OBJECTIVES To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing. DESIGN Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES GlaxoSmithKline's (GSK's) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK's Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults. DATA EXTRACTION AND SYNTHESIS For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals. RESULTS 33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK's summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used. CONCLUSIONS The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety. SYSTEMATIC REVIEW REGISTRATION OSF Home https://osf.io/4yvp2/.

中文翻译：

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通过共享数据更新对罗格列酮和心血管风险的认识：个体患者和汇总级别的荟萃分析。

目的 使用多个数据源和不同的分析方法对罗格列酮治疗对心血管风险和死亡率的影响进行系统评价和荟萃分析，并考虑三个目标：澄清罗格列酮心血管风险的不确定性；确定不同的分析方法是否可能改变不良事件荟萃分析的结论；并为促进临床试验透明度和数据共享的努力提供信息。设计 随机对照试验的系统评价和荟萃分析。数据来源 葛兰素史克 (GSK) 的 ClinicalStudyDataRequest.com 用于个体患者水平数据 (IPD) 和 GSK 的研究注册平台、MEDLINE、PubMed、Embase、Web of Science、Cochrane 对照试验中央注册中心、Scopus 和临床试验。gov 从开始到 2019 年 1 月的摘要级别数据。选择研究的资格标准 在成人中比较罗格列酮与任何对照至少 24 周的随机、对照、II-IV 期临床试验。数据提取和综合 对于可获得 IPD 的试验的分析，检查了急性心肌梗死、心力衰竭、心血管相关死亡和非心血管相关死亡的复合结果。这四个事件作为次要分析独立检查。对于包括无法获得 IPD 的试验在内的分析，检查了心肌梗塞和心血管相关的死亡，这些死亡是根据汇总水平数据确定的。进行了多项荟萃分析，其中一个或两个臂的事件为零的试验具有两个不同的连续性校正（0.5 常数和治疗臂），以计算具有 95% 置信区间的优势比和风险比。结果 从 ClinicalStudyDataRequest.com 中确定了 33 项符合条件的试验，其中 IPD 可用（21 156 名患者）。此外，103 项无法获得 IPD 的试验被纳入心肌梗死的荟萃分析（23 683 名患者），103 项无法获得 IPD 的试验有助于心血管相关死亡的荟萃分析（22 772 名患者） . 在 29 项 IPD 可用的试验中，这些试验包括在使用葛兰素史克的汇总水平数据进行的先前荟萃分析中，在 26 项试验中，使用 IPD 而非汇总水平数据确定了更多的心肌梗死事件，而在 5 项试验中，心血管相关的死亡人数更少。当分析仅限于有 IPD 可用的试验，并且使用 0.5 的恒定连续性校正和随机效应模型来解释仅在一只手臂中发生零事件的试验时，接受罗格列酮治疗的患者出现 33% 的风险增加复合事件与对照组相比（优势比 1.33，95% 置信区间 1.09 至 1.61；罗格列酮人群：11837 名患者中的 274 起事件；对照组：9319 名患者中的 219 起事件）。心肌梗死、心力衰竭、心血管相关死亡和非心血管相关死亡的比值比分别为 1.17（0.92 至 1.51）、1.54（1.14 至 2.09）、1.15（0.55 至 2.41）和 1.18（0.60 至 2. 30），分别。对于包括没有 IPD 的试验在内的分析，心肌梗死和心血管相关死亡的优势比降低（分别为 1.09、0.88 至 1.35 和 1.12、0.72 至 1.74）。当使用跨双臂零事件的试验重复分析并使用两个连续性校正中的任何一个时，结果大致一致。结论结果表明，罗格列酮与心血管风险增加有关，尤其是心力衰竭事件。尽管在分析中观察到心肌梗死风险增加，但在 IPD 之外使用汇总水平数据时，证据的强度各不相同，并且效果估计值减弱。由于 IPD 中报告的心肌梗塞和心血管相关死亡人数少于汇总级别数据，因此在进行侧重于安全性的荟萃分析时，共享 IPD 可能是必要的。系统审查注册 OSF 主页 https://osf.io/4yvp2/。