Faruque Labib Imran, Lin Meng, Battistella Marisa, Wiebe Natasha, Reiman Tony, Hemmelgarn Brenda, Thomas Chandra, Tonelli Marcello
University of Alberta, Edmonton, Canada.
University of Toronto, Toronto, Canada.
PLoS One. 2014 Jul 2;9(7):e101145. doi: 10.1371/journal.pone.0101145. eCollection 2014.
Anti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis.
We searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials.
VEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.
针对血管内皮生长因子（VEGF）的抗血管生成疗法目前用于治疗多种类型的癌症。我们对随机对照试验（RCT）进行了系统评价，以总结血管内皮生长因子抑制剂（VEGFi）的不良反应，重点关注那些具有血管发病机制的不良反应。
我们检索了MEDLINE、EMBASE和Cochrane图书馆，直至2012年4月19日，以确定在患有任何癌症的成年人中比较VEGFi与对照的平行RCT。我们使用随机效应模型汇总了死亡率、血管事件（心肌梗死、中风、心力衰竭和血栓栓塞）、高血压和新发蛋白尿的风险，并计算了未调整的相对风险（RR）。我们还进行了meta回归并评估了发表偏倚。我们从7901条已识别的文献中检索了72项研究（n = 38,078）中关于11种不同VEGFi的83项比较。VEGFi接受者的死亡风险显著低于对照组（汇总RR 0.96，95%置信区间[CI] 0.94至0.98，I2 = 0%，tau2 = 0；风险差异2%）。与对照组相比，VEGFi接受者发生心肌梗死（MI）的风险显著更高（RR 3.54，95% CI 1.61至7.80，I2 = 0%，tau2 = 0），动脉血栓形成事件（RR 1.80，95% CI 1.24至2.59，I2 = 0%，tau2 = 0）；高血压（RR 3.46，95% CI 2.89至4.15，I2 = 58%，tau2 = 0.16），以及新发蛋白尿（RR 2.51，95% CI 1.60至3.94，I2 = 87%，tau2 = 0.65）。MI的绝对风险差异为0.8%，动脉血栓形成事件为1%，高血压为15%，新发蛋白尿为12%。Meta回归未提示VEGFi治疗与任何血管事件之间关联的任何具有统计学意义的调节因素。局限性包括各试验之间的异质性。
VEGFi增加了MI、高血压、动脉血栓栓塞和蛋白尿的风险。额外风险的绝对幅度在临床上似乎具有相关性，因为伤害所需人数范围为7至125。这些不良事件必须与VEGFi治疗相关的较低死亡率相权衡。
