International Circulation: The SATURN trial looks at intensive statin therapy and its action on atherosclerotic plaque regression. Although this trial is not focusing on clinical outcomes， from your presentation we can see that major cardiovascular events in both drug groups were very low， about 7% in patients with established CAD. Do you think， from this and previous studies， that plaque regression can be translated into cardiovascular outcomes?
　　IC：SATURN观察了强化他汀治疗对动脉粥样硬化斑块逆转的作用。虽然这项试验并未重点观察临床结果，但是从您的报告中我们看到2组患者的主要心血管事件发生率均非常低，这组已明确诊断为冠心病的人群心血管事件发生率仅7%。从既往研究和SATURN试验结果看，您认为斑块逆转可以解读为临床结局的改善吗？
　　Prof Nicholls: We think so. We have looked at the relationship between plaque and outcome for many years， even before IVUS. It was quite clear that the more plaque you had， the more likely it was that you would have an event. And the more that plaque progresses over time， the more likely you would have an event as well. We saw that in our own data with IVUS in the last few years. I think what we have seen in this study is very reassuring for doctors and patients and that is if we use the highest doses of statin therapy， they are very safe and they are very well tolerated， they have very good effects on lipid levels leading to very low levels of LDL and actually very good levels of HDL and they actually also regress plaque. That was very much associated with a low event rate in those patients. So all together that is very encouraging for doctors who manage coronary disease.
　　Prof Nicholls: 我们认为是这样。即使在运用IVUS技术之前，我们已经对斑块和临床结果之间的关系观察了许多年。斑块越多，发生事件的可能性越高，这是非常明确的。而随着时间推移，斑块进展越明显，发生事件的可能性也越高。基于过去几年中我们自己进行的IVUS研究数据，我认为在SATURN试验中观察到的结果再次使医生和患者确信，使用最高剂量的他汀治疗非常安全，耐受性非常好，且对血脂水平由非常好的调节作用，达到非常低的LDL-C水平和很好的HDL-C水平，从而逆转斑块。这与患者非常低的事件发生率显著相关。总之，这一结果将大大增强医生管理冠心病的信心。
　　International Circulation: We know that the LDLc concentration has a positive linear correlation with disease progression. In the SATURN trial， both statins achieved very low levels of LDLc with rosuvastatin slightly better than atorvastatin. We also see that the reduction in total atheroma volume is significantly greater in the rosuvastatin group than the atorvastatin group. There is however no significant difference for the primary endpoint， PAV. What is your interpretation of that?
　　IC：我们知道LDL-C水平与疾病进展呈明显正线性关系。SATURN试验中，2种强效他汀均达到非常低的LDL-C水平，而瑞舒伐他汀组较阿托伐他汀组更低。同时瑞舒伐他汀组TAV的降低较阿托伐他汀组更显著。而PAV未达统计学差异。您如何理解这一结果？
　　Prof Nicholls: When we set out to do the SATURN study， the primary objective was to directly compare head-to-head the two statins， rosuvastatin and atorvastatin， and we have done that. What we observed is that there were some differences in lipid levels with rosuvastatin resulting in a slightly lower LDL and slightly higher HDL. We see that on the primary endpoint， both agents are very profound in terms of the regression; there is no difference between the two but there is a difference on the secondary endpoint. We know there are some differences between the two compounds and this is important information for doctors to use when trying to make choices for our patients in terms of how we manage patients with coronary disease. But overall， I think we have to be very satisfied that these are very effective agents. It is good to have choices.
　　Prof Nicholls:开展SATURN研究的主要目的是对瑞舒伐他汀和阿托伐他汀进行头对头比较。我们观察到2组血脂水平出现显著差异，瑞舒伐他汀治疗达到了更低的LDL-C和更高的HDL-C水平；对于主要终点，2种他汀均实现了斑块逆转而无显著差异，但次要终点显示了统计学差异。这些结果使我们认识到2种他汀间存在的差异，为医生治疗冠心病患者时选择用药提供了重要信息。2种药物均非常有效，我们对此感到满意，拥有多种选择是好事情。
　　International Circulation: You mentioned rosuvastatin achieved a slightly better HDL level than atorvastatin and also that in a subgroup， those with higher HDLc levels at baseline and those achieving higher HDLc levels than average responded better to rosuvastatin than atorvastatin with regard to PAV. What message does this give us?
　　IC：您提到瑞舒伐他汀治疗后达到了比阿托伐他汀组更好的HDL-C水平，并且在基线以及治疗后HDL-C水平更高的亚组中，瑞舒伐他汀组PAV的逆转也优于阿托伐他汀组。这一结果给我们什么样的启示？
　　Prof Nicholls: One always needs to be a little cautious in over-interpreting subgroups. We have been very cautious with that. We made a number of observations. It looked like patients who had high levels of HDL either at the start or the end of the study， tended to do better on rosuvastatin. Whether that reflects a difference in the functional activity of HDL (which is becoming very important in terms of our understanding the relationship between HDL and cardiovascular disease)， we don’t know. But it may reflect more functional HDL promoting more regression of disease but we obviously have a lot more work to do to try and understand these things more clearly.
