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 年由克里夫兰Case大学附属医院医学研究中心的Ilke Sipahi博士提出的关于血管紧张素受体抑制剂（ARBs）增加肿瘤发生风险的研究引起了广泛的讨论，为此，FDA专门进行了回顾分析，并得出结论，服用ARBs与癌症风险无关。Sipahi博士回应FDA的研究结果时说，他对FDA回顾的方法表示失望，指出FDA的研究不能反应患者水平的分析。

    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.

    根据heartwire 此前的报道，欧洲医学机构是第一个对首次meta分析进行回应的，宣称要对ARBs的患癌风险进行评估，FDA在不久后公布了他们的回顾分析。欧洲医学机构并未公布其回顾分析的结论。发言人在周五对 heartwire 证实，欧洲机构的回顾仍然在进行，并承诺一旦有了结果就马上会发表。

    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.

    调节性药物将会在药物分类的层面上进行回顾分析。消息一传出，马上引来高血压专家的批评。他们指出，相关药物已被处方多年，他们担心这将使患者中止治疗。

    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年先后发表了几份meta分析，但都未能确证第一份meta分析的研究结果。目前，在今天发表的一份安全性报告中，FDA表明在这些相关的meta分析里，并未发现有患癌风险的增加。“FDA总结说用ARB药物治疗并未增加患者患癌风险。”

    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.”

    根据这个警告，FDA使用156000名患者31个临床试验的试验水平数据，进行了平均为期39个月的随访，对比了使用ARB与不服用ARB患者的预后情况。FDA注意到，“这远远超过已发表的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.

    根据FDA的分析，ARB治疗组肿瘤发生率是1.82每100人年，而非ARB治疗组为1.84每100人年。FDA补充说道，不管使用何种统计方法或对照组是否服用安慰剂或其他药物，两组间的区别仍然维持统计学差异。一项专门研究两组间患癌症的类别不同的分析显示服用ARBs未增加患癌风险。

    “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 博士回应FDA的结论批评道，FDA未考虑“程序开放”（？）原则，也没有考虑ARBs的累积暴露效应。

    “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.”

    “无资料提及ARBs累积效应与患癌风险的关系，而这是研究药物或环境因素如辐射与患癌风险关系的最重要的方法。”他指出，FDA的研究已经近一年了，但仍然停留在试验阶段，而非患者水平的分析，“我对他们没有做患者水平分析感到很惊讶，因为他们有权从赞助商收集病人的相关资料，而正是这种方法可以排除肿瘤风险。光靠大样本长期暴露的试验和很多很多短期低剂量的药物试验的资料积累是不能排除患癌风险的。这种方法并不能确认出患癌风险。”

    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.”

    他补充说道，DIRECT临床试验癌症相关资料最近公布，显示大剂量的ARB（坎地沙坦32毫克）在良好依从性下持续服用5年可以增加患癌风险。“这个试验中，服用ARB的患癌风险显著上升。”

    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药物评价与研究中心心血管与肾脏药物安全部的副主任Mary Ross Southworth博士在一份寄往heartwire 的电邮中说道，原始的meta分析中有几处方法学上的局限，其中研究数量偏少、meta分析来源的临床试验及ARB暴露因素多数仅用了一种药物替米沙坦，这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.”

    “基于这些局限与Sipahi博士在meta分析中得出的风险估计，我们考虑了几种进一步研究服用ARB与患癌风险关系的可行方法，以研究更大样本试验水平的对照meta分析，为期最少1年，并使用相对标准的ARB剂量。”

    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博士解释试验水平meta分析的选择时指出，随访时间的考虑是安全性标志的有力证据。

    “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博士文章有种种局限，我们仍不能确定他文章所提到的由服用ARB引起的患癌风险是否存在。需要引起重视的是，这些临床试验都不是以癌症发生作为研究结局。我们之所以反对使用患者水平的meta分析是因为我们不相信这样的分析可以比综合试验水平meta分析在研究ARBs与患癌风险的关系上提供更多更确切的信息。”

    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.”

    纽约圣卢克罗斯福医院的Franz Messerli 博士是一位在随后众多未发现ARBs患癌风险的meta分析中其中一位协作者。他评论此消息时说，这是一个让人感到欣慰的结果。

    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.

    但他同时指出，患癌的相对风险（？）与心血管疾病需要重新列入考虑。对老年人，能降低心血管疾病的死亡风险可以延长存活时间，也相对增加了患癌风险。

    “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博士在电邮上写道：“很明显，抗高血压与抑制性的药物效能越强，即抗心血管死亡效果越好，就越能延长寿命，相对地就增加了患癌风险。这让我们看到了底线：如果心血管药物不能‘引起’肿瘤，那这种心血管药物的效能也不算足够！显然，我们不能从仅仅维持几年的随机试验就得出结果。然而，多数患者服用抗高血压或抑制性药物已有几十年的时间，在这个时间段里，相关的风险与结果就显得越来越重要了。”