Bevacizumab增加动脉血栓风险

由药厂赞助的临床试验数据分析显示，bevacizumab（Avastin，Genetech药厂制造）与动脉栓塞风险些微上升有关，但不会增加静脉栓塞风险；根据作者，同时也是该药厂研究者的Frank Scappaticci医师表示，项不良反应已经标示在产品说明书上，但是新的分析提供我们多的数据，这对于正在使用bevacizumab治疗之已转移癌症病患的医师而言是项重要讯息。

这项研究线上发表于8月7日的国家癌症机构期刊，且将发表于8月15日的期刊上；Genetech公司发言人Edward Lang在对这项研究做出评论时向Medscape表示，该公司已经决定继续分析这些数据，并附带表示这些新数据支持、且与我们过去的经验相符。

Bevacizumab是针对血管内皮细胞生长因子（VEGF）的单株抗体，为一种血管新生抑制剂；在癌症，该药物可以阻断新血管的生成，并且抑制肿瘤生长；该药物与其他化学治疗药物并用时，已经被证实可以延长许多种类癌症病患的存活时间；然而，作者假设其干扰VEGF的作用可能破坏一种牵涉到血管内皮细胞促发炎基因的逆向回馈路径，且可能导致原位栓塞的可能性。

在这项最新的分析中，研究者收集来自5项随机分派研究的数据，总共有1,745位罹患转移性大肠直肠癌、乳癌、非小细胞肺癌的病患，针对接受bevacizumab合并治疗与仅接受化学治疗病患进行比较。

接受合并治疗的病患，发生动脉栓塞的绝对风险为每100位每年5.5件，仅接受化学治疗病患，则是每100位每年3.1件（危险比值为1.8，95%信赖区间为0.94-3.33；P=0.076），这些数据与产品说明书中的有些差距（4.4%相较于1.9%），是原始发生率数据；作者表示这些原始发生率数据可能已经高估动脉栓塞的风险，因为接受bevacizumab治疗病患，其病情恶化所需时间较长，因此接受合并治疗组的病患，相对的药物安全观察期较长；他们表示，以每年每100人所发生事件数部分校正了这些差异。

他们附带表示，使用Kaplan-Meier风险估计也部份校正了这项差异，使用这种统计分析，他们发现加上bevacizumab增加动脉栓塞风险（危险比值为2.0；95%信赖区间为1.05-3.75；P=0.031），但是静脉栓塞风险并未增加（危险比值为0.89；95%信赖区间0.66-1.20；P=0.44）。

作者表示，有两族群病患风险显然特别高，分别是年龄超过65岁以上，以及那些已经有动脉栓塞病史病患；然而，这项研究排除了在过去一年有中风或是心肌梗塞的病患，且于这些病患使用bevacizumab的风险与利益尚未被建立；他们的评论是，许多重要的临床问题无法以这项研究结果回答，包括不同的肿瘤种类或是不同的化学治疗疗程，是否会进一步影响动脉栓塞风险。

作者提到的另一个进一步的问题是，同时并用aspirin是否会有任何影响？针对高动脉栓塞风险的癌症病患使用aspirin已经是标准照护；作者的评论是，目前并没有确切的结论，因为在这些癌症研究中，使用aspirin的病患数目太少，但他们附带表示使用aspirin并不会显著地增加与bevacizumab相关的出血事件机率；Aspirin会些微增加这两个治疗组严重出血风险，并用bevacizumab与化学治疗但未使用aspirin病患，风险增加3.6%，使用aspirin病患风险增加4.7%，相较于仅接受化学治疗病患，风险则自1.7%增加到2.2%。

Scappaticci医师与其同事的结论是，高动脉栓塞风险、且没有使用aspirin绝对禁忌症的转移性腺瘤病患，应该仔细地考虑以aspirin为主要的预防动脉栓塞事件措施。

Bevacizumab Increases Risk for Arterial Thromboembolism By Zosia Chustecka

Medscape Medical NewsBevacizumab(Avastin,Genentech)was associated with a modest increase in the risk for arterial,but not venous,thromboembolism in a new analysis of clinical data from company-sponsored clinical trials.This adverse effect is already listed on the product's data sheet,but the new analysis provides more details and also "important information for clinicians who use bevacizumab to treat patients with metastatic cancer," according to the authors,led by company researcher Frank Scappaticci,MD,PhD.The study was published online on August7in the Journal of the National Cancer Institute and is due to appear in the August15issue.Commenting on the paper,Genentech spokesperson Edward Lang told Medscape that the company had decided "to take another look at the data" and added that the results of this new analysis support and "are consistent with our experience."Bevacizumab,a monoclonal antibody targeted against vascular endothelial growth factor(VEGF),acts as an angiogenesis inhibitor.In the setting of cancer,it blocks the formation of new blood vessels,and this inhibits tumor growth; the drug had significantly prolonged survival when used in combination with chemotherapy in several cancer types.However,the authors speculate that its action of interfering with VEGF may disrupt a negative feedback loop involving proinflammatory genes in the vascular endothelial cells and could lead to potential in situ thrombus formation.In this latest analysis,the researchers pooled data from5randomized controlled trials involving a total of1745patients with metastatic colorectal,breast,or non–small-cell lung carcinoma.They compared patients treated with a combination of bevacizumab and chemotherapy with those treated with chemotherapy alone.The absolute risk of developing an arterial thromboembolism was5.5events per100person-years for those receiving combination therapy,compared with3.1events per100person-years for those receiving chemotherapy alone(hazard ratio[HR]=1.8;95%CI,0.94–3.33; P=.076).These rates are a little different from those in the product's data sheet(4.4%vs1.9%),which are raw incidence rates.The authors argue that these raw incidence rates may have overestimated the risk for an arterial thromboembolic event because of the delayed time to progression in the bevacizumab-treated group and hence the correspondingly longer safety observation period in the combination-therapy group.Their calculation of the rate of events per100person-years partially corrects for this difference,they write.It is also partially corrected for by using Kaplan-Meier hazard estimates,they add.Using this analysis,they found that the addition of bevacizumab increased the risk for an arterial thromboembolic event(HR=2.0;95%CI,1.05–3.75,P=.031),but not the risk for a venous thromboembolic event(HR=0.89;95%CI,0.66–1.20,P=.44).Two patient groups appeared to be at a higher risk — those aged65years or more and those who already had a history of an arterial thromboembolic event,the authors note.However,the trials excluded any patient who had a stroke or myocardial infarction in the preceding year,and so the risk and benefit of using bevacizumab in such patients have not been established.Also,several important clinical questions cannot be answered by this analysis,they comment,including whether or not the increased risk for arterial thromboembolism varies by tumor type or different chemotherapy regimens.

A further question the authors addressed is whether there was any impact from the concomitant use of low-dose aspirin,which is now a standard of care in patients at high risk for arterial thromboembolic events.No definite conclusions can be drawn,as the number of aspirin users in these cancer trials was small,the authors comment,but they add that concomitant aspirin use did not appear to substantially alter the increased risk of bleeding attributable to bevacizumab.Aspirin was associated with a modest increase in the risk of serious bleeding in both treatment groups — in patients on bevacizumab and chemotherapy,the risk increased from3.6%without aspirin to4.7%with aspirin,while in patients on chemotherapy alone,the risk increased from1.7%to2.2%."Aspirin-based prophylaxis for an arterial thromboembolic event should be carefully considered for individual patients with metastatic adenocarcinoma who are at high risk for an arterial thromboembolic event and who have no contraindications for aspirin use," Dr.Scappaticci and colleagues conclude.J Natl Cancer Inst.2007;99:1232-1239.