The only large clinical trial to find that statins reduce mortality in patients taking them for primary prevention – a group that comprises 75% of statin users – was so seriously flawed that its conclusions were termed “clinically inconsistent” and invalid by one group of researchers and “extreme and exaggerated” by another, according to separate reports in the June 28 Archives of Internal Medicine.

In the first critique of the 2008 JUPITER (Justification for the Use of Statins in Primary Prevention) trial, Dr. Michel de Lorgeril of Université Joseph Fourier and Centre National de la Recherche Scientifique, Grenoble, France, and his associates, analyzed the methods and findings of this only major study to claim that rosuvastatin produced a striking decrease in mortality in low-risk patients who have no evidence of coronary heart disease. These findings, which immediately provoked controversy, “have undoubtedly propelled many healthy persons without elevated cholesterol levels onto long-term statin treatment,” Dr. de Lorgeril and his colleagues said.

First among its major flaws, JUPITER was terminated early and apparently without proper justification according to the study’s own protocol prespecifications. Early termination, a practice confined largely to industry-sponsored trials, tends to introduce biases that exaggerate the benefit and minimize the long-term harm of the treatment being assessed, according to the researchers. In this case, it also meant that the study was stopped just as mortality curves between the statin group and the control group had begun to converge, “suggesting that the borderline significant difference between groups may have disappeared” if follow-up had not been prematurely terminated, they wrote.

The main justification for terminating JUPITER was explained as an “unequivocal reduction in cardiovascular mortality” with statin therapy. Yet the JUPITER investigators did not include data on cardiovascular mortality in their published report. Readers would have to infer this result by extrapolating from data on a table. When examined closely, however, that data showed identical cardiovascular mortality between the treatment groups.

“Such a lack of effect on cardiovascular mortality [together] with a strong effect on nonfatal complications strongly suggests a bias in the data set and should have led to the continuation of the trial rather than to its premature ending,” Dr. de Lorgeril and his colleagues asserted.

Second, the ratio of fatal to nonfatal MI was so low as to be “incredible.” In particular, the case-fatality rate in the placebo group was only 8% when it would be expected to be about 50%, “a clinical inconsistency that suggests a major flaw in the study.” Moreover, the case-fatality rate with rosuvastatin was 29%, which implies that the “beneficial” drug actually tripled the case-fatality rate, they noted.

Third, JUPITER failed to explain why a strikingly high number of deaths – 19 of 31 deaths in the rosuvastatin group and 25 of 37 deaths in the placebo group – were attributed to cardiovascular causes other than MI or stroke. Proponents of the JUPITER study argued after its publication that this referred to causes “such as aneurysm rupture.”

“Would this mean that in the same period of time there were 6 fatal infarctions and 25 fatal aneurysm ruptures in the placebo group? This is highly unlikely,” Dr. de Lorgeril and his associates commented.

JUPITER also failed to report data on sudden cardiac deaths, which is surprising given that this is “the simplest and most reliable diagnosis in cardiology” and that it usually comprises 65%-70% of total cardiac mortality. “The way sudden cardiac death is reported – or not reported – may be a good indicator of the quality of the methods used in a trial,” they noted.

Equally important to these methodological flaws, the JUPITER trial involved several conflicts of interest.

“It was conducted by a sponsor with obvious commercial interests. Nine of 14 authors of the JUPITER article have financial ties to the sponsor. The principal investigator has a personal conflict of interest as a co-holder of the patent for the C-reactive protein test” that figured prominently in the rationale for statin therapy.

In addition, the monitoring board that made the decision to halt the trial early was chaired by an investigator who “has been and still is involved in many other industry-sponsored lipid-lowering trials,” Dr. de Lorgeril and colleagues said (Arch. Intern. Med. 2010;170:1,032-6).

“In conclusion, the results of the JUPITER trial are clinically inconsistent and therefore should not change medical practice or clinical guidelines.” Given that all 12 of the other large cholesterol-lowering trials conducted so far have failed to show any benefit from statins as primary prevention, it appears that “the presumed preventive effects of cholesterol-lowering drugs have been considerably exaggerated,” they said.

