pdated June 3， 2011 （Rockville， Maryland） — An FDA review launched in the wake of a controversial 2010 meta-analysis by Dr Ilke Sipahi （University Hospitals Case Medical Center， Cleveland， OH） et al [1] suggesting an increased risk of cancer among patients taking angiotensin-receptor blockers （ARBs） has concluded that the drugs do not pose a cancer risk to patients [2]. But reacting to the FDA alert toheartwire ， Sipahi said he was disappointed with how the FDA conducted its review and， in particular， its failure to do a patient-level analysis.

    2010 年由克里夫蘭Case大學(xué)附屬醫(yī)院醫(yī)學(xué)研究中心的Ilke Sipahi博士提出的關(guān)于血管緊張素受體抑制劑（ARBs）增加腫瘤發(fā)生風(fēng)險(xiǎn)的研究引起了廣泛的討論，為此，F(xiàn)DA專(zhuān)門(mén)進(jìn)行了回顧分析，并得出結(jié)論，服用ARBs與癌癥風(fēng)險(xiǎn)無(wú)關(guān)。Sipahi博士回應(yīng)FDA的研究結(jié)果時(shí)說(shuō)，他對(duì)FDA回顧的方法表示失望，指出FDA的研究不能反應(yīng)患者水平的分析。

    As previously reported by heartwire ， the European Medicines Agency （EMA） was the first to react to that initial meta-analysis， announcing it was going to review the possible cancer risks associated with ARBs； the FDA announced its own review shortly thereafter. The EMA has not yet released any conclusions from its review. A spokesperson for the EMA confirmed to heartwire on Friday that the European agency's review is still ongoing and would be published once the review is finalized.

    根據(jù)heartwire 此前的報(bào)道，歐洲醫(yī)學(xué)機(jī)構(gòu)是第一個(gè)對(duì)首次meta分析進(jìn)行回應(yīng)的，宣稱(chēng)要對(duì)ARBs的患癌風(fēng)險(xiǎn)進(jìn)行評(píng)估，F(xiàn)DA在不久后公布了他們的回顧分析。歐洲醫(yī)學(xué)機(jī)構(gòu)并未公布其回顧分析的結(jié)論。發(fā)言人在周五對(duì) heartwire 證實(shí)，歐洲機(jī)構(gòu)的回顧仍然在進(jìn)行，并承諾一旦有了結(jié)果就馬上會(huì)發(fā)表。

    News that regulators would be reviewing the drug class was widely criticized by hypertension doctors， who pointed out they'd been using the agents for years and worried about the consequences of patients stopping their medications.

    調(diào)節(jié)性藥物將會(huì)在藥物分類(lèi)的層面上進(jìn)行回顧分析。消息一傳出，馬上引來(lái)高血壓專(zhuān)家的批評(píng)。他們指出，相關(guān)藥物已被處方多年，他們擔(dān)心這將使患者中止治療。

    Several subsequent meta-analyses， published last year and again in 2011， failed to confirm the alarming findings of the first， as reported by heartwire . Now， in a safety alert issued today， the FDA states that its findings are in keeping with those of the subsequent meta-analyses that showed no sign of a cancer risk. “The FDA has concluded that treatment with an ARB medication does not increase a patient's risk of developing cancer.”

    去年及2011年先后發(fā)表了幾份meta分析，但都未能確證第一份meta分析的研究結(jié)果。目前，在今天發(fā)表的一份安全性報(bào)告中，F(xiàn)DA表明在這些相關(guān)的meta分析里，并未發(fā)現(xiàn)有患癌風(fēng)險(xiǎn)的增加。“FDA總結(jié)說(shuō)用ARB藥物治療并未增加患者患癌風(fēng)險(xiǎn)。”

    According to the alert， the FDA used trial-level data from 31 trials and 156 000 patients， comparing outcomes in patients randomized to an ARB or “non-ARB treatment，” with an average follow-up of 39 months. The FDA notes that this is “far more than the approximately 62 000 patients in the published analysis.”

    根據(jù)這個(gè)警告，F(xiàn)DA使用156000名患者31個(gè)臨床試驗(yàn)的試驗(yàn)水平數(shù)據(jù)，進(jìn)行了平均為期39個(gè)月的隨訪(fǎng)，對(duì)比了使用ARB與不服用ARB患者的預(yù)后情況。FDA注意到，“這遠(yuǎn)遠(yuǎn)超過(guò)已發(fā)表的62000名患者的分析”。

    According to the FDA's analysis， incident cancer events in the ARB group were 1.82 per 100 patient-years， compared with 1.84 per 100 patient-years in the non-ARB group. The lack of a difference between the two groups was maintained， no matter what statistical method was used or whether the comparator group was taking a placebo or another drug， the FDA adds. An analysis looking at differences between groups based on type of cancer also showed no signal of cancer risk with ARBs.

