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[AHA2011]AHA主席Gordon F. Tomaselli教授谈大会亮点与基因检测进展
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作者:GordonF.Tomaselli 编辑:国际循环网 时间:2011/11/21 16:31:00 关键字:AHA2011 大会亮点 Gordon F. Tomaselli  心脏病预防 基因 

    Gordon F. Tomaselli    美国约翰霍普金斯大学医学院心脏病学系
    <International Circulation>: What would you describe as the highlights of this AHA 2011 Meeting?

  《国际循环》:你认为本次AHA2011大会有哪些要闻?
    Prof.Tomaselli: First of all, the meeting is very broad-based. We cover everything from fundamental science (signaling in hearts and in stem cells) to research (things like the HOOP study, looking at healthcare outcomes and operations trying to figure out which systems of care are best to manage people with cardiovascular disease). Four thousand abstracts were selected. The things that really bubble to the top are the late-breaking clinical trials. I think the late-breaking clinical trials are the things that people focus on and probably appropriately if you are a practitioner. Those are the things that are often closest to being implemented in the clinical world and there are five late-breaking clinical trials on show here. One was concerning thrombosis and I believe the key studies here concerned the new factor Xa inhibitors and the role they are going to have in managing patients with acute coronary syndromes in particular. There were studies concerning electrophysiological problems with new antiarrhythmic agents, celivarone and a relatively new agent dronedarone. With regard to dronedarone, we were provided with some caution about the use of dronedarone in permanent atrial fibrillation. If you don’t get a rhythm benefit out of that drug, you should not expect there to be a benefit from some of the other things that it has been proposed it does outside of correcting rhythm. So that’s an important caveat and I would be very reluctant to use this drug in patients with heart failure. Celivarone didn’t really seem to be any better than placebo. The other topics were related to the role of catheter ablation in atrial fibrillation and surgical ablation in atrial fibrillation, which seemed to have a role particularly in complicated patients or patients who have been difficult to manage with less-invasive therapies. The other interesting thing which I think has some relevance to prevention of all kinds and dovetails nicely with other studies that have been presented in various forms around the world including at ESC and the Great Wall meeting, are the results of the delivery or distribution of medications to people who have acute coronary syndrome and cardiovascular disease for nothing, for free. The fact is that there are secondary prevention measures that we know work and that we know people don’t take (not just in the US but all around the world. In the countries studied, secondary prevention measures (statins, blood pressure control, beta-blockers) in patients with acute coronary syndromes are not being prescribed or are not being taken. I think it was a very innovative study by, in fact, an insurance company to say, we are going to give people the medicines they need post-infarction (aspirin, beta-blockers and statins) for nothing, no copay, nothing. The consequence was that compliance increased but increased only marginally and outcomes didn’t change. But it is not only about the money but systems of care and making people aware of the fact that these are important secondary prevention measures that really help and people need to take. The other one that I thought was interesting was the HOOP study that was meant to be presented at ESC but wasn’t quite ready. We are faced (and I am sure it is an even bigger problem in China) with a manpower resource problem with managing cardiovascular disease. The question is, moving forward, how do you get to a stage where you can take care of the mass of people who have coronary disease, heart failure and so on? The HOOP study asked the question, can you manage patients and improve adherence in patients who have heart failure by using the primary care doctor supplemented by a pharmacist in the practice? Again, there was a marginal improvement in adherence, but no change in outcomes. I view that as being a bit optimistic. In fact, I think if you need to do that, you can make some inroads with a combination of primary