Bevacizumab增加動(dòng)脈血栓風(fēng)險(xiǎn)

由藥廠贊助的臨床試驗(yàn)數(shù)據(jù)分析顯示，bevacizumab（Avastin，Genetech藥廠制造）與動(dòng)脈栓塞風(fēng)險(xiǎn)些微上升有關(guān)，但不會(huì)增加靜脈栓塞風(fēng)險(xiǎn)；根據(jù)作者，同時(shí)也是該藥廠研究者的Frank Scappaticci醫(yī)師表示，項(xiàng)不良反應(yīng)已經(jīng)標(biāo)示在產(chǎn)品說(shuō)明書上，但是新的分析提供我們多的數(shù)據(jù)，這對(duì)于正在使用bevacizumab治療之已轉(zhuǎn)移癌癥病患的醫(yī)師而言是項(xiàng)重要訊息。

這項(xiàng)研究線上發(fā)表于8月7日的國(guó)家癌癥機(jī)構(gòu)期刊，且將發(fā)表于8月15日的期刊上；Genetech公司發(fā)言人Edward Lang在對(duì)這項(xiàng)研究做出評(píng)論時(shí)向Medscape表示，該公司已經(jīng)決定繼續(xù)分析這些數(shù)據(jù)，并附帶表示這些新數(shù)據(jù)支持、且與我們過(guò)去的經(jīng)驗(yàn)相符。

Bevacizumab是針對(duì)血管內(nèi)皮細(xì)胞生長(zhǎng)因子（VEGF）的單株抗體，為一種血管新生抑制劑；在癌癥，該藥物可以阻斷新血管的生成，并且抑制腫瘤生長(zhǎng)；該藥物與其他化學(xué)治療藥物并用時(shí)，已經(jīng)被證實(shí)可以延長(zhǎng)許多種類癌癥病患的存活時(shí)間；然而，作者假設(shè)其干擾VEGF的作用可能破壞一種牽涉到血管內(nèi)皮細(xì)胞促發(fā)炎基因的逆向回饋路徑，且可能導(dǎo)致原位栓塞的可能性。

在這項(xiàng)最新的分析中，研究者收集來(lái)自5項(xiàng)隨機(jī)分派研究的數(shù)據(jù)，總共有1,745位罹患轉(zhuǎn)移性大腸直腸癌、乳癌、非小細(xì)胞肺癌的病患，針對(duì)接受bevacizumab合并治療與僅接受化學(xué)治療病患進(jìn)行比較。

接受合并治療的病患，發(fā)生動(dòng)脈栓塞的絕對(duì)風(fēng)險(xiǎn)為每100位每年5.5件，僅接受化學(xué)治療病患，則是每100位每年3.1件（危險(xiǎn)比值為1.8，95%信賴區(qū)間為0.94-3.33；P=0.076），這些數(shù)據(jù)與產(chǎn)品說(shuō)明書中的有些差距（4.4%相較于1.9%），是原始發(fā)生率數(shù)據(jù)；作者表示這些原始發(fā)生率數(shù)據(jù)可能已經(jīng)高估動(dòng)脈栓塞的風(fēng)險(xiǎn)，因?yàn)榻邮躡evacizumab治療病患，其病情惡化所需時(shí)間較長(zhǎng)，因此接受合并治療組的病患，相對(duì)的藥物安全觀察期較長(zhǎng)；他們表示，以每年每100人所發(fā)生事件數(shù)部分校正了這些差異。

他們附帶表示，使用Kaplan-Meier風(fēng)險(xiǎn)估計(jì)也部份校正了這項(xiàng)差異，使用這種統(tǒng)計(jì)分析，他們發(fā)現(xiàn)加上bevacizumab增加動(dòng)脈栓塞風(fēng)險(xiǎn)（危險(xiǎn)比值為2.0；95%信賴區(qū)間為1.05-3.75；P=0.031），但是靜脈栓塞風(fēng)險(xiǎn)并未增加（危險(xiǎn)比值為0.89；95%信賴區(qū)間0.66-1.20；P=0.44）。

作者表示，有兩族群病患風(fēng)險(xiǎn)顯然特別高，分別是年齡超過(guò)65歲以上，以及那些已經(jīng)有動(dòng)脈栓塞病史病患；然而，這項(xiàng)研究排除了在過(guò)去一年有中風(fēng)或是心肌梗塞的病患，且于這些病患使用bevacizumab的風(fēng)險(xiǎn)與利益尚未被建立；他們的評(píng)論是，許多重要的臨床問(wèn)題無(wú)法以這項(xiàng)研究結(jié)果回答，包括不同的腫瘤種類或是不同的化學(xué)治療療程，是否會(huì)進(jìn)一步影響動(dòng)脈栓塞風(fēng)險(xiǎn)。

作者提到的另一個(gè)進(jìn)一步的問(wèn)題是，同時(shí)并用aspirin是否會(huì)有任何影響？針對(duì)高動(dòng)脈栓塞風(fēng)險(xiǎn)的癌癥病患使用aspirin已經(jīng)是標(biāo)準(zhǔn)照護(hù)；作者的評(píng)論是，目前并沒(méi)有確切的結(jié)論，因?yàn)樵谶@些癌癥研究中，使用aspirin的病患數(shù)目太少，但他們附帶表示使用aspirin并不會(huì)顯著地增加與bevacizumab相關(guān)的出血事件機(jī)率；Aspirin會(huì)些微增加這兩個(gè)治療組嚴(yán)重出血風(fēng)險(xiǎn)，并用bevacizumab與化學(xué)治療但未使用aspirin病患，風(fēng)險(xiǎn)增加3.6%，使用aspirin病患風(fēng)險(xiǎn)增加4.7%，相較于僅接受化學(xué)治療病患，風(fēng)險(xiǎn)則自1.7%增加到2.2%。

Scappaticci醫(yī)師與其同事的結(jié)論是，高動(dòng)脈栓塞風(fēng)險(xiǎn)、且沒(méi)有使用aspirin絕對(duì)禁忌癥的轉(zhuǎn)移性腺瘤病患，應(yīng)該仔細(xì)地考慮以aspirin為主要的預(yù)防動(dòng)脈栓塞事件措施。

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.