In an accompanying editorial, Dr. Lee A. Green, of the department of family medicine at the University of Michigan Medical School, Ann Arbor, pointed out that Dr. de Lorgeril’s analysis highlighted several anomalies in the JUPITER trial data. In particular, early termination of the study allowed for inflated estimates of benefits, understated harms, allowed the findings to be published earlier (and hence used to advantage in marketing), and reduced the cost of the trial – which all significantly benefited the industry sponsor and a financially invested research team (Arch. Intern. Med. 2010:170;1,007-8).

In the second study, Dr. Kausik K. Ray of the University of Cambridge (England) and his associates performed a meta-analysis of 11 randomized controlled trials that assessed the effects on all-cause mortality of statins versus a placebo or control therapies on all-cause mortality. They restricted their analysis to data on high-risk patients with no known cardiovascular disease and included previously unpublished data, “to provide the most robust information to date” on statins as primary prevention in this patient group.

The metaanalysis involved 65,229 men and women in predominantly Western populations, with approximately 244,000 person-years of follow-up. There were 2,793 deaths during an average of 4 years of follow-up.

All-cause mortality was not significantly different between patients taking statins and those taking placebo or control therapies. This suggests that “the all-cause mortality reduction of 20% reported in JUPITER is likely to be an extreme and exaggerated finding, as often occurs when trials are stopped early,” Dr. Ray and his colleagues said (Arch. Intern. Med. 2010;170;1,024-31).

This meta-analysis shows that statin therapy as primary prevention in high-risk patients is less beneficial than is generally perceived, and it can be inferred to be even less helpful in low-risk patients, they added.

One of Dr. de Lorgeril’s associates served as an expert in litigation involving the pharmaceutical industry (not involving rosuvastatin), as an unpaid consultant to the Federal Bureau of Investigation and the U.S. Department of Justice in investigations involving the pharmaceutical industry, and as a consultant to Wells Fargo Insurance Services. Dr. Ray and an associate reported financial ties to the majority of companies that market lipid-lowering agents; other associates reported ties to Pfizer Inc., Astra Zeneca, Bristol-Myers Squibb, and Merck & Co.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据6月28日出版的《内科学文献》中分开发表的报道，惟一一项发现患者将他汀类药物作为一级预防用药可降低死亡率的大型临床研究(他汀使用者占75%)被批评有重大缺陷，一组研究者称此研究结论为“与临床不一致”并视其无效，另一组研究者认为该研究“过分夸大”。

 

2008年的JUPITER(他汀类药物用于一级预防的合理性研究)试验声称，瑞舒伐他汀使无冠心病征象的低危患者的死亡率显著下降，这是获得此结果的惟一一项大型研究，法国格勒诺布尔第一大学、法国国家科学研究中心的Michel de Lorgeril博士及其同事在对其进行的首篇评论中分析了这一研究的研究方法和结果。这些结果不久就引发争论，“毋庸置疑，这些结果将许多未发生胆固醇水平升高的健康人推向了长期他汀类药物治疗中，”de Lorgeril博士及其同事说。

 

其首要缺陷为，根据该研究本身预先限定的方案，JUPITER被提前终止，很明显此举并无合理的依据。据研究者称，提前终止在很大程度上限于制药业申办的试验，往往会产生偏倚，夸大收益，使所评估的治疗的长期危害最小化。在这种情况下，还意味着该研究刚好在他汀治疗组与对照组的死亡率曲线开始重叠时被停止，若未提前终止随访，则“提示组间临界值的显著差异可能早已消失”，他们写道。

 

终止JUPITER研究的主要依据被解释为，采用他汀类药物治疗“使心血管死亡率无可厚非地减少”。但JUPITER研究者在其发表的报告中并未包括有关心血管死亡率的数据。读者将不得不通过对表中的数据进行推算才能推出此结果。但仔细检查时发现，数据显示两治疗组之间的心血管死亡率完全相同。

 

“缺少对心血管死亡率的影响及对非致死性并发症的巨大影响，这种情况明显表明研究数据存在偏倚，本应因此继续进行试验而非提前终止，”de Lorgeril博士及其同事声称。

 

