研究發現降膽固醇治療心梗和中風新藥

For the first time since statins have been regularly used, a large study has found that another type of cholesterol-lowering drug can protect people from heart attacks and strokes.

自從他汀類成爲常規藥物以來，專家首次在一項大規模研究中發現，另一種降膽固醇的藥物，也可以預防心肌梗死和腦卒中。

The finding can help millions at high risk of heart attacks who cannot tolerate statins or do not respond to them sufficiently. And it helps clarify the role of LDL cholesterol, the dangerous form. Some had argued that statins reduced heart attack risk not just by lowering LDL levels but also by reducing inflammation. The new study indicates that the crucial factor is LDL, and the lower, the better.

無數患者可能會從該發現中受益。這些人心肌梗死的風險較高，但又不能耐受他汀，或者攝入他汀的效果不明顯。這一發現還有助於研究者進一步認識危險的低密度脂蛋白(LDL)膽固醇的作用。一些人認爲，他汀類藥物之所以能減少心肌梗死的風險，是因爲它不僅降低了LDL水平，而且還減少了炎症。而這項新的研究表明，LDL纔是關鍵因素，並且它的水平越低越好。

The six year study, reported Monday at the annual meeting of the American Heart Association, involved 18,000 people who had had heart attacks or episodes of chest pain so severe they went to a hospital. They were randomly assigned to take a statin or a combination of a statin and the alternative drug to further reduce LDL levels. Both groups ended up with very low LDL levels – those taking the statin, simvastatin, had an average LDL of 69, and those taking simvastatin and the other drug, ezetimibe, or Zetia, in a combination pill sold as Vytorin, had an average LDL of 54. No clinical trial had ever asked what happened when LDL levels get below 70 because, said Dr. Robert Califf, a Duke cardiologist and the study chairman, "many people were nervous about going this low and imagined a lot of possible toxicities."

本週一，相關研究人員在美國心臟協會(American Heart Association)的年會上做了報告。這項研究耗時六年，涵蓋1.8萬名患者。他們均曾經歷過心肌梗死，或者嚴重到需要到醫院就診的胸痛發作。研究人員隨機向他們分配了他汀，或者他汀和替代藥物組成的複方藥，以便進一步降低他們的LDL水平。結果兩組患者的LDL都減至非常低的水平——服用他汀類藥物辛伐他汀的患者，LDL的平均水平爲69，而服用複方藥的患者，LDL的平均水平爲54。該複方藥的商品名爲葆至能(Vytorin)，由辛伐他汀和依折麥布組成，而後者又稱爲艾澤庭(Zetia)。這項研究的主管、杜克大學的心臟病學家羅伯特·卡里夫(Robert Califf)博士說，之前沒人通過臨牀試驗來研究LDL水平低於70時會發生什麼狀況，因爲“LDL降到這麼低的水平令很多人感到緊張，覺得可能會產生很多壞處。”

Statins lower LDL by preventing it from being made. Ezetimibe lowers LDL by preventing cholesterol from being absorbed in the gut.

他汀降低LDL的方式是防止它生成，而依折麥布降低LDL的方式是防止腸道吸收膽固醇。

The drugs were so effective that there were few cardiac events among the participants but eventually a difference emerged: 6.4 percent fewer heart disease deaths, heart attacks, strokes, bypass surgery, stent insertion and severe chest pain leading to hospitalization in those assigned to take Vytorin. The amount corresponded to what was predicted from the extra degree of cholesterol lowering with the combination drug.

兩種藥物均非常有效，參與實驗的患者出現心血管意外的次數不多，但差別最終浮現了出來：在心臟疾病死亡、心肌梗死、腦卒中、搭橋手術、支架置入和導致住院的嚴重胸痛方面，攝入葆至能的患者相對低6.4%。考慮到葆至能可以把膽固醇水平降得更低，據此預測的水平與以上實驗數據相符。

Those results translate into 2,742 events in those taking simvastatin and 2,572 in those taking the combination drug. That means, said Dr. Christopher Cannon, a principal investigator and cardiologist at Brigham and Women’s Hospital, that two out of every 100 people who would have had a heart attack or stroke by taking the statin avoided those outcomes by taking the combination drug.

這些結果對應的數據是，服用辛伐他汀的患者中出現了2742次心血管意外，而服用葆至能的患者中有2572次。布萊根婦女醫院(Brigham and Women’s Hospital)的首席研究員、心臟病學專家克里斯托弗·坎農(Christopher Cannon)博士說，這意味着，在100個服用了他汀但仍會心肌梗死或中風的患者，如果服用的是複方藥，本來應該可以避免2例這種情況。

And, adds Dr. Califf, the study found absolutely no side effects from ezetimibe — no excess cancer, no muscle aches no headaches. “It looks like placebo,” he said.

卡里夫博士稱，該研究還發現，依折麥布完全沒有副作用——不會增加罹患癌症的風險，不會造成肌肉痠痛或頭痛。“看上去就像安慰劑，”他說。

The study was sponsored by Merck, the maker of Vytorin, but the investigators had the right to publish what they wanted, with final say over what they wrote.

