Lars Wallentin教授 瑞典Uppsala临床研究中心（UCR）
<International Circulation>: Atherosclerosis has become the "number one killer of human health". Stabilizing the vulnerable plaque is the important goal of prevention of acute cardiovascular events. What do you believe are effective measures to stabilize this vulnerable plaque?
Prof. Lars Wallentin: It is a very important topic and a difficult question. I think so far in order to stabilize the plaque the best strategy seems to be to lower the LDL cholesterol concentration because then you get less of the lipid infiltration in the plaque and it seems to be the lipid infiltration which starts the inflammatory process that will lead to the softening of the plaque with a raised risk for plaque rupture. So far I think statin treatmetnt is the best opportunity here. I will be discussing at this meeting a new possibility to use an anti-inflammatory treatment to reduce the risk of plaque rupture. I will have that presentation on the Thursday， the first day of the meeting. The presentation will discuss the development of a new anti-inflammatory agent which inhibits the activity of lipoprotein bound phospholipase A2 (LpPLA2) by a compound called Darapladib manufactured by the company GSK. We are currently leading a collaborative large scale phase III trial in 15，000 patients over 3 to 5 years to see whether anti-inflammatory treatment really can stabilize the lesion and improve outcomes. Therefore I think that direct anti-inflammatory treatment may be a future opportunity to prevent plaque rupture. This is a new concept and we will not of course present the main result at this meeting but rather the underlying biochemistry and the pathophysiology of the process where this compound inhibits inflammation. The main results of this STABILTY trial will be presented in March next year.
《国际循环》：动脉粥样硬化已成为威胁人类健康的头号杀手。稳定易损斑块是预防急性心血管事件的重要目标。稳定易损斑块的有效措施有哪些？
Lars Wallentin教授：这是一个非常重要话题，也是一个棘手的问题。我认为目前稳定斑块的最佳策略可能还是降低LDL-C浓度。因为脂质浸润会启动炎性反应，使斑块软化从而增加斑块破裂风险，降低LDL-C浓度则有助于减少斑块中的脂质浸润。因此，目前来说，我认为他汀治疗是稳定斑块的最佳选择。在本届大会上，我还将讨论采用抗炎治疗降低斑块破裂风险的可能性。我将在大会的第1天，也就是周四，做这个讲座，就葛兰素史克研发的名为Darapladib、能抑制脂蛋白相关磷脂酶A2（LpPLA2）活性的新型抗炎药物进行讨论。我们目前正在开展一些大型III期临床试验--STABILTY试验，对15 000例患者进行3~5年的研究以确定抗炎治疗是否真的能够稳定病灶、改善预后。因此，我认为未来直接的抗炎治疗可能会成为预防斑块破裂的新方法。这是一个新的理念。当然，在此次大会上我们还无法公布该研究的主要结果。此次，我主要是解析该复合物一直炎症的生化及病理生理机制。STABILTY试验的主要结果将于明年3月份公布。
<International Circulation>: The rupture or the erosion of coronary artherosclerosis plaque has been associated with the developments of acute coronary syndrome (ACS)， you will talk about this at Eurothrombosis 2013. Can you give us a glimpse as to what you believe are some key steps in the development of modern treatment of ACS will be?
