Background Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

中文翻译：

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临床研究中的统计争议：评估抗血管生成疗法评估血管不良药物事件的开放标签研究的局限性-荟萃分析。

背景以前的荟萃分析显示，接受抗血管生成药物（AA）的患者出现出血和血栓形成事件的风险反常增加，这可以通过包括的研究设计来简单解释。通过一种元流行病学方法，我们旨在研究双盲（DB）和开放标签研究设计对接受过癌症治疗的癌症患者的出血，静脉血栓形成事件（VTE）和动脉血栓形成事件（ATE）风险的影响机管局。材料和方法我们搜索了Medline，Cochrane，ClinicalTrials.gov数据库和主要肿瘤大会的会议记录，以进行2003年1月至2016年1月发布的临床试验。出血事件风险的组合比值比（OR），计算VTE和ATE以进行公开和DB试验。治疗效果的估计偏差由OR比率确定，方法是将开放标签试验中获得的OR值除以DB试验中获得的OR值。结果基于文献的荟萃分析包括166个试验（72024例患者）。对于出血事件，AA与对照的比较得出的总OR为2.41 [95％置信区间（95％CI）2.12-2.73；P <0.001]，但在开放标签研究中，该风险被高估1.68（95％CI 1.33-2.13）。关于VTE，AA的OR总体为1.19（95％CI 1.04-1.35； P = 0.012），但仅考虑DB试验（OR 0.99，95％CI 0.83-1.17）时，这种影响消失了。在开放标签试验中，相应的OR比率显示出明显高估了1.53（95％CI 1.19-1.96）。对于ATE，OR为1.59（95％CI 1.30-1.94; P <0。在开放标签试验中，观察到001）与1.65（95％CI 1.13-2.43）的显着高估有关。结论开放标签研究高估了AA引起血管不良事件的风险至少50％。因此，评估不良药物事件的荟萃分析应仅限于DB随机试验。