Eugene Braunwald MD
Distinguished Hersey Professor of Medicine
Harvard Medical School
Chair， TIMI Study Group
Brigham and Women’s Hospital
Boston MA

Q: What are the key outcomes of benefits and risks in TRITON-TIMI 38?
请您谈一下TRITON-TIMI38研究显示的主要获益与风险

Prof. Braunwald: The trial tested two thienopyridines drugs on platelet function and on clinical outcomes， the one drug is clopidogrel that has been widely used， and is a very important drug in the treatment of patients with ACS and PCI. The drug that we tested against clopidogrel which is the standard of care is the drug called prasugrel， which is also a thienopyridines but it is more powerful and has a very little variability in response， clopidogrel of course has great variability in response. We studied 30 608 patients with ACS across the whole spectrum from unstable angina to NSTEMI to STEMI who were going on to PCI. This is a head to head randomized double blind placebo control trial involved in 30 countries， 313 sites. The primary end point was cardiovascular death， myocardial infarction or stroke. We found that there was 19 percent reduction with prasugrel compared to clopidogrel， this was highly statistically significant， the actual P value was 0.0004，and this was driven largely by the reduction of myocardial infarction， so there was 19 percent reduction in this total composite end point， but there was no significant reduction of mortality and was no effect on stroke. So if you looked at myocardial infarction， those actually a 24 percent reduction of that. On the other side of the coin， I think that when ever you give a drug， that interferes with normal thrombotic system， whether it is anticoagulant like heparins or whether it is a antiplatelet drug like aspirin， the more intense that you block the system， the more likely you get bleeding， and we did see an increase in bleeding events. The primary bleeding end point that we pre-specified was a TIMI major bleeding which is very serious bleeding and we saw that in 2.4 percent of the patients on the new drug prasugrel and 1.8 percent of patients on clopidogrel. Among the patients with major bleeding there was also some fatalities which were more frequent in patients on prasugrel than patients on clopidogrel. We did another analysis called next clinical benefits， the next clinical benefits was the sum of mortality， myocardial infarction， stroke and major bleeding. Next clinical benefits analysis show that the benefits is balance，  14 percent reduction in the composite end point included major bleeding and that was again highly significant specific. So we think on the whole， the trial was beneficial and the new drug is beneficial for patients.
TRITON-TIMI 38研究对比观察了两个噻吩并吡啶类药物对血小板功能和临床结果的影响。一个药物是氯吡格雷，这是一个非常重要的药物，目前已经广泛用于急性冠脉综合征患者和PCI治疗中。试验中另一个药物是prasugrel，它是一个强效的噻吩并吡啶类药物，二者的不同之处在于，氯吡格雷个体反应差异很大，而prasugrel的个体反应差异性比较小。该研究入选了30 608例ACS患者，范围涉及了不稳定性心绞痛、非ST段抬高心肌梗死和ST段抬高心肌梗死并将要行PCI的患者。这是一个随机、双盲、安慰剂对照的多中心研究，有30个国家的313个中心参加。研究的一级终点是心血管死亡、心肌梗死和中风，主要以心肌梗死事件的减少为驱动。prasugrel组与氯吡格雷组相比一级终点事件减少了19%，具有显著的统计学差异，P=0.0004。但是对于降低总死亡率，两组没有显著差异，对于卒中发生率也没有影响。仅从心肌梗死事件发生率来看，prasugrel组实际上减少了24%。当我们使用影响凝血系统的药物时，不管是肝素类的抗凝药物，还是阿司匹林这一类抗血小板药物，作用强度越大，出血的危险也就越大。我们确实在该研究中发现出血事件发生率增加。预设的主要出血事件终点是TIMI定义的严重出血，这是一类非常严重的出血事件。研究发现prasugrel的TIMI出血事件发生率2.4%，而氯吡格雷为1.8%。在发生严重出血事件的患者中，prasugrel组的死亡事件多于氯吡格雷组。次临床获益（死亡、心肌梗死、卒中和出血事件的总和）分析显示，总体获益是平衡的。包括出血事件的联合终点事件减少了14%，具有显著统计学差异。因此，从总体上分析，prasugrel是有益的，该研究结果对患者来说是有价值的。                

Q:  At the meeting， some experts pointed out that the population enrolled in the study was quiet a narrow one， so the results maybe not completely in line with the full clinical practice. For Some patients the drug maybe not suitable and other patients maybe need a dose reduction. Do you agree with it?
有专家指出，该研究入选的患者是一组非常窄的人群，因此试验结果可能与临床实践不一致。有些患者不适合使用prasugrel， 有些患者可能需要减量。你同意这中看法？

Prof. Braunwald: I think this is a very good point of view. I think you can apply the results of the trial only to the population we studied. We think it is a very relevant population. After we saw the overall results， we did what is called a post-hoc subgroup analysis. It is important to point out that this was not pre-specified and there a lot of problem specifically with that. Physicians want to know their patients who turn out not to be aided by the drug. So we looked at the broad array of subgroups， remember this is a post-hoc analysis， there was once a group in which there was harm， and those patients who have had a previous stroke or transient ischemic attack are amount to 4 percent of the population. I would probably not want to give them prasugrel. There were two other subgroups in which the next clinic benefit was 1.0. It does not mean that prasugrel was harmful， it was as good as clopidogrel， is just wasn’t better. These patients’ next clinical benefit was 1.0 or over cross 1.0， because they bleed a little more， they were patients over the age 75， and they were the patients under 60 kg. Those two groups together was amount to 16 percent of the population in the trial. We believe that these two groups’ patients had a higher concentration of the drug. These two groups’ patients probably should get a lower dose of the drug. We have seen excess bleeding in patients over 75， we will able to reduce the excess bleeding in the elderly patients by giving them a lower dose by used 75 percent of the dose. I think something like this will happen here as well， and I think that will cover 95 percent the patients who were studied in this trial. One important subgroup of the patients is the patients with renal dysfunction， and the result on those patients contrary to what has been speculated in the late press. The patients with renal dysfunction would have worse outcomes. That wasn’t the case at all， because this drug is not excreted by kidney. So if you have poor renal function it does not mean that you cumulate the drug， it is metabolized by the liver， it is 0 that comes out of urine.
我同意这一观点，该研究结果只能用于研究涉及的特殊类型人群。研究结束后，我们进行了事后亚组分析。应该强调的是，事后亚组分析没有预设的重点，许多相关的特殊问题都列入分析之中。临床医生希望了解哪些患者不能够从治疗中获益，所以观察目标是一个宽谱队列亚组。请记住这是事后分析，分析发现有一些者接受噻吩并吡啶类药物治疗后风险增加，这些患者有卒中或短暂性脑缺血发作史，占总数的4%左右。我认为这些患者不适合噻吩并吡啶类药物治疗。还有其他两组患者的次临床获益为1.0，这并非说明prasugrel是有害的，只是表示在这些患者中prasugrel与氯吡格雷获益相当，而不是prasugrel比氯吡格雷更好。这两组患者分别是年龄超过75岁的患者和体重低于60kg的患者，这些患者出血发生率略有增加。这两组患者加起来占参加试验患者总数的16%左右。这两组患者患者可能需要给予低剂量的prasugrel。我们给予75岁以上老年患者常规剂量<