<International Circulation>: The International Carotid Stenting Study (ICSS) is a multicenter randomized controlled study of carotid artery stenting (CAS) compared with carotid endarterectomy (CEA) in patients with symptomatic carotid stenosis. It has received a lot of attention since first published in the Lancet in 2010. Interim analysis of the study showed that CEA is still the main treatment for patients suitable for surgery. As the chief investigator of ICSS， could you talk about the influence of these results on clinical practice?
Prof. Brown: Yes I can. I think it was worth pointing out that these are only interim analyses and we have recently completed a more complete analysis of the data long-term follow up which was presented at the Stroke conference but has not yet been published. I’ve drafted the paper and it will be coming out. In the interim it has led to caution among neurologists recommending stenting as an alternative to endarterectomy and if a patientis suitable for endarterectomy.It has also led people to think carefully about who should receive stenting and who should receive endarterectomy at least in Britain and neurology based centers throughout the world share this caution. It may have had less interest in North American Cardiologists who still find stenting a good alternative to surgery.
《国际循环》：国际颈动脉支架研究（ICSS）是一项多中心随机对照研究，于症状性颈动脉狭窄患者中对颈动脉内膜切除术（CEA）与颈动脉支架置入术（CAS）实施了对比分析。自其结果首次于2010年在《柳叶刀》发表以来，该研究备受关注。其中期分析结果显示，CEA仍是手术患者的主要治疗方法。作为ICSS研究的首席研究员，您认为这些结果会给临床实践带来怎样的影响？
Brown教授：我认为这些仅是中期分析的结果。我们最近已经完成并在卒中大会上发布了对其长期随访数据的更完整的分析，但相关结果尚未公开发表。我正在撰写相关文章，不久就将写完。在此期间，中期分析结果会使神经学家在对无动脉内膜切除术禁忌证的患者作出用支架置入术替代动脉内膜切除术的推荐时更为谨慎，使人们更仔细的思考哪些患者应该应用支架、哪些患者应该选择动脉内膜切除术。至少在英国以及其他以神经病学为基础的中心中，会出现上述谨慎的态度。但是，对北美的心脏病学家而言则影响不大，他们仍然认为支架置入术是动脉内膜切除术的良好选择。
<International Circulation>: I came across CREST (North American) study. Can you discuss the differences a bit?
Prof. Brown: That’s right and in fact， it’s quite interesting that CREST has been interpreted as showing different results but in fact it doesn’t. It shows the same results in terms of symptomatic patients in terms of our primary analysis. It depends on what you find to be the most important analysis. We presented in the interim paper 120-day outcomeevent， which was a combination of stroke， myocardial infarction (MI) and death.
In our analysis， we defined MI as a clinically diagnosed event and there were very few of those and therefore of little interest. We found the main influence to be stroke. The same was the case in CREST. There was an excess of stroke found in stenting compared with endarterectomy. Actually our results were extremely similar when you look at stroke and death rates. However， the difference is that the CREST trials had many more MI but they used a different definition of MI.
They screened for them using enzyme measures 48 hours after treatment. Many patients had a rise in cardiac enzymes and a change in ECG results， both of which were required for their definition， which differs from our trial.
I think there were two reasons for this. One was the screening. We said that we are interested only in the clinically relevant diagnosis of MI. The other probable reason is the use of selection criteria for patients. Because a lot of their investigators are cardiologists， they were more likely to include patients with ischemic heart disease than we were. That’s evident when you look through the baseline data. In their analysis， they equated MI with stroke in that they had similar numbers， which led to stroke rates with CASin their study being canceled out by MI with CEA. So they stated that the two treatments were equivalent.
However， most neurologists will say that a stroke is a more important outcome event than MI. I think it’s worth looking into the raw data if you would like to know more about it.
Subsequently， we’ve looked at the impact of all events in ICSS on disability. In other words， we looked to see if MI had an impact on daily living and to see if stenting/stroke events affected daily living. And I do have to say they do cancel each other out. ICSS defines very similar measures of disability in the long-term follow-up paper presented at the European Stroke conference.We found that the modified distribution in rank and scores (distribution from 0 to 6: 0 being no symptoms at all， 6 being death) in the two arms of our trial (stenting vs endarterectomy) was identical.
So although there was an excess of stroke， it didn’t translate into long-term disability after stenting. One thing to note is that one design feature of CREST is that their main they combined patients who never had carotid artery symptoms with those who did. In ICSS， we only included patients who only had recent symptoms. We know that the risks of treatment are higher for patients with recent symptoms. Therefore， ICSS applies only to symptomatic patients.