care and ancillary providers to get people to the stage where they will at least see a practitioner who is going to take care of their cardiac problem to get them on the right medications. The point is that we don’t necessarily need more cardiologists but if we don’t have enough we can’t supplement them with these ancillary services. I think in Asia in particular, the burden of cardiovascular disease is really quite high due to population pressure and I think it is a point for people to consider and to consider implementing. Not to mention that we hear from our Chinese colleagues that for the rural population, the level of training is really quite variable amongst practitioners. This may even be a way to standardize medical care in a better way. There were also a couple of lipid trials that were important. One is the study of evacetrapib which is a cholesterol esterase transport inhibitor. A previous member of this class of drug, torcetrapib, had adverse side effects and no beneficial effects and now evacetrapib and dalcetrapib are two new agents that we know, at least, do not have the adverse side effects and can move forward. That class of drugs and the concept of HDL increasing (whether it is a biomarker of something else or in itself is important) can proceed. The SATURN trial asked, is there a difference, within class, of high dose statins of different types in terms of endpoints? It didn’t meet its primary endpoint but in fact, both drugs seemed to lower atheroma burden and as a secondary endpoint, it may be that high dose rosuvastatin outdoes atorvastatin although I am not sure if hard conclusions can be drawn from the secondary endpoint. That was a surrogate endpoint study and not an outcomes study so it is hard to know what those results will mean. We don’t know what that change or lack of statistically significant change in IVUS-determined plaque volume means. And then there is the AIM-HIGH trial, the niacin trial, which was stopped prematurely due to futility. I think we still have some work to do in lipid management. The trial on early surgical intervention in infective endocarditis seems to have captured a lot of attention; appropriately because for clinicians it is a very difficult management problem. It is very difficult to decide when a patient should go to surgery if they have valvular dysfunction in infective endocarditis. It is a much more difficult surgical operation because there is infected tissue that is more difficult to suture. These data tell us that at least from the standpoint of stroke, these people do better with early surgical intervention. I don’t think a big trial is ever going to be done on this disease because it is just so difficult to control and we are going to need to use some other statistical measurement to try and assess how comparable people are who undergo surgery and don’t undergo surgery whether it be propensity-matching analysis or something else. The other one of interest is the TIMI 51 trial which looked at genotyping and platelet function in patients who are being treated with clopidogrel. We know this is a prodrug and people with a hyperfunctioning *2 allele don’t metabolize clopidogrel into the active drug. On average, these patients have lower platelet inhibition on clopidogrel than people who don’t have this allele. This is a bit variable from patient to patient; it is a population-based study. Often if you don’t have the genotype on the chart when people are presenting with acute events, you really don’t know about it at the time. Genotyping, particularly in the long term, might be of some utility in patients who would be treated with clopidogrel and/or in the sense that it may inform on dose, and it might inform or not whether to use another antiplatelet agent. Those are the highlights from this meeting in terms of late-breaking trials. There are a number of other sessions that I thought were interesting; some I got to see, others I have reviewed after the fact. There was a session on innovation and acceleration of technology from bench to bedside and a number of presenters talked about the regulatory barriers to get an agent from concept and into patients and how that may need to change as we move forward. It was pointed out in this session how we might need to think about different ways to fill the drug pipeline for new agents