编者按：降脂治疗是心血管疾病（CVD）管理的重要内容之一。在美国心脏协会（AHA）2015科学年会上，关于他汀及非他汀应用、老年人群他汀使用、CVD预防中的争议等话题，美国西北大学费恩伯格医学院Neil J Stone教授作了多场学术报告。关于血脂管理问题，《国际循环》记者在会议现场采访了Stone教授。Stone教授是美国西北纪念医院心脏病学家，2012年被任命为美国西北大学费恩伯格医学院预防心脏病学Bonow教授。他在血脂管理方面有长达35年的丰富经验，因此获奖无数。他也是2013年ACC/AHA治疗血胆固醇以降低动脉粥样硬化性CVD（ASCVD）指南的编写委员会主席。

　　International Circulation: Dr. Stone， the results of IMPROVE-IT study were announced at last AHA annual meeting， which confirmed for the first time that on the basis of statins， using non-statins could further reduce the cardiovascular events of atherosclerotic patients. How do you evaluate the anti atherosclerotic effects of non-statins and its application prospect?

　　《国际循环》：IMPROVE-IT研究结果在去年AHA公布，首次证实了在他汀类基础上，加用非他汀类药物可更进一步降低动脉粥样硬化患者血管事件。您如何评价非他汀类药物的抗动脉粥样硬化疗效及其在该领域的应用前景？

　　Dr. Neil Stone: Thank you. So our 2013 ACC/AHA guidelines simply said that statins were first line drugs to lower blood cholesterol and to reduce the risk of atherosclerotic heart disease， heart attack， and stroke in the US population. We said that non-statins were not first line， but we did say that if a person belonged to a high risk group， that is secondary prevention. LDL cholesterol of greater than 190 or a patient with diabetes 40 to 75 with an LDL of 70 to 190， then you could consider a non-statin if two things or three things occurs at once. First the patient was statin intolerant， second the person could not get the desired or anticipated effect， because remember in these high risk groups we wanted maximum statin therapy to lower LDL by at least 50%， and so we said in that setting a person could use a non-statin drug but we preferred it be one that was shown in a randomized control trial to lower LDL and provide incremental benefit on top of the benefits seen with the statin. Now the IMPROVE-IT with ezetimibe we have not just a lower LDL but in this very high risk group， the best results were seen in those with diabetes and acute coronary syndrome. Over the 6 or 7 years of the study， they were shown to have a lower rate of heart attack and stroke with these lower LDL levels than those who just stayed on the moderate intensity statin alone. Now IMPROVE-IT did not actually have an arm testing what we recommended what was a high intensity statin， but some groups and this is true for Asians， may not tolerate a high intensity statin， and so IMPROVE-IT could have important consequences where they show a moderate intensity plus ezetimibe gave results really equivalent to what we think a high intensity would have shown. IMPROVE-IT is completely consistent with what our guideline said and we are fortunate to have a drug now that is both safe and shown effective when added to a statin.

　　Neil Stone教授：2013版ACC/AHA指南推荐他汀类药物作为美国人群的一线降胆固醇药物，用于降低动脉粥样硬化性心脏疾病、心脏病发作及卒中风险，未将非他汀类药物作为一线选择。但指南也指出，当患者属于高危人群时，非他汀类药物可用于二级预防。LDL-C>190 mg/dl者或LDL-C 70~190 mg/dl的40~75岁糖尿病患者，LDL-C需要至少降低50%，若无法耐受他汀治疗、他汀治疗后未达到预期效果，则应考虑应用非他汀类药物。随机对照临床试验显示，在他汀治疗基础上加用非他汀类药物可为患者带来额外获益。IMPROVE-IT研究结果显示，对高危人群而言，在他汀治疗基础上加用依折麦布不仅可进一步降低LDL-C，还降低血管事件发生风险，尤以在合并糖尿病及急性冠脉综合征的患者中作用最显著。随访6~7年发现，与仅接受中等强度他汀治疗者相比，他汀治疗基础上加用依折麦布使LDL-C水平进一步降低的患者，其心脏病发作及卒中发生率更低。IMPROVE-IT研究中未设立指南推荐的高强度他汀治疗组，这主要因为亚洲人可能不耐受高强度他汀治疗。该研究结果显示，中等强度他汀治疗与依折麦布联用即可达到与既往研究中高强度他汀相当的效果，具有重要的意义。实际上，该研究结果与指南推荐完全一致，我们非常幸运和高兴能有一种可在他汀治疗基础上加用的安全有效调脂药物。

　　International Circulation: My second question is elderly patients are the main population of atherosclerosis. For those age after 75， what are the recommendations of 2013 ACC/AHA cholesterol guideline? How to do primary and secondary prevention with statins and nonstatins work for them?