《国际循环》：在北美进行的CREST研究与您的研究有哪些不同之处？
Brown教授：非常有趣的是，CREST研究被认为取得了不同的结果，但事实上并非如此。在有症状的患者中，其结果与我们的最初分析结果是一样的。这取决于分析的关注重点。在我们的中期报告中，我们关注的是120天结局事件即卒中、心肌梗死及死亡的复合终点。在我们的分析中，我们将心肌梗死定义为临床诊断事件，其较少发生因而不太受关注。我们发现受影响最大的是卒中，这与CREST研究的结果（与动脉内膜切除术相比，支架置入术组卒中发生率更高）相一致。其实，就卒中发生率及死亡率而言，我们的结果是非常相似的。所不同的是，CREST试验心肌梗死发生率更高些，这可能与其所应用的心肌梗死定义与我们不同有关。他们是通过测定治疗48小时候的酶含量，根据心肌酶增高伴心电图改变来定义心肌梗死的。很多患者都会有上述两种情况。这与我们的试验是有所不同的。我认为，这样做的原因有两种。其一是就筛查而言，我们只对临床诊断的心肌梗死有兴趣；其二是所用的患者入选标准不同。因为CREST研究中很多研究者都是心脏病学家，所以与我们相比他们可能入选了更多的缺血性心脏病患者。通过基线数据，我们可以很容易地证实这一点。同时在CREST研究中，心肌梗死与卒中患者的数量相当，因此他们研究中行CEA时的心肌梗死发生率超过了行CAS时的卒中发生率，故其认为两种治疗是等效的。然而，大多数神经病学家会认为，与心肌梗死相比，卒中是更为重要的结局事件。通过寻找和查看原始数据，我们发现事实确实如此。随后，我们观察了ICSS研究中所有事件结局对患者日常生活的影响。换句话说，我们探讨了心肌梗死及支架植入/卒中是否会影响患者的日常生活。在欧洲卒中大会上我们公布了长期随访的相关结果，即两者对日常生活的影响是相当的，试验中支架置入术及内膜切除术两组患者的MRS评分相同。因此，虽然卒中发生率增多了，但并不影响支架置入术后患者长期的日常生活能力。需要强调的是，CREST研究的设计特点是其同时入选了伴有及不伴有颈动脉症状的患者，而在ICSS研究中我们仅入选了有近期症状的患者。伴有近期症状的患者，存在更好的治疗风险，故ICSS的结论仅适用于有症状的患者。
<International Circulation>: Your team published a paper on the characteristics of ischemic brain lesions after stenting or endarterectomy for symptomatic carotid artery stenosis on diffusion-weighted magnetic resonance imaging (MRI) in Stroke this year The results showed that， compared with patients undergoing CEA， patients treated with CAS had higher numbers of periprocedural ischemic brain lesions and that lesions were smaller and more likely to occur in cortical areas and subjacent white matter. How do you interpret these results? Has this once again proved that treatment with CAS is inferior to CEA?
Prof. Brown: I believe it has confirmed the main results of an excess of results with stenting. It was an important study to do because one of the advantages of MRI imaging is that it allows for blinded analysis. You can analyze results without knowing what treatment the patient had. Whereas the patient follow-up is not really blind because you cannot really blind the patient or the doctor. That could have led to some bias， not that I think I did. The MRI imaging confirmed the results. The other thing it shows the excess of stents appears to be minor areas of damage， due to small emboli dislodged during the stenting procedure. That isthe same as what we found in the main study (that the excess events were minor in effect). I think it does show that CAS does cause more minor embolization to the brain during treatment than does CEA.
What we really don’t know is whether those small lesions lead to permanent problems. Our long-term study suggests that it doesn’t lead to any major differences in disability despite the fact that there were more minor lesions and more scars on the brain. Again， when interpreted with a long-term data， yes there are certainly more minor events， which are not desirable， but they did not lead to long-term disability.