and agents that are not only broadly active in a population but targeted to specific targets and specific populations perhaps even with genotype considerations factoring into all of this. That session also talked a little bit about the Science Accelerator Program that the American Heart Association began with the notion that what you want to do is move something that is a prototype, that is a tested agent, that has plausibility to improve cardiovascular health and move it along to be a commercially available product. Pharmaceutical companies and device companies are critically challenged these days as they have shrinking budgets too and are not willing to get into the process at the very early stages of the game but wait until the latter stages. The other thing I would want to highlight from the meeting is this year’s International Congress which was on prevention. There was a lot of energy and a lot of sessions around the prevention of cardiovascular disease – secondary prevention, primary prevention and primordial prevention. It not only focused on drug therapy but focused on a lot of other things like lifestyle which actually does dovetail very nicely with the UN Ministerial Summit which was held in the Fall and the Great Wall meeting, at which Professor Hu Dayi was really focused on prevention and how he wants to implement prevention measures in China, and the upcoming World Congress of Cardiology in Dubai. All-in-all, a nice stream of recognition of the problem and attempts to generate what are called ‘best buys’ that will get us to better prevention at the lowest cost that will make it happen.

    Tomaselli教授:首先,本次会议内容广泛,范围包括从基础科学(心脏信号以及干细胞),到临床研究(例如HOOP研究,这个研究关注卫生服务效果,并且试图研究哪种卫生服务系统对治疗心血管疾病患者最有利),共入选4000篇摘要。最引人注目的是近期揭晓的临床试验。我认为近期揭晓的临床试验是大家最关注的,对于临床医师来说也是最实用的。临床试验最接近临床实践,本次会议共包括5个近期揭晓的临床试验。一个是关于血栓的,我认为这个研究的关键之处在于新的Xa因子抑制剂,以及这个药物在临床上处理急性冠脉综合征中扮演的角色。有关于电生理的,新的抗心律失常药物方面的试验,即塞利瓦隆以及一个相对新的药物决奈达隆。关于决奈达隆,我们提供了一些决奈达隆在永久性心房颤动方面应用的注意事项。如果你不能使用这个药物在心脏节律方面获益,那么就不能期待它有我们过去曾经期望过的,在心脏节律之外方面的作用。因此,这是一个重要的警示,对于心力衰竭的患者,我就很不愿意使用这个药物。塞利瓦隆看上去并不比安慰剂更优。其他的专题与房颤导管消融和房颤外科消融的角色有关,房颤外科消融似乎对于病情复杂的患者或者对于用相对保守的疗法难以处理的患者有用。另外一个有趣的发现是关于心血管疾病预防的,并与世界其他地方,例如ESC以及长城会上以不同形式做的学术报告相契合。即对于急性冠脉综合征以及心血管疾病患者的药物,进行免费分配。事实是,很多我们所熟知的二级预防的有效措施,患者却没有采取。这不仅在美国,而在全世界都是如此,在进行研究的国家中,对急性冠脉综合征患者,包括他汀类药物,血压控制,β阻滞剂等的二级预防措施,并没有被使用。我认为这是一个很有创新性的研究,事实上,保险公司会说,我们会给患者提供免费得心肌梗死后所需要的药物(阿司匹林,β阻滞剂以及他汀),没有个人支出,完全免费。结果是依从性增加,但是很有限,结局也没有改变。因此,对于二级预防真正重要,并且我们应当采取的措施,不仅仅是钱,更重要的是医疗体系,让患者重视起来。我认为另外一个有趣的发现是HOOP研究。这个研究原本要在ESC大会上作报告,但是因为准备不充分而没做。我们将面对处理心血管疾病的人力资源问题(我很肯定这在中国是个更大的问题)。问题是,你如何得到一个你可以治疗患有冠心病、心衰以及其他心脏病的众多患者的舞台呢?HOOP研究提出了这个问题,你能够通过基本医疗以及药剂师,治疗心衰患者,并提高其依从性吗?又一次,依从性提升很有限,临床结局没有改变。我认为还是应当乐观一点。事实上,我认为如果你需要那样做,你可以通过基本医疗以及配套措施来努力使患者达到以下条件:至少有一个临床医师来治疗他们的心脏问题,让他们正确用药。关键问题是,我们不一定需要更多的心血管专科医师,但是如果医师数量不足,我们就无法提供相应配套服务。我认为,尤其在亚洲,由于人口压力,心血管疾病的负担非常高。我认为关键在于实施。而且,我们从中国同行那里听说,在农村地区,临床医师之间的训练水平有相当大的差异。这甚至可以成为更好进行标准化医疗的的好方法。还有几个重要的血脂方面的试验。其中之一是胆固醇酯酶转运抑制剂evacetrapib。过去同属这类药物的torcetrapib有不良反应,并且无获益。目前evacetrapib和dalcetrapib是两种至少没有不良反应的新药,因此可以继续进行研究。这类药物以及关于升高HDL的概念(重要的生物标记物或本身重要)的研究继续进行。SATURN试验提出问题,即不同种类的高剂量他汀,在终点事件方面是否存在差异。尽管在主要终点方面无差异,但是在次要终点方面,两种药物都可以逆转斑块。高剂量瑞舒伐他汀有可能比高剂量阿托伐他汀更优,尽管我不肯定是否能从次要重点得出肯定结论。本研究是是个替代终点研究而非结果研究,因此对于结果的意义较难判断。我们并不知道IVUS测量的斑块体积的变化有无统计学差异的意义。AIM-HIGH试验,即烟酸试验,因为无效而被提前终止。我认为,在血脂管理方面我们还有工作要做。关于感染性心内膜炎早期外科干预的研究引起了很多关注,因为对临床医生来说这是个很难处理的问题。很难决定有瓣膜功能障碍的感染性心内膜炎患者是否应当接受外科手术。因为感染组织更难缝合,手术难度很大。数据告诉我们,早期接受外科干预的患者至少可以在卒中方面获益。我认为因为试验难以控制,所以对于这个疾病不会有大型的试验。我们需要使用其他的统计方法,来分析和评估接受或不接受外科手术的患者,进行倾向匹配分析或其他分析的时候是否能够进行比较。另外一个热点是TIMI 51试验。TIMI 51试验关注接受氯吡格雷治疗的患者的基因型和血小板功能。我们知道氯吡格雷是个前体药物,而等位基因机能亢进的患者不能将氯吡格雷转化为活性药物。平均来说,这些患者和没有此等位基因的患者相比,接受氯吡格雷治疗时血小板抑制程度较低。本研究是以人群为基础的研究,患者之间稍有差异。在患者突发急性事件的时候,往往并不知道其基因型,因此也就不知道处理方法。而在长期治疗中,基因型对接受氯吡格雷的患者来说就有意义,可以根据它在剂量方面作出调整,或者决定是否接受其他抗血小板药物治疗。以上就是本次大会中近期揭晓的临床试验方面的要闻。也有另外一些有趣的议题,有些我去现场听了,其他的我在会后回顾了。有一个关于从实验室到临床的技术创新和推进,有些讲者讨论了治疗方法从概念到临床应用之间的障碍,以及我们在未来应当如何改变这种现状。在这个议题中,讲者指出我们应当如何考虑不同的方法,以便使新药,以及仅在特定适应症,特定人群和基因型中使用的药物推广使用。这个议题还讨论了一些关于AHA科学促进计划,本计划关注应当采取何种措施,以使一些有可能促进心血管健康的原型,测试方法,变成市场产品。制药公司以及器械公司近期以来因为预算减少而遇到很大困难,所以不愿意进行前期研究,而是等待后期阶段。另一件我在本次大会中强调的事是关于预防的国际会议。关于心血管疾病的预防方面有很多会议和热点,包括二级预防,一级预防以及零级预防。这些议程不光聚焦于药物治疗,还关注其他一些在例如生活方式调整的措施。这些措施在一系列国际会议中进行了讨论,包括秋天进行的联合国部长峰会,即将在迪拜举行的世界心脏大会,以及长城会。在长城会上,胡大一教授聚焦于心血管疾病预防,并且希望在中国能够对预防措施进行落实。总而言之,对这个问题的认识趋势良好,而且我们在努力寻找对花费少、效果好的“性价比最高”的预防措施。



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