一種可能會大幅降低心肌梗死和中風風險的藥

A new class of experimental cholesterol drugs might sharply reduce the risk of heart attacks and strokes, researchers reported on Sunday, citing what they described as preliminary evidence.

週日，研究人員援引“初步證據”稱，一類新的實驗性降膽固醇藥物可能會大幅降低心肌梗死和中風風險。

The drugs, one being developed by Amgen and the other by Sanofi and Regeneron Pharmaceuticals, are already known to sharply reduce so-called bad cholesterol, sometimes to levels lower than those achieved by statins like Lipitor, the mainstay lipid-lowering medicines.

上述報告中的藥物是指由美國安進公司(Amgen)以及賽諾菲(Sanofi)和瑞澤恩製藥公司(Regeneron Pharmaceuticals)研發的。目前已經確知它們可以大幅減少所謂的“壞膽固醇”（即LDL膽固醇[低密度脂蛋白膽固醇]——譯註），有時其效力甚至會超過主流降脂藥物，如立普妥(Lipitor)等他汀類藥物。

What has not been known, however, is whether the drugs do what patients and doctors really care about: protect against heart attacks, strokes and other cardiovascular problems or “events.”

然而，對於醫生和患者真正關心的問題——預防心肌梗死、中風和其他心血管疾病或“事件”——這些藥物的效果如何，目前尚不十分清楚。

The early results suggest that there might be such a benefit, maybe even a big one. In small studies sponsored by the manufacturers, both drugs reduced the rate of such cardiovascular problems by about half.

早期的研究結果表明，它們非但有益，甚至還可能是大有益處。在由藥品製造商贊助的兩項小型研究中，這兩種藥物分別將此類心血管問題的發生率減少了一半左右。

“To see a reduction in cardiovascular events already is very encouraging that we’re on the right track,” Dr. Jennifer G. Robinson, the lead investigator in the trial of the Sanofi drug, said in an interview.

賽諾菲藥物試驗的研究負責人，珍妮弗·G·魯賓遜(Jennifer G. Robinson)博士在接受採訪時說：“看到心血管事件的減少真是非常令人鼓舞，這說明我們是走在正確的道路上。”

The studies were published in The New England Journal of Medicine and were being presented at the annual meeting of the American College of Cardiology taking place through Monday in San Diego.

該研究發表在《新英格蘭醫學雜誌》(The New England Journal of Medicine)上。從週一起在聖地亞哥舉行的美國心臟病學會(American College of Cardiology)年會上，也對其進行了介紹。

Researchers cautioned, however, that the studies were small and intended to assess whether the drugs lowered the bad cholesterol and were safe, not whether they staved off heart attacks. That could make the conclusions about heart attack and stroke risk less trustworthy. Judging those effects will require larger trials involving tens of thousands of people; such studies are underway and are expected to be completed by 2017.

但是，研究人員警告說，上述研究規模較小，且研究目的是評估這些藥物的安全性以及它們能否降低“壞膽固醇”，而不是它們能否避免心肌梗死。因此，據此得出心肌梗死和中風風險降低的結論，可能並不足信。要對上述效果做出可信的判斷，需要進行涉及數萬人的大規模試驗。目前這些研究還在進行當中，預計將於2017年完成。

“I do not think that either study answers the question definitively of cardiovascular benefit,” said Dr. Steven E. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, referring to the drug makers’ research. He was not involved in either study.

未參與上述任何一項研究的科學家，克利夫蘭診所(Cleveland Clinic)心血管醫學部主任史蒂文·E·尼森(Steven E. Nissen)表示：“我認爲（藥品製造商的）這兩項研究都未能明確回答這些藥物是否對心血管有益。”

Researchers said long-term safety still must be assessed, especially since these drugs are reducing LDL cholesterol to levels never achieved by medicines before. While the drugs appeared generally safe, there was evidence that they could cause memory problems.