《国际循环》：您的团队在今年的《卒中》杂志中曾发表了一篇有关症状性颈动脉狭窄患者行CAS或CEA后缺血性脑损伤临床特点的文章。其结果显示，与CEA相比，接受CAS治疗的患者围术期缺血性脑损伤的发生率更高，病变更小，更易发生与皮质区及下方的大脑白质。您对这些结果是如何解释的？这是不是再次证明CAS不如CEA？
Brown教授：我认为，这已经证实了支架置入术存在更多不良结局。该研究的重要性在于其采用了MRI影响分析，其优点在于能够进行盲态分析。研究者能在不知道患者接受了哪种治疗的情况下，对患者的结果进行分析。而之前的随访研究因为无法真正的使患者或医生处于盲态，所以并不是在真正的盲态下进行的。这就存在一定的偏倚。MRI成像证实了这一结果。此外，其显示，支架置入术组增多的脑损伤似乎面积较小，可能是由支架植入过程中小栓子的脱落所导致的。这与我们ICSS研究的结果（增多的结局事件对后续日常生活影响较小）相一致。我认为，研究已经明确表明，与CEA相比，CAS治疗容易造成更多的轻微脑栓塞。但目前尚不清楚这些小的病变是否会导致永久性问题。我们长期研究的结果提示，虽然CAS治疗组患者存在更多脑损伤，大脑中存在更多的疤痕，但这并不会对患者的日常生活能力产生太大的影响。同样，长期数据提示，虽然，CAS组肯定会出现更多的轻微事件，但并不会影响患者的日常生活能力。
<International Circulation>: Finally， how do we select patients for carotid intervention? What are some of the common complications and how can they be prevented?
Prof. Brown: I think that’s a very important question because based on what our study has shown is， if everything is equal， CEA is probably the treatment of choice; otherwise， there are definite advantages to CAS in that it does avoid MI and the scar on the neck which can damage cranial nerves， and in a small number of patients cause long-term disability as well as more blood clots in the neck for surgery patients than with stenting. Therefore， if you could chose a patient in whom CAS is equivalent in risk for stroke to CAE， there would be good reason to recommend CAS as a better treatment for that patient.
I think the evidence says that we’re beginning to acquire some good ways of selecting patients. One of the most important analyses we’ve done since publishing the interim analysis was with some small data from three European trials (3S). That showed rather convincingly that age was an important factor in choosing between risks for the two procedures. In fact， for patients over the age of 70， CAS had a much higher risk of stroke， whereas patients under the age of 70 there was no difference in stroke risk for CAS or CAE. Indeed， the younger the patient， the more likely that CAS was to be superior to CAE. The first thing is that now that we’ve shown in our long-term study the difference in disability， we’ve also shown that it’s durable (there’s no difference in the risk of restenosis. That being said， I think one can recommend CAS as an appropriate alternative to CAE in patients in younger age groups (70 years of age or less).
The second thing we’ve just published， and I can send you the press release， is a paper showing the degree of white matter damage on the brain scan. These patients had a much higher risk from CAS than if they had a lower amount of white matter damage. In the patients with lower amounts of white matter damage， there was no difference in risks between CAE and CAS in terms of stroke. Again， we should be using brain scans to select patients for these two treatments.
《国际循环》：在进行颈动脉干预时我们应如何进行患者的选择？其常见的并发症有哪些？我们应如何预防？
Brown教授：我认为患者的选择是个非常重要的问题，因为我们的研究结果显示，在同等条件下，CEA是更为合适的治疗选择；但CAS也有自己独特的优势，那就是能够避免心肌梗死的发生，且不会产生可损伤脑神经的颈部疤痕。与支架置入术患者相比，少数接受CEA手术的患者颈部会出现更多血块，并影响其颈部活动能力。对应用CAS及CAE时存在同等卒中风险的患者而言，CAS是一种更好的治疗之选。我们正在开始探寻能够进行更好的患者选择的方式。在发布中期分析结果后，我们对三项欧洲研究的一部分数据进行了分析。结果发现，年龄是两种治疗方式风险的重要评估因素。在年龄大于70岁的患者中，行CAS存在更高的卒中风险；在年龄小于70岁的患者中，CAS及CAE的卒中风险则并无差异。实际上，患者越年轻，与CAE相比，CAS的优势越明显。其一，虽然我们的长期研究已经发现生活能力及再狭窄的风险并无差异，但我仍然推荐年龄≤70岁的年轻患者采用CAS替代CAE。我们刚刚发表的一篇文章探讨了大脑白质损伤的程度。结果显示，大脑白质损伤程度越高，CAS治疗相关的风险越大。而在大脑白质损伤较少的患者中，CAE与CAS的卒中风险并无差异。因此，我们可以采用脑部扫描进行两种治疗方式的患者选择。
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