Prof. Lars Wallentin: I have been very much involved in the treatment of acute coronary syndromes over the last 20 years during which time it was realized that it was a plaque erosion and starting a thrombic process that led to attempts to use antithrombotic drugs. The first antithrombotic treatment use was aspirin. Our group was the first showing the efficacy of the low dose aspirin- to-day the mainstay of the treatment in ACS. In the mid 1980s we randomized patients with acute coronary syndrome to 75 mg of aspirin once a day versus placebo and showed a more than 50% reduction in myocardial infarction or cardiovascular death. This has been the basic treatment of this condition since the beginning of the 1990s and was the first attempt to attenuate the development of the thrombotic growth process at the lesion. In the mid 1990s when we came up with the hypothesis that low molecular weight heparin given subcutaneously might further reduce the event rates. Within our network in Sweden we were therefore able to perform the first trial comparing low molecular weight heparin with placebo on top of aspirin which resulted in a further 50% reduction in cardiovascular death or myocardial infarction in the acute phase during the hospital stay. Based on these result a combination of aspirin and low molecular weight heparin has since then been a cornerstone of the treatment in acute coronary syndrome since the mid 1990. At the end of the 1990s more efficacious platelet inhibition with clopidogrel was shown to further reduce the event rates by around 20%. Finally over the last few years our group together with a global network of investigators has shown that using the new ADP receptor inhibitor ticagelor further can reduced event rate by another 20%. Now we have the combination of aspirin and ticagelor as cornerstones of an antiplatelet treatment in combination with anticoagulation with low molecular weight heparin in patients with acute coronary syndrome. In addition to that， also in the end of the 1990s we were the first group to show that an early invasive procedure with PCI or CABG surgery was efficacious in reducing both myocardial infarction and cardiovascular death. Thus， in addition to antithrombotic treatment with aspirin， low molecular weight heparin and ticagelor also almost all patients are treated with an early catherization and， at significant lesions also revascularization by PCI with stenting or eventually open heart surgery with coronary bypass. These are the key elements of management of acute coronary syndrome in order to stabilize the thrombotic process by medication and to eliminate the coronary lesion by coronary dilatation and stenting. These elements are now included in the treatment guidelines around the world， both in the European guidelines， the American guidelines and applied as the basic treatment.
《国际循环》：冠状动脉粥样硬化斑块的破裂或蚀损与急性冠状动脉综合征（ACS）的发生密切相关。您在欧洲血栓峰会上讲到相关话题。您能否简要概述一下您认为ACSACS的现代化治疗的关键流程有哪些？
Lars Wallentin教授：过去20年间，人们意识到急性冠状动脉综合征是由斑块蚀损所致，需进行抗栓治疗，并积极开始应用抗栓药物。在此期间我对急性冠状动脉综合征的治疗极为关注。第一个被用作抗栓治疗的药物是阿司匹林。我们的研究组首先发现低剂量阿司匹林能治疗ACS。目前，低剂量阿司匹林认识ACS抗栓治疗的中流砥柱。20世纪80年代，我们入选急性冠状动脉综合征患者将其随机分组后分别接受阿司匹林（75 mg/d）或安慰剂治疗。结果发现，与安慰剂组相比，阿司匹林组患者心肌梗死或心血管死亡事件减少了50%。因此，从20世纪90年代开始，低剂量阿司匹林成为急性冠状动脉综合征征患者的基础治疗，也成为缓解病变处发生血栓形成的首次尝试。20世纪90年代中期人们提出了“低分子量肝素皮下注射能进一步降低事件发生率”的假说。在瑞典我们得以开展了首项比较低分子量肝素与安慰剂分别与阿司匹林联用疗效的试验。结果发现，与安慰剂相比，低分子量肝素与阿司匹林联用能使住院期间急性期心血管死亡或心肌梗死的发生率进一步降低50%。正是因为如此，从20世纪90年代中期开始阿司匹林与低分子量肝素联用成为急性冠状动脉综合征治疗的基石。20世纪90年代末，人们发现，氯吡格雷能更有效地抑制血小板，使事件发生率降低20%。最后，在过去的几年中，我们的研究组与全球的研究者均发现，新型ADP受体拮抗剂替格瑞洛能进一步使事件发生率降低20%。现在，对急性冠状动脉综合征患者，我们经常在应用低分子量肝素抗凝的基础上进一步选用阿司匹林及替格瑞洛联用作为抗血小板治疗的基石。此外，同样是在20世纪90年代末，我们的研究组首先发现，尽早实施PCI或CABG治疗也能有效降低心肌梗死及心血管死亡事件。因此，除了应用阿司匹林、低分子量肝素及替格瑞洛行抗栓治疗外，几乎所有的ACS患者都应尽早接受PCI支架植入术或开放性的冠状动脉搭桥术对明显的病变进行血运重建。上述就是通过药物稳定血栓形成或通过扩张冠状动脉及支架植入术来消除病变治疗急性冠状动脉综合征的关键方法。这些方法现在已经被纳入至包括欧洲、美国在内的世界各地的ACS治疗指南中，并成为ACS的基本治疗措施。
<International Circulation>: As a follow up， what do you see coming next with regards to the development of treatment with ACS?