這項研究由葆至能的生產商默克公司(Merck)贊助，但研究人員有權按照自己的意願來發布內容，對報告的撰寫擁有最後決定權。

“Fantastic,” said Dr. Sekar Kathiresan of the Broad Institute and Massachusetts General Hospital who studies the genetics of heart disease but had no part in the study. “A truly spectacular result for patients.”

“這項研究太棒了，對於患者來說，這是一大福音，”在博德研究所(Broad Institute)和馬薩諸塞州綜合醫院(Massachusetts General Hospital)研究心臟疾病基因的謝卡爾·卡斯瑞斯安(Sekar Kathiresan)博士說。他本人並未參與這項研究。

Dr. Harlan M. Krumholz, a Yale cardiologist not associated with the study, said he wished there was a peer-reviewed journal article instead of a presentation of the results at a meeting — the data analysis was completed just last week — but, assuming the result holds up, “this is the result we were hoping for.”

耶魯大學心臟病學專家哈倫·M·克魯姆霍爾茨(Harlan M. Krumholz)博士也沒有參與該研究。他表示，希望這項成果以同行評議的期刊文章方式發表，而不是在會議上做演示——研究的數據分析上週剛剛完成——但是，假設這個結果經得起推敲，“這會是我們希望看到的結果。”

At the same time, and by sheer coincidence, two other groups of researchers reported genetic studies that supported the trial’s conclusions. One, led by Dr. Brian A. Ference of Wayne State University School of Medicine found that gene mutations mimicking the effect of ezetimibe and ones mimicking the effect of statins had the same effect on heart disease risk for a given reduction in cholesterol. The implication, he said, is that “lowering cholesterol with ezetimibe, or a statin, or both, should each lower the risk of heart disease by about the same amount.”

純屬巧合的是，另外兩個研究團隊也在同時發佈了遺傳學領域的成果，支持了該臨牀研究的結論。其中一個團隊由韋恩州立大學(Wayne State University)醫學院的布萊恩·A·費倫斯(Brian A. Ference)領導。他們發現，對於給定的膽固醇減少量，模仿依折麥布效果的基因突變，和模仿他汀效果的突變，對心臟疾病風險產生了相同的效果。這意味着，“用依折麥布降低膽固醇，或者用他汀，或兩者都用，應該都可以同等程度地降低心臟疾病風險，”他說。

The other, led by Dr. Kathiresan, examined mutations that disabled one copy of the cholesterol absorption gene, producing the same effect as ezetimibe. The result was a 50 percent reduction in cholesterol absorption — the same as produced by ezetimibe — and an LDL reduction of 12 milligrams per deciliter of blood, also the same amount as produced by ezetimibe. The mutation, which gave people the equivalent of a lifelong exposure to ezetimibe, reduced the heart attack rate by 50 percent.

另外一個團隊則在卡斯瑞斯安博士的領導下，研究了讓一個膽固醇吸收基因拷貝無法發揮作用的突變，獲得了和使用依折麥布相同的效果。他們的結論是，膽固醇吸收量減少了50%——與依折麥布效果相同——每100豪升血液的LDL降低了12毫克，也與依折麥布的效果相同。這個突變相當於終生攝入依折麥布，可讓心肌梗死機率降低50%。

The study’s results are making many wonder about the latest cholesterol guidelines, which did not mention any drug other than a statin. And instead of providing goals for cholesterol levels, they simply advised those at high risk to take a statin. Period.

得知這項研究的結果後，很多人對最新的膽固醇指南產生了困惑。文中沒有提及他汀之外的任何藥物，也沒有提供膽固醇水平的目標值，只是勸高風險人羣攝入他汀。別無其他。

“The guidelines didn’t say they didn’t believe in cholesterol, but they made it clear that the evidence is for a statin, not for any agent that lowers cholesterol,” said Dr. Eugene Braunwald, a study chairman who is a cardiologist at Brigham and Women’s and a longtime leader in the field.

“指南沒有說他們不相信膽固醇的作用，但他們明確表示，相關證據只涉及他汀，不涉及其他降膽固醇的藥物，”該領域長期以來的領軍人物尤金·布朗瓦德(Eugene Braunwald)博士說。他是一個研究會的主席，也是布萊根婦女醫院的心臟病學專家。

Dr. Neil Stone, the head of the guidelines committee and a cardiologist at Northwestern University, has a more nuanced view of what the guidelines say, but adds that the study result “gives doctors another option if they have a patient who can’t tolerate a high-intensity statin.”

西北大學(Northwestern University)心臟病學專家尼爾·斯通(Neil Stone)博士是膽固醇指南委員會的主管。對於指南內容的含義，他認爲比布朗瓦德的說法更爲微妙。但他也表示，“如果遇到無法耐受大劑量他汀的患者”，這項研究結果“給醫生提供了另一個選擇”。