International Circulation: Then why would they be more commonly used in the United States?
　　《国际循环》：为何在美国会广泛使用这些炎症标志物？
　　Prof Libby: It is in the guidelines and the US is a post-mature society and China is an emerging economy and the health priorities and challenges are different. One of the things I did speak about in Sydney was the clinical utility of inflammatory biomarkers. I mentioned three categories in clinical utility. One was useful in screening. One was a target for therapy， and by that I mean: if we titrate our doses of cholesterol medicines to the level of cholesterol， we titrate our dose of blood pressure medications to the blood pressure measurement; can we use inflammatory biomarkers to reach a certain goal? The third category was whether we could guide therapy by using inflammatory status. That’s a whole day’s debate in those three points. I did not consider at length the issue of screening. I think that in any healthcare situation with limited resources， indiscriminate or mass screening of populations of unknown risk may not prove to be cost-effective. I also prefer to stay away from the screening argument because my employer (but not me) has a financial interest in the tests. My employer holds the patent on the use of CRP in cardiovascular diagnosis and receives income from licensing and so I am not comfortable making a public statement about the use of this test in screening and it has not been proven to be cost-effective， but I have to declare this potential institutional conflict of interest. The second point is as a target of therapy and that’s an interesting conjecture. There are some data about that in secondary prevention but there is no new data and it has never been tested in a prospective randomized clinical trial. The third issue， whether an inflammatory biomarker could be a guide for therapy， I did discuss in Sydney because there are data. The JUPITER trial， which was not conducted in Asians， although 25% of the >17000 cohort in JUPITER were under-represented minorities， we did not enroll Asians in the trial because at the time the agent that we used in this study， rosuvastatin， did not have sufficient safety permission in Asian populations so these data are not directly extrapolatable to Chinese populations because they were excluded. JUPITER was a trial that involved individuals who had no history of coronary artery disease， who had LDL-cholesterol less than 130mg/dl so they were below anyone’s threshold for starting a statin drug， but who had a little bit of inflammation as judged by a high-sensitivity C-reactive protein of  >2mg/L. We randomized these people to rosuvastatin， a potent LDL-lowering and potent CRP-lowering statin versus placebo and we counted events. We found that there was a reduction， not only in our primary endpoint， but also in total mortality， so I use this as an example of the clinical application of inflammatory biomarkers. These are people who would not be captured if they were candidates for statin therapy by the usual lipid criteria. I also used being on the plenary stage at an international atherosclerosis meeting to deal with something that is of current interest in the US. That is the issue of the use of statins in primary prevention in women. Six weeks ago， the Women’s Health Initiative published a paper that was a retrospective analysis that cast some doubt on the use of statins in women. This was not randomized data; this was retrospective non-randomized observational data post hoc. That generated another spike of interest in the media chatter about statins in women for primary prevention. There was a Time magazine article a year or so ago to that effect and any search of the internet reveals all sorts of information that it is risky but there was no proof that they were. I went through some data that was assembled by one of my young faculty members， Dr Samia Mora， and she did a meta-analysis which included the JUPITER trial which had almost 7000 women involved in primary prevention， the MEGA trial which was a trial which was done in Japan so was on Asians with pravastatin， and another primary prevention trial done in the US which had few women， maybe 1500， called AFCAPS/TexCAPS， which showed that the statins were quite effective in reducing events. I don’t understand why people don’t look at the evidence-base about using statins in women. I dealt a little bit with the controversy of whether the benefits in JUPITER were due to LDL-lowering or an anti-inflammatory effect as revealed by reductions in CRP， or both. We have prespecified statistical analyses that suggest some of each but in fact， JUPITER could never deconvolute the anti-inflammatory effect of statins versus the LDL-lowering effect of statins. So our next mission is to try to use anti-inflammatory strategies in a similar approach， hence the CANTOS trial and enrollment has just begun on that trial.
　　Prof Libby：美国指南作出了相应的推荐，并且美国是一个发达国家，而中国是一个新兴的经济体，公众健康的首要问题和所面临的挑战是不同的。我在悉尼谈到的一个问题是炎症标志物的临床应用。我提到了临床应用的3个等级。一个是用于筛检；一个是用于治疗的靶标，在这一点上我认为：我们滴定降胆固醇药物的剂量直至胆固醇水平达标，滴定抗高血压药物剂量直至血压达标；那么我们能否使用炎症标志物达到一个特定的目标呢？第三类是，我们能否使用炎症状态来指导治疗。这就是全天讨论的3个关键论点。我并不非常赞同将其用于筛检，我认为对于资源有限的任何健康问题，对风险未知的人群进行不加选择的大规模筛检都不具有成本效益。我仍然倾向于不去进行有关筛检的讨论，因为我的雇员与这些检测有利益关系，他们拥有将CRP用于心血管诊断的专利，获得销售许可而盈利，我不会对这种检测用于筛检作出公开声明，这种举措也未被证明具有成本效益，但我必须澄清这其中存在潜在的利益冲突。第二点是作为治疗靶标，这是一个有趣的话题。在二级预防研究中获得了一些数据，但缺乏新的数据，且这一问题从未得到前瞻性随机临床试验的验证。第三个问题，炎症标志物能否指导治疗，我在悉尼对此进行了讨论，因为我们取得了数据。JUPITER试验未在亚洲进行，虽然超过17 000例受试者的JUPITER研究队列中，有25%是不具代表性的少数族裔。没有纳入亚洲受试者是因为当时研究所使用的药物瑞舒伐他汀并未取得在亚洲人群中的安全性许可，因此其研究数据不能推广至中国人群。JUPITER试验纳入的个体均无冠心病病史，LDL-C水平<130 mg/dl（低于启动他汀治疗的阈值），但CRP>2 mg/L，表明其存在轻微炎症。我们将这些受试者随机分配接受强效降LDL和强效降CRP药物瑞舒伐他汀或安慰剂，随访2组的事件数。我们发现瑞舒伐他汀组不但主要终点，而且总死亡率均显著降低，因此我将其作为炎症标志物临床应用的事例。这些个体如果使用常规的血脂标准，将错过他汀治疗。在一次国际动脉粥样硬化会议的全体大会期间，我还利用上述数据阐述了当前美国学术界非常感兴趣的一些问题的处理，即他汀在女性一级预防中的应用。6周前，妇女健康行动（the Women’s Health Initiative）发表了一篇文章，报告一项回顾性数据分析，对女性使用他汀提出了质疑。这不是随机化的数据，而是回顾性、非随机的事后观察数据。该文引起媒体对他汀在女性一级预防中应用的广泛争论。大概1年前，《时代周刊》发表的一篇文章谈到这种效应，对各种信息的网络调查结果显示，人们认为这样做有风险，但并无证据证实这一观点。我回顾了我的一位年轻同事Samia Mora博士汇总的一些数据，她进行了一项荟萃分析，其中纳入JUPITER试验，这当中包含近7000名进行一级预防的女性；在日本的亚洲人群中使用普伐他汀的MEGA试验；以及在美国进行的另一项一级预防研究，包括1500名女性的AFCAPS/TexCAPS试验。分析显示他汀可非常有效地减少事件。我不理解，为何人们不重视女性使用他汀的这些证据基础。我还对JUPITER试验中获益是源于降LDL还是抗炎作用还是两者均有的争论阐述了观点。我们预先设定的统计分析对上述任何一点都提示了线索，但实际上，JUPITER试验无法厘清他汀抗炎作用与降LDL作用之间的对比关系。因此我们下一个任务，就是以相似的方式使用抗炎策略，CANTOS试验已经开始纳入受试者。