　　《国际循环》：老年患者是动脉粥样硬化的主要群体。对于年龄>75岁者，2013 ACC/AHA胆固醇指南对其他汀使用做出了怎样的推荐？如何对此类患者使用他汀类和非他汀类药物进行一级预防与二级预防？

　　Dr. Neil Stone: So what we said for the group who were more than 75， we said that for primary prevention， we could not make a definite recommendation based on the randomized control trials， but we definitely could make a recommendation for secondary prevention. In the secondary prevention trials， there was benefit shown for moderate intensity for sure and in some cases high intensity. We recommended as a first choice moderate intensity for the over 75 group， because first of all， those in the randomized trial group probably are not as healthy as the average person over 75 that a clinician may see. Number 2; patients over 75 are often on many more medications and we are worried about adverse effects related to the drug and drug interactions， so we recommended definitely a moderate intensity. A good example of this was the PROSPER study. The PROSPER study looked at participants 70 to 83， and it showed a clear benefit in those with secondary prevention， but it did not show a benefit in primary prevention. On the other hand， the guidelines also recognized that there might be patients in primary prevention who would benefit from a statin or who would want to continue the statin they are on. That is why we recommended the patient clinician risk discussion. The key to that risk discussion was that you decide by looking at other risk factors， are they optimal with lifestyle， what is the potential for benefit from a statin， the potential for adverse effects or drug and drug interactions， and lastly some informed patient preference. In that setting， a statin could be used in primary prevention， but it was not to be automatic.

　　Neil Stone教授：就年龄>75岁的老年人群而言，指南未能根据随机对照试验作出明确的一级预防推荐，但对其二级预防作了明确推荐。二级预防相关临床试验显示，对该人群而言，中等强度他汀治疗的获益比较肯定，且有些患者使用高强度他汀治疗也有获益。因此，对年龄>75岁的老年人，我们推荐首选中等强度他汀治疗。这主要因为这些随机试验中所入选的这些患者可能没有临床实践中的同龄患者健康。此外，75岁以上老年人通常需要合并应用多种药物，为避免发生药物不良反应及药物相互作用，故推荐应用中等强度他汀。PROSPER研究是很好的例子，其对70~83岁的老年人进行了研究，结果发现，中等强度他汀治疗可为研究人群的二级预防带来明确获益，但对一级预防未见明显益处。另外，指南也意识到，就一级预防而言，可能有些75岁以上患者能够从他汀治疗中获益或愿意应用他汀治疗。正因如此，我们推荐临床医生要与患者探讨并评估治疗风险。探讨和评估治疗风险时，要考虑其他危险因素、患者生活方式、他汀治疗的潜在获益及不良反应、药物相互作用及患者意愿。某些情况下，有些75岁以上老年人可使用他汀进行一级预防，但并非所有75岁以上老年人均可以。

　　International Circulation: My third question is there still exists great debates in CVD prevention about HDL and triglyceride. What are your comments about this controversy?

　　《国际循环》：心血管疾病预防时，关于对HDL与甘油三酯的干预存在争议，您对这些争议有何看法？

　　Dr. Neil Stone: I think the controversy on HDL cholesterol is really no longer a controversy with very hard to show now with so many negative trials that raising HDL cholesterol with medication is a preferred strategy. There is a different focus now. We are still waiting on the results of one CETP inhibitor trial， but numerous trials have failed to show that if you are on a statin and have a low LDL that adding a drug to raise HDL makes a difference， for example the AIM-HIGH and HPS2-THRIVE trials did not show benefits from niacin， it showed side effects from niacin in those trials. We are not clear that the benefits outweigh the risks， so we did not recommend a strategy to raise HDL in either primary or secondary prevention. We did not recommend a strategy to lower triglyceride in primary or secondary prevention.