    根據(jù)FDA的分析，ARB治療組腫瘤發(fā)生率是1.82每100人年，而非ARB治療組為1.84每100人年。FDA補(bǔ)充說(shuō)道，不管使用何種統(tǒng)計(jì)方法或?qū)φ战M是否服用安慰劑或其他藥物，兩組間的區(qū)別仍然維持統(tǒng)計(jì)學(xué)差異。一項(xiàng)專(zhuān)門(mén)研究?jī)山M間患癌癥的類(lèi)別不同的分析顯示服用ARBs未增加患癌風(fēng)險(xiǎn)。

    “You Can't Find Cancer Risks Like This”

    Reacting to the FDA's conclusions， Sipahi criticized what he called a lack of “open process” on the part of the FDA， as well as the agency's failure to address cumulative exposure to ARBs.

    Sipahi 博士回應(yīng)FDA的結(jié)論批評(píng)道，F(xiàn)DA未考慮“程序開(kāi)放”（？）原則，也沒(méi)有考慮ARBs的累積暴露效應(yīng)。

    “There is no information about the relationship between cumulative exposure [to ARBs] and cancer risk， which is the most important approach when cancer risk with drugs or other environmental factors such as radiation is examined.”

    He points out that the FDA “has been working on this analysis for almost a year now” yet conducted only a trial-level， not a patient-level， analysis. “I am surprised they did not do a patient-level analysis， because they have the authority to collect individual patient-level data from the sponsors，” he told heartwire . “That's how you rule out cancer； you don't rule out cancer by lumping data from large trials with long exposure and many， many . . . smaller trials with short duration and low drug dose： you can't find cancer risk like this.”

    “無(wú)資料提及ARBs累積效應(yīng)與患癌風(fēng)險(xiǎn)的關(guān)系，而這是研究藥物或環(huán)境因素如輻射與患癌風(fēng)險(xiǎn)關(guān)系的最重要的方法。”他指出，F(xiàn)DA的研究已經(jīng)近一年了，但仍然停留在試驗(yàn)階段，而非患者水平的分析，“我對(duì)他們沒(méi)有做患者水平分析感到很驚訝，因?yàn)樗麄冇袡?quán)從贊助商收集病人的相關(guān)資料，而正是這種方法可以排除腫瘤風(fēng)險(xiǎn)。光靠大樣本長(zhǎng)期暴露的試驗(yàn)和很多很多短期低劑量的藥物試驗(yàn)的資料積累是不能排除患癌風(fēng)險(xiǎn)的。這種方法并不能確認(rèn)出患癌風(fēng)險(xiǎn)。”

    Of note， he added， cancer data from the DIRECT trial recently became available， showing that with a high-dose ARB （candesartan 32 mg）， given for nearly for five years with a high compliance rate， “there was a statistically significant excess in cancers with the ARB in this trial.”

    他補(bǔ)充說(shuō)道，DIRECT臨床試驗(yàn)癌癥相關(guān)資料最近公布，顯示大劑量的ARB（坎地沙坦32毫克）在良好依從性下持續(xù)服用5年可以增加患癌風(fēng)險(xiǎn)。“這個(gè)試驗(yàn)中，服用ARB的患癌風(fēng)險(xiǎn)顯著上升。”

    The FDA Responds

    But in a statement emailed to heartwire ， Dr Mary Ross Southworth， deputy director for safety in the Division of Cardiovascular and Renal Drugs in the FDA's Center for Drug Evaluation and Research， pointed to what she called “several methodological limitations to the original meta-analysis”——among them the limited number of studies， inclusion of the trial that prompted the meta-analysis， and the fact that most of the ARB exposure was to one ARB， telmisartan.

    FDA藥物評(píng)價(jià)與研究中心心血管與腎臟藥物安全部的副主任Mary Ross Southworth博士在一份寄往heartwire 的電郵中說(shuō)道，原始的meta分析中有幾處方法學(xué)上的局限，其中研究數(shù)量偏少、meta分析來(lái)源的臨床試驗(yàn)及ARB暴露因素多數(shù)僅用了一種藥物替米沙坦，這都是研究不足的地方。

    “Given these limitations and the size of the risk identified in the Sipahi meta-analysis， we considered the available methods to further assess a possible risk of cancer with ARB use [and] decided to perform a larger trial-level meta-analysis of controlled studies of at least one year's duration and relatively standard ARB doses.”