　　Prof Nicholls: 在解读亚组分析结果时需保持谨慎。我们进行了一些观察，似乎在基线以及治疗后HDL-C水平更高的患者中，瑞舒伐他汀的作用更好。我们还不清楚这是否反映了HDL-C功能活性的差异。这些数据可能反映了更多的功能性HDL-C促使病变更多的逆转，我们需要做更多工作以更好地理解这些发现。
　　International Circulation: In statin treatment， we know the most important thing is to reach the LDL target and this year’s ESC/EAS Joint Guidelines on dyslipidemia management recommended even lower LDLc levels. For example， for patients at very high risk， the goal is <70mg/dl or at least a 50% reduction. What are your thoughts on strategies using different statin agents in clinical practice in order to achieve these goals?
　　IC：他汀治疗最重要的目的是使LDL-C达标，2011 ESC/EAS血脂异常管理指南对LDL-C目标值提出了更严格的要求，如，对极高危患者要求将LDL-C降至<70mg/dl或至少降低50%。在临床实践中，为使LDL-C达标，您对他汀药物的选择有何建议？
　　Prof Nicholls: I think this ends up being the most fundamental aspect of SATURN. We are very good at prescribing statins for our patients for coronary disease but in general we don’t tend to increase the doses. Our guidelines are telling us that more and more patients are likely going to have treatment targets that are lower and lower.  More and more people are going to have get an LDL <70mg/dl. For a lot of patients they are not going to be able to do that with low dose statin therapy alone. They are going to have to have their statin dose increased but there seems to be some reluctance to do that in clinical practice; both doctors and patients don’t like to use the higher doses of these medications. They are worried about safety; they even question if there is an added benefit by doing that. The results of this study are very helpful for clinicians. First of all， they show the drugs are very safe and well-tolerated and that is a very important observation， even without looking at the ultrasound. The fact that we can get the LDL levels where we do， the HDL levels where we do， and on top of that， you regress a lot of plaque from the artery wall， it really does emphasize the benefit the patients are receiving， at least in terms of looking at plaque. We obviously need to see how that translates into clinical events but I think it is an important message for doctors who are managing patients with coronary disease that using higher doses of statins is safe and well-tolerated and more likely to get more of your patients to goal. That will be associated with a greater chance of regressing plaque and we think that is a good thing.
　　Prof Nicholls: 我想这也是SATURN试验最根本的意义。我们都非常乐于为冠心病患者处方他汀，但很少会增加剂量。指南也要求越来越多患者的LDL-C水平应该越来越低，越来越多的患者需要将LDL-C降至<70mg/dl，但多数患者使用低剂量他汀难以达到上述目标。对这些患者需要增加他汀剂量，但临床上却很少这样做，医生和患者都不愿意服用更高剂量的他汀。他们担心药物的安全性，甚至质疑这样做能否增加获益。SATURN试验结果对医生非常有帮助。首先，结果表明高剂量他汀是安全的，耐受性良好，即使不论IVUS结果，这也是重要的发现。我们使LDL-C和HDL-C都达到了我们所期望的水平，并逆转了动脉壁上的大量斑块，至少在斑块的变化上显示了患者的显著获益。当然我们需要进一步观察这种获益与临床事件的相关性，但我认为这些结果已经为医生管理冠心病患者提供了重要信息，即，使用高剂量他汀是安全的，耐受性良好，且可使更多患者达标，从而有更多机会逆转斑块。
　　International Circulation: What are your thoughts on LDL targets? Is it the lower， the better? Even lower than 70mg/dl?
　　IC：您如何看待LDL-C的目标值？是否越低越好？甚至较70mg/dl更低？
　　Prof Nicholls: That’s a big question moving forward. To-date， the lower the better has always been the story and every time we have looked we have been able to extend the line. When we get to 60mg/dl， we still see even more regression at that level. The Cholesterol Treatment Trialists observed that the lower your LDLc is， the fewer cardiovascular events you have. The next question is， what if we take LDL even lower? We are born with an LDL of about 40mg/dl. What if we get it down to those types of levels? There are now some interesting therapies in development which on top of a statin may have the potential to have an LDL of 35 or 40mg/dl. It will be interesting to see how they evolve and whether they will result in even more regression and even more prevention of cardiovascular events. It is an exciting time.