研究人員表示仍須對這些藥物的長期安全性進行評估，鑑於它們可將LDL膽固醇降低到此前通過藥物從未達到的水平，尤其應當如此。雖然大體上應該是安全的，但也有證據表明，它們可能會導致記憶問題。

Still, the findings could help smooth the way for regulatory approval, wider use of the drugs by doctors and possibly reimbursement by insurers.

儘管如此，上述研究結果很可能有助於爲這些藥物獲得監管部門的批准，被醫生廣泛應用，並納入保險公司的報銷範圍鋪平道路。

The drugs, evolocumab from Amgen and alirocumab from Sanofi and Regeneron, inhibit a protein in the body called PCSK9 that helps regulate cholesterol. In the studies detailed on Sunday, both drugs reduced the bad cholesterol by about 60 percent, to about 50 milligrams per deciliter from about 120 at the start of the studies. In many cases such big reductions were achieved even though the patients were already taking statins.

這兩種新藥分別是安進公司(Amgen)研發的evolocumab，以及賽諾菲和瑞澤恩(Sanofi and Regeneron)製藥公司的alirocumab，它們的作用機理都是抑制PCSK9——體內的一種協助調節膽固醇的蛋白質。週日發表的文章對兩項研究都進行了詳細的介紹：這兩種藥物將“壞膽固醇”從研究開始時的每分升約120毫克降到了約50毫克，降幅達60%左右。在許多病例中，甚至在患者已在服用他汀類藥物的情況下，仍然實現瞭如此大的降幅。

Both drugs could win approval from the Food and Drug Administration by this summer. Analysts say the drugs will have billions of dollars in annual sales and will be taken by millions of people who cannot lower their cholesterol enough using statins alone or cannot tolerate statins. (However, the PCSK9 drugs are taken by injection every two weeks or four weeks, which could deter some users.)

這兩種藥物有望在今年夏天贏得美國食品和藥品監督管理局(Food and Drug Administration)的批准。分析人士預計其年銷售額將達到數十億美元，數以百萬計單靠他汀類藥物無法將膽固醇降低至滿意水平或不能耐受他汀類藥物的患者都可能選用這些藥物（然而，每兩週或四周一次注射給藥的方式，卻也會令某些用戶對這些PCSK9藥物望而卻步）。

Statins reduce cardiovascular risk and scientists believe it is because they decrease low-density lipoprotein, or LDL, the so-called bad cholesterol. But merely looking at cholesterol levels can be misleading. The drug niacin did not protect against heart attacks and strokes even though it raised so-called good cholesterol and modestly lowered bad cholesterol.

科學家們認爲，他汀類藥物之所以可以降低心血管問題的風險，是因爲它們可降低“壞膽固醇”，既即LDL低密度脂蛋白膽固醇的水平。然而，單以膽固醇水平論事可能會造成誤導。例如，煙酸這種藥物可以提高“好膽固醇”的水平，並可適度降低“壞膽固醇”水平，但它對心肌梗死和中風就沒有預防作用。

Insurers in particular might demand proof that the PCSK9 drugs stave off heart attacks, strokes, deaths from coronary disease and procedures to open arteries before agreeing to pay for them for many patients. Executives at CVS Health, a leading pharmacy benefits manager, recently said that PCSK9 inhibitors might cost $7,000 to $12,000 a year and would strain health care budgets because so many people might use them.

保險公司對此尤其關注。在同意替患者爲這些藥物埋單之前，他們將要求研究提供明確的證據，證實PCSK9藥物確實可以預防心肌梗死、中風、因冠心病死亡以及動脈擴張手術等。CVS健康公司(CVS Health)是美國名列前茅的一家醫藥福利管理公司，其高管最近表示，在PCSK9抑制劑上的年花費預計達7000美元至12000美元，由於使用者人數衆多，它將給醫療預算帶來沉重的壓力。

“Managed care pharmacy, indeed the health care system, has never seen a challenge like this to our resilience in absorbing costs,” they wrote in the Health Affairs blog.

