<International Circulation>: Do you think we should start the statin therapy early to prevent the recurrent stroke?
《国际循环》：您认为是否应该早期应用他汀类药物预防卒中复发？

Prof. Amarenco: There is no clear date. I think the earlier the better， but we cannot demonstrate this from SPARCL because the mean randomization was three months after the qualifying event. There is a lot evidence in the literature that the earlier the better. The MIRACL trial， for example， demonstrated that if you give a statin immediately after the myocardial infarction， at four months you reduce the risk of myocardial infarction， stroke， vascular death， and re-hospitalization. Stroke was reduced by 50% in MIRACL. I think the three messages from these trials are， the lower the LDL-C the better， the earlier the better， and we have to treat the patients long-term. In patients with stroke we want to reduce the risk of coronary events and the risk of coronary events slowly increases over time， and if you don’t treat the patients for a sufficient length of time， you will not stop these coronary events. So， we need to treat these patients five years and then later I think we need to continue the treatment beyond the five years that we tested in SPARCL. Another message that is very important and it will be published soon as another paper from SPARCL， is that there is a clear additive effect of LDL-C lowering and blood pressure lowering. That means that patients who had the lowest LDL-C in SPARCL and those who also had a blood pressure less than 120/80 mm Hg had the greatest benefit. We need also to tightly control blood pressure and we can have a deeper risk reduction and avoid hemorrhagic stroke.
Amarenco教授：对于卒中预防中应用他汀类药物的时机，目前还未达成共识。我个人认为越早越好。但是SPARCL研究无法回答这个问题，因为该研究的平均入组时间为事件发生后3个月。已经有大量研究证实，他汀类药物的应用越早越好。MIRACL研究表明，发生心肌梗死的患者立即应用他汀类药物治疗可以降低4个月的心肌梗死、卒中、血管性死亡和再次入院的危险，其中卒中的发生降低50%。我认为一系列的研究传达了三大讯息，即LDL-C降得越低越好、越早应用他汀类药物越好、同时应长期治疗。我们期望能够降低卒中患者发生冠状动脉事件的危险，而随着时间推移发生冠状动脉事件的危险逐渐增加，如果治疗的时间不够，可能就无法避免冠状动脉事件的发生。所以在SPARCL研究中患者应用他汀类药物5年，我认为之后应当继续他汀类药物治疗。从SPARCL研究中我们还得到另一个重要启示，即降低LDL-C和降压之间存在明显的累积效应，这意味着SPARCL研究中LDL-C水平最低同时血压<120/80 mm Hg的患者获益最大，该结果将于近期发表。在应用他汀类药物的基础上要严格控制血压，这样就能进一步减少事件的发生，预防出血性卒中。

<International Circulation>:  Do you think the effect of prevention of stroke is a class effect of statins?
《国际循环》：你认为预防卒中是他汀类药物的“类效应”吗？

Prof. Amarenco: In primary prevention of stroke we can clearly say that there is a class effect. The reduction of stroke has been shown with pravastatin， simvastatin， atorvastatin in TNT， ASCOT， Etc. Also， now with rosuvastatin in the JUPITER trial presented earlier this week at the AHA meeting， they showed that in patients with LDL-C less than 130mg/dl and a high CRP level above 2mg/dl， after two years of treatment there was a 48% reduction in stroke risk. Again， this trial showed that the lower the better because on average these patients had an LDL-C at baseline of 108mg/dl and with rosuvastatin 20mg they were down to 55mg/dl.

What normal LDL cholesterol level is in humans we know is not 108mg， but less than 55mg. You can look at what the level of LDL cholesterol is in humans in rural china. People between 20 and 30 years old have an LDL cholesterol level of 25mg/dl. In suburban areas it is about 80mg/dl and in urban areas it is about 110mg/dl. The good level of LDL cholesterol is probably 25mg because these people live normally with this level of cholesterol. So， it is not a surprise that in JUPITER by reducing LDL-C level from 108mg/dl to 55mg/dl they reduced the risk of stroke and other cardiovascular events. Everything was positive in JUPITER. In primary prevention there is clearly a class effect of statins that reduces the risk of cardiovascular events， including stroke. In secondary prevention， we only have two trials. In the HPS trial they found that recurrent stroke was 10.3% in the simvastatin group and 10.4% in the placebo group. So， there was no difference， but in SPARCL there was a significant difference. The difference between these two trials is that one was designed to show recurrent stroke reduction and the other was not. In HPS they did not have the power to show a difference so it would be unfair to say that HPS did not find a reduction in stroke incidence. They had a neutral result because they were not powered for this. Only the SPARCL trial was powered for this finding of stroke risk reduction. Right now we don’t have the evidence that there is a class effect， but it is likely.


Amarenco教授：对于卒中的一级预防来讲，他汀类药物的确存在“类效应”，这是比较明确的。TNT和ASCOT等研究表明，普伐他汀、辛伐他汀和阿托伐他汀均能降低卒中发生的危险。另外，本次AHA年会上公布的JUPITER试验表明，对于LDL-C<130 mg/dl同时C反应蛋白≥2 mg/dl的患者，应用瑞舒伐他汀2年可以降低卒中风险达48%。JUPITER研究再次证实LDL-C降得越低越好，因为这些患者基线时LDL-C均值为108 mg/dl，服用20 mg的瑞舒伐他汀后LDL-C降至55 mg/dl。我们知道，LDL-C的正常值不是108 mg/dl，而是55 mg/dl以下。中国20～30岁农村人口的LDL-C水平为25 mg/dl，郊区为80 mg/dl，市区大约为110 mg/dl。因此，合理的LDL-C水平可能是25 mg/dl，因为LDL-C为该水平的人身体正常。所以，JUPITER试验中LDL-C水平从108 mg/dl降至55 mg/dl可以降低卒中和其他心血管事件的危险并不让人觉得意外。JUPITER试验得出了很好的结果。综上所述，在卒中的一级预防中，减少心血管事件和卒中确实是他汀类药物的“类效应”。

关于他汀类药物用于卒中的二级预防，目前只开展了两项研究。HPS研究显示，辛伐他汀组卒中的复发率为10.3%，安慰剂组为10.4%，两组之间无显著差异。但是SPARCL研究提示阿托伐他汀组和安慰剂组之间存在显著差别。这两项研究的区别在于设计SPARCL研究的目的是观察卒中复发，而HPS研究则不是。在HPS研究中，没有足够效能来发现两组之间的差异，但是因此说HPS研究未能发现他汀减少卒中发生是不合理的。HPS得出中性结果是由于没有足够的统计学效能。只有SPARCL研究具有足够的效能来发现卒中危险性的降低。目前，我们还不能肯定地说卒中二级预防是他汀类药物的“类效应”，但是有可能是这样。