　　Prof Nicholls: 这是一个需要继续研究的重大问题。截至目前，越低越好一直被证实是正确的，每次（更新）都将目标值移至更低。当LDL-C降至60mg/dl的水平时，我们观察到更多的斑块逆转。胆固醇治疗研究者（CTT）观察到LDL-C越低，心血管事件越少。下一个问题是，如果我们将LDL-C降至更低，结果会如何？我们出生时的LDL-C水平约为40 mg/dl，如果降至这个水平会怎样？目前正在研发中的一些新疗法，在他汀治疗基础上有可能将LDL-C降至35~40 40mg/dl的水平。这种策略如何发展，能否获得更多的斑块逆转和更好地预防心血管事件，其结果非常令人期待。
　　International Circulation: The SATURN trial showed that even with that intensive statin therapy and a low LDL level， some one third of the patients still showed some progression of plaque. Does that tell us that LDL alone is not enough to reverse the disease process?
　　IC：SATURN研究表明，即使强化他汀治疗达到非常低的LDL-C水平，仍有近1/3的患者斑块继续进展。这是否提示单独降低LDL-C还不足以彻底逆转疾病进程？
　　Prof Nicholls: That is a critical point and the therapies are great. We talk about residual risk of clinical events a lot but we also have residual risk of disease progression. In this study， about a third of the patients progress. That emphasizes to us that we have come a long way but we have a long way to go. As we start to understand the factors that are associated with the likelihood that you will progress in this study maybe that will point to the factors that we need to be targeting in addition to lowering LDL. We know it is a multiple risk disease and it is likely that those who are progressers are more likely to be diabetic， hypertensive and/or obese and these are the other therapeutic areas we need to look at on a constant basis in addition to lowering LDL.
　　Prof Nicholls: 这是很重要的问题。我们对临床事件的剩留风险谈论很多，但疾病的进展也有严重的剩留风险问题。SATURN试验中，1/3的患者斑块仍在进展，说明我们已经走了很长的路，但还有很长的路要走。SATURN试验使我们开始理解了与疾病进展相关的因素，并可能提示我们需要制定除LDL-C以外的治疗靶点。我们知道动脉粥样硬化是多种危险因素综合作用导致的疾病，而那些病变进展者多为糖尿病、高血压和/或糖尿病，在降低LDL-C之外需要根据病情给予其他相应的治疗。
　　International Circulation: This year， the European Guidelines recommended using ApoB as a secondary treatment target. The SATURN trial showed that rosuvastatin achieved a lower ApoB and non-HDLc level than atorvastatin. Does this have some clinical significance?
　　IC：2011 ESC/EAS血脂异常管理指南建议将ApoB和非HDL-C作为次级治疗靶点。SATURN结果显示瑞舒伐他汀组ApoB和非HDL-C水平低于阿托伐他汀组。这有何临床意义？
　　Prof Nicholls: It could. I think there is an emerging story. The LDLc does not show us the whole picture. It tells us how much cholesterol is carried in the particles but it doesn’t tell us about the particles themselves. It doesn’t tell us how many particles there are; whether they are small and dense (which we think are atherogenic) or whether they are larger and fluffy (and less atherogenic). We will be exploring those relationships further to see what impact changes in ApoB or other changes in measures of the particles may have on a greater likelihood to regress or a greater likelihood to progress. Stay tuned!
　　Prof Nicholls: 有一定临床意义。有迹象表明，LDL-C并不是故事的全部，LDL-C只告诉我们颗粒携带了多少胆固醇，但并未告诉我们颗粒本身的状况，不能反映有多少颗粒，是否小而密的颗粒（致动脉粥样硬化）或是否大而松软的颗粒（致动脉粥样硬化作用较弱）。我们将进一步探讨其关联，观察ApoB或其他反映颗粒的测量指标的变化对斑块逆转或进展有何影响。我们将拭目以待。
　　International Circulation: Your data shows that the female subgroup had a better response to rosuvastatin than to atorvastatin. Do you have an explanation for that?
　　IC：您的数据提示女性患者对瑞舒伐他汀的疗效反应较阿托伐他汀更好，如何解释这一结果？
　　Prof Nicholls: That observation is an interesting one. When we have looked before in other studies， we have always been able to show that females do as well as males. Here， almost for the first time， at least in our experience， we see the females doing better on rosuvastatin. Again， one has to be cautious about subgroups; often the randomization is not equal and there may be a lot of differences between men and women so we are exploring that right now. We know that atherosclerotic cardiovascular disease is a significant problem in females; this is not just a male disease. Females need to be treated as aggressively and I think what we see in the SATURN study is， if you do that， you can actually have profound benefits in terms of the amount of regression we see. We look forward to exploring that further.
　　Prof Nicholls: 这是一个有趣的发现。既往研究中，女性获益与男性相当。SATURN试验是第一次观察到女性接受瑞舒伐他汀治疗效果更好。当然，对亚组分析结果需保持谨慎，通常可能出现随机化不够均等、男女之间存在诸多差异，对此结果我们正在进行研究。我们知道动脉粥样硬化性心血管疾病不仅是一种男性疾病，也是女性的重要问题。女性需要更积极的治疗，SATURN试验提示我们，强化他汀治疗对女性病变逆转具有显著的益处。我们将在未来继续深入研究。