　　The reason why we did not recommend a specific drug to focus on triglycerides was we had an AHA statement on triglycerides in cardiovascular health from 2012， and there were essentially no new trials available since that statement. That statement puts strong emphasis on lifestyle change， getting more exercise， losing weight， restricting sugars and other simple carbohydrates in the diet， they could lower triglycerides substantially in the range of 200 to 500， we found no clinical trial data that said that you should add a fibrate or a niacin or an omega 3 fatty acids to a statin. Now some trials are going to take place or give us results and then we will see. We will be particularly interested in a trial that looked at whether using a fibrate in those with high triglycerides would make a difference. So far the fibrate trials have not focused on that group. The important point though is the guidelines always said that you do not add a non-statin unless you have truly optimized lifestyle change and have really tried to maximize the statin if you can. We feel that the evidence still supports what we recommended in terms of optimizing lifestyle， maximize the statin intensity appropriate for that patient’s risk， and then and only then would you consider a non-statin， but currently you would not give a non-statin to raise HDL or to lower triglycerides based on this data. The one exception of course would be the person with very high triglycerides who is at risk for pancreatitis， and again the panel deferred to the 2011 triglyceride statement by the AHA， and there of course is a different story where you would want to address that， but that had nothing to do with atherosclerotic cardiovascular disease， so it was not a part of our statement.

　　Neil Stone教授：我认为有关HDL-C的争议真的已不再是争议，因为已有很多探讨使用药物升高HDL-C的治疗策略相关试验得到了阴性结果。尽管我们仍在等待CETP抑制剂相关研究结果，但已有大量试验未能发现在接受他汀治疗且LDL-C水平较低情况下加用1种升高HDL-C的药物可带来获益。例如，AIM-HIGH研究及HPS2-THRIVE研究均未发现在他汀治疗基础上加用烟酸升高HDL-C可为患者带来获益，相反还会带来不良反应。鉴于目前尚不清楚干预HDL-C的获益是否超过风险，因此，不论一级预防还是二级预防，均不推荐升高HDL-C的干预策略，也不推荐降低甘油三酯的干预策略。

　　之所以美国没有推荐专门针对甘油三酯的药物，是因为2012年AHA发表了一项有关甘油三酯与心血管健康的声明，自该声明发布至今尚无新的相关临床试验。AHA声明强调，改变生活方式、多运动、减重、限制饮食中糖及其他简单碳水化合物的摄入可显著降低甘油三酯水平。目前尚无临床试验数据显示，甘油三酯水平处于200~500 mg/dl时，在他汀治疗基础上应该加用贝特类药物或ω-3脂肪酸。目前，有些相关试验正在或将要开展，我们现在只能拭目以待。我们对在甘油三酯水平较高的患者中应用贝特类药物能否为患者带来获益的试验非常感兴趣。但是，目前有关贝特类药物的试验尚未关注上述人群。非常重要的一点是，指南通常认为，除非患者作了优化生活方式改变并已经应用了最大剂量的他汀，才可以加用非他汀类药物。现有证据也支持指南的这一推荐，即在优化生活方式及根据患者的风险进行了最大强度他汀治疗后，才可以考虑应用非他汀类药物。从目前的数据及证据来看，我们还不能首选非他汀类药物来升高HDL或降低甘油三酯。但是，需要强调的是，当患者的甘油三酯水平非常高且存在胰腺炎风险时，按照2011年AHA有关甘油三酯管理的声明则可以选择应用非他汀类药物降低甘油三酯。但是，这与动脉粥样硬化性心血管疾病无关，因此我们的声明未提及这方面的内容。

　　International Circulation: How do maximize the evidence based cholesterol lowering therapy for prevention? Are there any difficulties or problems?

　　《国际循环》：如何最大化实施基于证据的降胆固醇治疗策略来进行预防？存在哪些困难和问题？

　　Dr. Neil Stone: How to optimize evidence based therapy? First， it is very important to try to understand what risk group the person belongs to. Is this a high risk patient who has secondary prevention issues? Who has diabetes or an LDL greater than 190? Or is it a lower risk person who has an ASCVD risk greater than 7.5%? It appears that our 7.5% is about 10% with the NICE guidelines， because they have different endpoints， but we did not say in primary prevention in younger patients under 75 that you would use a 7.5% as an automatic statin assignment. Rather we said you would trigger a clinician patient risk discussion and that is where you would try to figure out with the addition of family history or other factors， even calcium score， if this would make a difference for your patient.

　　Neil Stone教授：就如何优化基于证据的治疗而言，首先非常重要的是要明确患者的危险分层。高危患者是否存在二级预防问题？哪些人群有糖尿病或LDL>190 mg/dl？是否属于ASCVD风险>7.5%的低危患者？美国指南推荐的7.5%的ASCVD风险与英国NICE指南推荐的10%风险相当，他们使用的终点不同，我们未将ASCVD风险>7.5%作为＜75岁的较年轻患者使用他汀进行一级预防的硬性标准。相反，我们认为临床医生应与患者就风险进行讨论，根据其家族史、其他危险因素、甚至是钙化评分等评估降胆固醇治疗能否为其带来获益。