    “基于這些局限與Sipahi博士在meta分析中得出的風(fēng)險(xiǎn)估計(jì)，我們考慮了幾種進(jìn)一步研究服用ARB與患癌風(fēng)險(xiǎn)關(guān)系的可行方法，以研究更大樣本試驗(yàn)水平的對(duì)照meta分析，為期最少1年，并使用相對(duì)標(biāo)準(zhǔn)的ARB劑量。”

    Pressed to explain the choice of a trial-level meta-analysis， Southworth pointed out that an important consideration in following up on “safety signals” is the strength of evidence in the “signal source.”

    Southworth博士解釋試驗(yàn)水平meta分析的選擇時(shí)指出，隨訪(fǎng)時(shí)間的考慮是安全性標(biāo)志的有力證據(jù)。

    “Because of the limitations in the Sipahi paper， we were uncertain that his paper represented a true signal for cancer in ARB users. It is important to remember that the vast majority of these trials were not designed to look at cancer as an end point.” She continued： “We decided against a patient-level meta-analysis because we were not convinced that such an analysis would provide any better information about the relationship between ARBs and cancer than a more comprehensive trial-level meta-analysis.”

    “由于Sipahi博士文章有種種局限，我們?nèi)圆荒艽_定他文章所提到的由服用ARB引起的患癌風(fēng)險(xiǎn)是否存在。需要引起重視的是，這些臨床試驗(yàn)都不是以癌癥發(fā)生作為研究結(jié)局。我們之所以反對(duì)使用患者水平的meta分析是因?yàn)槲覀儾幌嘈胚@樣的分析可以比綜合試驗(yàn)水平meta分析在研究ARBs與患癌風(fēng)險(xiǎn)的關(guān)系上提供更多更確切的信息。”

    Also commenting on the FDA's conclusions for heartwire ， Dr Franz Messerli （St Luke‘s Roosevelt Hospital， New York NY）， a coauthor on one of the subsequent meta-analyses that found no cancer risk with ARB， called the news “reassuring.”

    紐約圣盧克羅斯福醫(yī)院的Franz Messerli 博士是一位在隨后眾多未發(fā)現(xiàn)ARBs患癌風(fēng)險(xiǎn)的meta分析中其中一位協(xié)作者。他評(píng)論此消息時(shí)說(shuō)，這是一個(gè)讓人感到欣慰的結(jié)果。

    But he also points out that the “competing risks” of cancer and cardiovascular disease need to be taken into account. In older patients， a drug that reduces their risk of CV death will increase their life expectancy， potentially increasing the likelihood that they will develop cancer.

    但他同時(shí)指出，患癌的相對(duì)風(fēng)險(xiǎn)（？）與心血管疾病需要重新列入考慮。對(duì)老年人，能降低心血管疾病的死亡風(fēng)險(xiǎn)可以延長(zhǎng)存活時(shí)間，也相對(duì)增加了患癌風(fēng)險(xiǎn)。

    “Obviously， the more efficacious antihypertensive drugs and statins are——ie， the better they prevent cardiovascular death——the more they will increase life expectancy and thus the risk of cancer，” Messerli said in an email to heartwire . “This brings us to the bottom line： unless a cardiovascular drug 'causes' cancer， it is not an efficacious cardiovascular drug！ Clearly， we may not observe this in randomized trials lasting a few years only. However， most patients are on antihypertensives and statins for decades， and within this time frame， the competing risk and its consequences become increasingly important.”

    Messerli博士在電郵上寫(xiě)道：“很明顯，抗高血壓與抑制性的藥物效能越強(qiáng)，即抗心血管死亡效果越好，就越能延長(zhǎng)壽命，相對(duì)地就增加了患癌風(fēng)險(xiǎn)。這讓我們看到了底線(xiàn)：如果心血管藥物不能‘引起’腫瘤，那這種心血管藥物的效能也不算足夠！顯然，我們不能從僅僅維持幾年的隨機(jī)試驗(yàn)就得出結(jié)果。然而，多數(shù)患者服用抗高血壓或抑制性藥物已有幾十年的時(shí)間，在這個(gè)時(shí)間段里，相關(guān)的風(fēng)險(xiǎn)與結(jié)果就顯得越來(lái)越重要了。”