03）,而且可以改善患者的生存质量（RR=2.06,95%CI：1.67~2.52,P<0.000 01）,此外,可以降低不良反应发生率。结论：现有临床证据表明在FOLFOX化疗方案基础上联用康艾注射液对结直肠癌有一定的辅助治疗作用,值得临床推荐使用。但本研究结论尚需更多设计合理、严格执行的大样本随机双盲对照试验加以证实。     

Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance

Introduction: Bipolar disorder is characterized by a complex set of symptoms, including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of patients with bipolar disorder is mandatory to prevent symptom relapse and episode recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence combinations of mood stabilizers and antipsychotics are widely utilized in patients showing no or partial response to, as well as intolerance to, monotherapies. This may offer a therapeutic advantage, however, the possibility of an increased incidence of side effects should be considered.

Areas covered: This paper reviews the current treatment guidelines for the treatment of bipolar disorder and examines the rationale behind the use of aripiprazole in combination with mood stabilizers for acute and long-term treatment of bipolar disorder.

Expert opinion: The combination of aripiprazole and mood stabilizers seems to offer an effective and relatively well-tolerated option for the treatment of acute mania and for the maintenance treatment of patients with bipolar I disorder. The combination presents a lower risk of metabolic side effects compared with other combination therapies, but increases the risk of extrapyramidal side effects with long-term treatment. The aripiprazole–valproate combination seems to be particularly promising in the treatment of patients with comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to confirm these observations and to provide a useful insight for improving the use of drug combinations in bipolar patients.     

A Systematic Review and Meta-analysis of the Incidence of Cancer in Randomized,Controlled Trials of Verapamil

We conducted a systematic review of all published randomized, controlled trials to assess the risk of cancer or death in patients receiving verapamil for hypertension, angina pectoris, or cardiac arrhythmias. Meta-analysis comparing the risk of new cancers, cancer deaths, and all deaths was performed. Thirty-nine trials comprising 11,201 patients were eligible. Study durations ranged from 8 days-6 years (mean 29.5 wks). Nine trials (6507 patients) were 24 weeks in duration or longer. For cancer and cancer death, OR was 1.20 (95% CI = 0.60–2.42) for verapamil versus active controls and 0.73 (95% CI = 0.39–1.39) for verapamil versus placebo. For all deaths, OR was 1.13 (95% CI = 0.70–1.82) for verapamil versus active controls and 0.85 (95% CI = 0.71–1.00) for verapamil versus placebo. Sensitivity analysis for the 9 trials 24 weeks' duration or longer gave similar results. There is no statistically significant increased risk of cancer or deaths with verapamil compared with active controls or placebo.     

中药抗病毒注射剂治疗呼吸道感染随机对照试验Meta分析文献的质量评价

目的:为提高国内Meta分析研究水平提供参考。方法:以检索到的13篇国内中药抗病毒注射剂随机对照试验的Meta分析报告为研究样本,采用QUOROM声明、CONSORT声明、Jadad评分标准、Sacks等提出的Meta分析质量评价方法综合评价13篇Meta分析报告的质量。如果有争议采取讨论和仲裁方式解决。结果:13项研究的平均得分为(64±10.13)分,最高得分为84分,最低为52分。此次质量评价中考虑了5个方面的25个项目,13项研究都覆盖了这5个方面,对25个项目的覆盖率最低为60%,最高为88%。结论:Meta分析的应用在我国已取得长足进步,为使Meta分析结果更完善,更具可靠性,仍需对Meta分析方法的应用加以规范,只有规范严谨的分析方法才能得到可靠正确的结论。     

From Randomized Controlled Trials of Antidepressant Drugs to the Meta-Analytic Synthesis of Evidence: Methodological Aspects Lead to Discrepant Findings

During the last decade, several meta-analytic studies employing different methodological approaches have had inconsistent conclusions regarding antidepressant efficacy. Herein, we aim to comment on methodological aspects that may have contributed to disparate findings. We initially discuss methodological inconsistencies and limitations related to the conduct of individual antidepressant randomized controlled trials (RCTs), including differences in allocated samples, limitations of psychometric scales, possible explanations for the heightened placebo response rates in antidepressant RCTs across the past two decades as well as the reporting of conflicts of interest. In the second part of this article, we briefly describe the various meta-analyses techniques (e.g., simple random effects meta-analysis and network meta-analysis) and the application of these methods to synthesize evidence related to antidepressant efficacy. Recently published antidepressant metaanalyses often provide discrepant results and similar results often lead to different interpretations. Finally, we propose strategies to improve methodology considering real-world clinical scenarios.     

Impact of Perioperative Levosimendan Administration on Risk of Bleeding After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials

American Journal of Cardiovascular Drugs - Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen...     

Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia

Background:

Despite adequate treatment with antipsychotics, a substantial number of patients with schizophrenia demonstrate only suboptimal clinical outcome. To overcome this challenge, various psychopharmacological combination strategies have been used, including antidepressants added to antipsychotics.

Methods:

To analyze the efficacy of add-on antidepressants for the treatment of negative, positive, cognitive, depressive, and antipsychotic-induced extrapyramidal symptoms in schizophrenia, published randomized controlled trials assessing the efficacy of adjunctive antidepressants in schizophrenia were reviewed using the following parameters: baseline clinical characteristics and number of patients, their on-going antipsychotic treatment, dosage of the add-on antidepressants, duration of the trial, efficacy measures, and outcomes.