他們在健康事務(Health Affairs)網站的博客中寫道：“保健藥學管理，實際上，整個衛生系統都未曾面臨過像這樣的對吸納成本適應能力的嚴峻挑戰。”

Whether the results from these two small studies will be persuasive enough remains to be seen.

至於這兩項小型研究的結果是否具有足夠的說服力，還有待觀察。

The study of Amgen’s evolocumab involved 4,465 patients with various degrees of risk, two-thirds of whom were randomly chosen to get the drug in addition to the medication they were already taking. After one year, 0.95 percent of those in the group that received the drug had suffered a heart attack, stroke or other cardiovascular problem, compared with 2.18 percent in the group that did not take the drug. By a measure known as the hazard ratio, the risk of cardiovascular events was reduced by 53 percent.

安進公司的evolocumab研究納入了4465名風險程度不一的患者，從中隨機選擇了三分之二在已服用藥物的基礎上使用新藥。一年後，接受新藥的那組患者中只有0.95%發生過心肌梗死、中風或其他心血管問題，相比之下，未服用此藥的那組患者中該比例爲2.18%。以風險比(hazard ratio)這一指標衡量時，心血管事件的風險降低了53%。

The alirocumab study involved 2,341 patients. After one and a half years, the rate of cardiovascular events was 1.7 percent in those who received the drug, versus 3.3 percent in those who received a placebo, a risk reduction of 48 percent.

關於alirocumab的研究入組了2341名患者。一年半之後，在接受該藥的患者中心血管事件的發生率爲1.7%，而在接受安慰劑的患者中爲3.3%，風險降低了48%。

Dr. Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, said analyses of one measure from trials meant to assess other things were “notorious for not being reliable.” He said the results would not be sufficient to support widespread use of and reimbursement for the drugs.

希德斯-西奈醫療中心（Cedars-Sinai Medical Center，位於美國洛杉磯）的心臟病專家桑賈伊·考爾(Sanjay Kaul)博士表示，拿一項對旨在評估其他問題的試驗中的指標來說事兒“實在不靠譜”。他認爲這些結果不足以支持廣泛使用這些藥物並將其納入報銷範圍。

He noted, for instance, that the alirocumab trial used a narrower definition of cardiovascular events than the evolocumab trial used. Using a broader definition, alirocumab did not provide a statistically significant reduction in cardiovascular problems.

例如，他指出，alirocumab試驗中使用的心血管事件定義要比evolocumab試驗中的窄。如果使用更寬泛的定義，那麼alirocumab減少心血管問題的效果就失去了統計學顯著意義。

The evolocumab study, for its part, did not use a placebo, so patients and doctors knew who was getting the drug, which could have affected the outcome.

至於evolocumab研究，由於它沒有使用安慰劑，患者和醫生們都知道哪些人接受了新藥而哪些人沒有，這也可能對患者的預後造成影響。

But Dr. Marc S. Sabatine, a cardiologist at Brigham and Women’s Hospital and the lead investigator of the evolocumab study, said the fact that both trials had similar results was reassuring, suggesting the effect was real. The results were also plausible, he said, because people who have genetic mutations that reduce their PCSK9 levels have very low rates of heart attacks.

但evolocumab研究的負責人，布萊根婦女醫院(Brigham and Women’s Hospital)的馬克·S·薩巴蒂尼(Marc S. Sabatine)博士稱，這兩項試驗得到了類似的結果，這項事實本身就說明結果可靠，那些效果是真實存在的。他還說，會發生這些結果也尤其合理性，因爲帶有基因突變，致使PCSK9水平偏低的人心肌梗死的發生率就很低。

Dr. Sabatine and Dr. Robinson have been paid consultants to the companies sponsoring the trials they led.

薩巴蒂尼博士和魯賓遜博士均在資助他們負責的研究的那些公司中擔任有酬顧問。