Prof. Lars Wallentin: That is a rather challenging question. I will touch on that in my lecture. We have been so successful in reducing thrombotic events by the combination of antithrombotic agents and also by stenting the lesion that it is difficult to further improve outcomes， especially in the acute phase. We have tried by adding additional antithrombotic agents with new or anticoagulants for long term and even the addition of a third antiplatelet agent but， although event rates might be slightly further reduced， you get unfortunate consequences with bleeding. Therefore it seems that to further inhibition of the thrombotic process might be hazardous and associated with too much bleeding. Therefore， currently， I think the focus now should be on trying to stabilize the lesion probably eventually with more effective lipid lowering or eventually by testing anti-inflammatory agents.
《国际循环》：您如何看待未来ACS治疗的发展方向？
Lars Wallentin教授：这是一个非常具有挑战性的问题。在我的讲座中，我也将提到这一点。通过联用抗栓药物及在病变处放置支架我们已经成功地降低了血栓事件的发生率，因此进一步改善患者的临床结局，尤其是急性期结局具有一定的难度。我们曾试图通过长期加用抗凝剂及其他新型抗血栓药物甚至加用第三种抗血小板药物来进一步降低事件的发生率。尽管这样做之后，事件发生率能进一步小幅降低，但却会增加出血风险。因此，进一步抑制血栓形成过程可能对患者不利，会使出血风险增加。因此，我认为，目前的重点还是要通过更有效的降脂治疗或抗炎药物来积极稳定病灶。
<International Circulation>: In your opinion， you just spoke towards how to draw a balance between the treatment of ACS and reducing the occurrence of bleeding events. What do you believe would be a very efficacious way with anticoagulation and risk of bleeding in order to have the best outcome benefit for the patients?
Prof. Lars Wallentin: The future challenge will be to balance between the different options for antiplatelet agents like aspirin or platelet inhibition with ticagrelor and the new oral anticoagulants like rivaroxaban. I think we might need to identify which 2 of those 3 will be most effective and in which setting. Of course one hypothesis is that you might not need aspirin. But no one knows until such new strategies have been prospectively tested in new randomized trials. In addition it will be difficult to compete with aspirin because it is such a cheap and effective agent and all the new agents will be considerably more expensive while the incremental benefit in relation to the incremental cost might still be too small to replace aspirin. So I think there is an ongoing discussion within many pharmaceutical companies which direction to take. There are now several antiplatelet agents and thrombin inceptor inhibitors. Obviously we cannot use all of them in every patient so we have to identify which patients that could be tailored to the best response to a specific combination. However to come up with evidence for such a treatment approach will be a very costly undertaking. The main problem for long term treatment will be that no more than 2 antithrombic agents will be tolerated neither because of safety or based on costs.
《国际循环》：您刚才提到了如何维持ACS治疗与降低出血事件之间的平衡。要想为患者带来最大程度的临床获益，您认为应采取怎样有效的方式来实现抗凝治疗与出血风险之间的平衡？
Lars Wallentin教授：未来的挑战将是如何在阿司匹林、血小板抑制剂替格瑞洛及新型口服抗凝剂如利伐沙班之间进行选择。我认为，我们可能需要确定这三种药物中哪两种药物在哪种情况下最有效。当然有一种假说认为，可能我们将不再需要阿司匹林。但是，到目前为止，在得到前瞻性随机试验的验证前，没有人能肯定这一点。此外，其他药物要想与阿司匹林进行竞争还是非常困难的，因为阿司匹林既经济又有效，而其他新型制剂则相当昂贵、成本效益比较小，故而仍无法替代阿司匹林。因此，很多制药公司都在探讨未来的发展方向。目前有很多抗血小板药物及凝血酶受体抑制剂。很显然，我们不能在每位患者中都应用它们。这就需要我们来确定哪些患者对某一特定的药物联合治疗具有更好的反应性。但是，要想获得上述治疗方法的循证依据是需要投入大量资本的。长期治疗的主要问题鉴于安全性及成本考虑，可能患者无法承受两种以上的抗血栓药物。
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