Results:

There were 36 randomized controlled trials reported in 41 journal publications (n=1582). The antidepressants used were the selective serotonin reuptake inhibitors, duloxetine, imipramine, mianserin, mirtazapine, nefazodone, reboxetin, trazodone, and bupropion. Mirtazapine and mianserin showed somewhat consistent efficacy for negative symptoms and both seemed to enhance neurocognition. Trazodone and nefazodone appeared to improve the antipsychotics-induced extrapyramidal symptoms. Imipramine and duloxetine tended to improve depressive symptoms. No clear evidence supporting selective serotonin reuptake inhibitors’ efficacy on any clinical domain of schizophrenia was found. Add-on antidepressants did not worsen psychosis.

Conclusions:

Despite a substantial number of randomized controlled trials, the overall efficacy of add-on antidepressants in schizophrenia remains uncertain mainly due to methodological issues. Some differences in efficacy on several schizophrenia domains seem, however, to exist and to vary by the antidepressant subgroups—plausibly due to differences in the mechanisms of action. Antidepressants may not worsen the course of psychosis. Better designed, larger, and longer randomized controlled trials are needed.     

Effect of Vortioxetine on Cognitive Impairment in Patients With Major Depressive Disorder: A Systematic Review and Meta-analysis of Randomized Controlled Trials

BackgroundDementia and depression are increasingly common worldwide, and their effective control could ease the burden on economies, public health systems, and support networks. Vortioxetine is a new antidepressant with multipharmacologic actions that elevate the concentration of serotonin and modulate multiple neurotransmitter receptors in the brain. We conducted a meta-analysis to explore whether the cognitive function of patients with major depressive disorder (MDD) treated with vortioxetine would improve.MethodsWe systematically reviewed randomized controlled trials (RCTs) in the PubMed, Embase, and Cochrane databases to assess the treatment effects of vortioxetine on the cognitive function of patients with MDD. The outcome measures included the Digit Symbol Substitution Test (DSST), Perceived Deficits Questionnaire (PDQ), and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Pooled results were calculated using a fixed-effects or random-effects model according to the heterogeneity of the included trials.ResultsSix RCTs with a total of 1782 patients were included in the meta-analysis, which demonstrated that vortioxetine improved DSST, PDQ, and MADRS scores in patients with MDD. The results were consistent at the 10- and 20-mg doses. In the 20-mg group, the decrease in MADRS scores was more significant than that in the placebo group.ConclusionsBoth the 10- and 20-mg doses of vortioxetine can significantly increase DSST scores and decrease PDQ and MADRS scores in patients with MDD and cognitive dysfunction, but further studies with longer follow-up periods to assess mental function are required.     

药物临床试验安全性报告的规范

从药物临床试验的定义及各分期对安全性的要求强调安全性报告的重要性。简单介绍药物临床试验安全性报告的现状,并对CONSORT声明扩展版中针对药物有害性临床试验报告的标准及条目进行解释。     

随机对照试验设计及实践心得

随机对照临床试验是医学研究最重要的研究类型之一，科学的设计和规范的实施是保证研究结果真实、可靠的重要前提。作者结合临床试验方案设计的准则及实践心得，对开展随机对照临床试验的研究终点、样本量估算、随机化和分配隐藏、盲法、分析集、中期分析、在线注册、数据管理、研究报告撰写等关键环节进行了简明的总结，以期为临床试验项目的开展提供参考。     

Zonisamide for bipolar disorder, mania or mixed states: a randomized, double blind, placebo-controlled adjunctive trial

Objective

This is the first multicenter, double blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar mania or mixed state.

Experimental design

One hundred four patients with Bipolar Disorder, Type I, II or NOS, in a manic, hypomanic or mixed state of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases: a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. The primary outcome variable for manic and hypomanic patients was the Young Mania Rating Scale (YMRS) both the YMRS and Montgomery Asberg Depression Rating Scale (MADRS) served as primary outcome variables for patients in mixed states. Secondary outcome measures included the Clinical Global Impression for Bipolar Disorder (CGI-BP), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also analyzed. Side effects were measured using the SAFTEE.

Principal observations

There were no statistically significant differences for any of the primary or secondary outcome measures between zonisamide and placebo-treated patients.

Conclusions

In contrast to previous studies that suggested efficacy of adjunctive zonisamide in bipolar mania or mixed state, these results were not confirmed in this double blind controlled study.     

真实世界证据与随机对照试验：RCT DUPLICATE项目概述

摘 要近年来,利用真实世界数据（real world data, RWD）通过恰当的设计和分析产生真实世界证据（real world evidence, RWE）,已经成为学术界、工业界和监管机构共同关注的话题。但RWE能否代替来自严格受控的随机对照试验（RCT）产生的证据仍不确定。为此,2018年美国启动了RCT DUPLICATE项目,旨在利用真实世界证据,通过非随机的观察性研究来重复RCT的结果。本文回顾了RCT DUPLICATE产生的背景,重点介绍了该项目的研究团队、研究目的、研究内容及项目意义,以期促进国内学者更好地理解RWE的适用范围和应用价值。