其次，致死性与非致死性心肌梗死(MI)的比值低得“不可思议”。特别是安慰剂对照组的病死率仅为8%，而其预计值大约为50%， “与临床的不一致性体现了此研究的一个严重缺陷”。而且，瑞舒伐他汀治疗组的病死率为29%，暗示这种“有益的”药物实际上使病死率翻了3翻，他们指出。

 

第三，JUPITER研究未能解释死亡例数为何高得惊人——瑞舒伐他汀治疗组的31例死亡中有19例，安慰剂对照组的37例死亡中有25例归因于心血管病变而非MI或卒中。JUPITER研究的支持者在发表研究后反驳称，这是指“动脉瘤破裂”等病因。

 

de Lorgeril博士及其同事评论道：“这是意味着安慰剂对照组在同一时期发生了6例致死性梗死和25例致死性动脉瘤破裂吗？这极不可能。”

 

JUPITER还未能报告有关心脏猝死的数据，这是“在心脏病学中最简单且最可靠的诊断”，而总的心源性死亡中通常有65%~70%系此病所致，缺少这类数据真令人意外。他们指出：“报告或未报告心脏猝死可以作为一项试验中衡量方法质量的一个较好指标。”

 

与上述方法缺陷同等重要的是，JUPITER试验包括多个利益冲突。

 

“该试验赞助方存在明显商业利益目的。JUPITER论文的14个作者中有9个与赞助方存在经济关联。主要研究者本人的利益冲突声明为C反应蛋白试验专利的共同持有者”，而该试验在他汀类药物治疗的理论依据中得到了重点描述。

 

另外，de Lorgeril博士及其同事说，做出停止试验决策的监测委员会主席为“至今仍参与其他许多制药业赞助的降脂药试验”的研究者(Arch. Intern. Med. 2010;170:1,032-6)。

 

“总之，JUPITER试验的结果与临床不一致，因此不应改变医疗实践或临床指南。”假如其他12项大型的降胆固醇试验至今均未能证明他汀类药物用于一级预防有任何收益，那么“所认为的降胆固醇药有预防作用实为过分夸大事实”，他们说。

 

密歇根大学医学院安娜堡分校全科医学系的Lee A. Green博士在随刊编者按中指出，de Lorgeril博士的分析强调了JUPITER试验数据中存在的多个异常问题。尤其是，研究提前终止致使收益被高估而危害被低估，使结果得以提前发表(以用于推动上市)，同时减少了试验费用——所有这些均为制药业赞助方以及得到资助的研究小组带来极大收益(Arch. Intern. Med. 2010:170;1,007-8)。

 

在第2项研究中，英国剑桥大学的Kausik K. Ray博士及其同事对11项随机对照试验进行了荟萃分析，这些试验均评估了他汀类药物对全因死亡率的影响并与安慰剂或对照治疗药进行了比较。他们将分析数据限定为无已知心血管病变的高危患者的数据，并包括先前未发表的数据，“旨在提供迄今有关他汀类药物用于一级预防对这类患者影响的最具说服力的信息。”

 

荟萃分析包括65,229位男性和女性，以西方人为主，大约随访了244,000人-年。在平均4年随访期中，共发生2,793例死亡。

 

服用他汀类药物的患者与服用安慰剂或对照治疗药的患者之间在全因性死亡率方面无显著差异。Ray博士及其同事说，这表明“JUPITER研究报道的全因死亡率减少20%很可能是对结果的过分夸大，这也是提前终止试验时常有的事情。” (Arch. Intern. Med. 2010;170;1,024-31)。

 

这项荟萃分析显示，他汀类药物用于高危患者一级预防的收益程度低于大家普遍认为的水平，由此可见，该药对低危患者益处会更少，他们补充说。

 

de Lorgeril博士的合作者之一曾担任与制药业(不包括瑞舒伐他汀)有关的诉讼专家和联邦调查局及美国司法部制药业相关性调查的无薪顾问，以及富国银行保险服务公司的顾问。Ray博士及其合作者报告与大多数降脂药销售商有经济关系；其他合作者报告与辉瑞、阿斯利康、百时美施贵宝以及默克公司有联系。

 

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