Nearly two years ago, a study known as the JUPITER trial hinted at a new era in the use of statins -- one in which the cholesterol-busting drugs could be used to stave off heart-related death in many more people than just those with high cholesterol.
Now, however, researchers behind a new review that takes a second look at the findings of the landmark study say that these results are flawed -- and that they do not support the benefits initially reported.
Not only did this second look turn up no evidence of the "striking decrease in coronary heart disease complications" reported by investigators behind JUPITER (Justification for the Use of Statins in Primary Prevention), but it has also called into question drug companies' involvement in such trials, according to an article in the June 28 issue of Archives of Internal Medicine.
Moreover, Dr. Michel de Lorgeril of Joseph Fourier University and the National Center of Scientific Research in Grenoble, France, and coauthors argue that major discrepancies exists between the significant reductions in nonfatal stroke and heart attacks reported in the JUPITER trial and what has been found in other research.
"The JUPITER data set appears biased," Lorgeril and coauthors wrote in conclusion.
Dr. Paul Ridker of Harvard Medical School and Brigham and Women's Hospital in Boston dismissed de Lorgeril's criticisms. Ridker reported the JUPITER results at the American Heart Association meeting in 2008.
In an email to MedPage Today, Ridker said that JUPITER data "overwhelmingly stand for themselves. Among a group of individuals with low levels of cholesterol, we clearly demonstrate that those with elevated levels of [the inflammation marker] hsCRP are in fact a high-risk population, and that using statin therapy in this group cuts event rates for [heart attack] and stroke in half."
Ridker also pointed out that the "FDA has extensively reviewed these data, found the trial to be well conducted, and recently provided a new indication for the use of statins in primary prevention on the basis of the JUPITER data."
AstraZeneca, maker of the popular statin Crestor (known generically as rosuvastatin), also defended the JUPITER results and the way in which the study was conducted.
Donna Huang, an AstraZeneca spokesperson, told MedPage Today in an email that the study "was undertaken with a fully independent steering committee, data and safety monitoring board, and academic study statistician."
She also said Ridker and his co-investigators controlled all data. "AstraZeneca played no role in conducting data analyses and had no access to unblinded trial data," she wrote.
De Lorgeril and coauthors point out that nine of 14 authors of the JUPITER article have financial relationships with AstraZeneca, which sponsored the trial. Ridker has a patent interest in the assay for C-reactive protein (CRP), an inflammation biomarker evaluated in all JUPITER trial participants.
"The sponsor's pervasive role is clearly described in the second paragraph of the 'Methods' section of the report: 'the sponsor collected the trial data and monitored the study sites,'" the authors wrote.
De Lorgeril and coauthors concluded that "the results of the JUPITER trial are clinically inconsistent and therefore should not change medical practice or clinical guidelines. The results of the JUPITER trial support concerns that commercially sponsored clinical trials are at risk of poor quality and bias."
Adding to the controversy, authors of another article in the same issue of Archives reported that a review of 11 large primary-prevention trials showed no effect of statin therapy on deaths in high-risk patients.
The JUPITER trial has stood alone in its finding of a significant benefit in patients with no evidence of coronary heart disease. The trial examined the effect of rosuvastatin in patients with normal or low cholesterol levels but elevated levels of CRP.
Investigators randomized 17,802 apparently healthy men and women to receive either the statin rosuvastatin or a placebo, and then they studied these groups to compare how many suffered heart attacks, strokes and other heart-related problems. The trial ended early when an interim analysis showed a 44 percent reduction in these events in the group taking the statins; with results this positive, the logic went, why continue the study?
But de Lorgeril and his coauthors cited the early termination as one of several methodologic problems with JUPITER. Although prespecified early stopping points are a well-accepted feature of clinical trials, the rules for stopping should be clearly described. That was not the case in the published description of the JUPITER protocol.
"Indeed, we still do not know which endpoint was used to define [the rules for stopping], or which level of benefits ... was required to justify early termination," de Lorgeril and coauthors wrote.
The authors also expressed concern that the trial ended early despite the fact that the data were not consistent with a large difference between the actual drug and the placebo.
On the basis of their review, de Lorgeril and coauthors concluded that "the time has come for a critical reappraisal of cholesterol-lowering and statin treatments for the prevention of CHD complications. The emphasis on pharmaceuticals for the prevention of CHD diverts individual and public health attention away from the proven efficacy of adopting a healthy lifestyle, including regular physical activity, not smoking, and a Mediterranean-style diet."
The meta-analysis reported in the same issue of the journal, led by Dr. Kausik Ray of the University of Cambridge in England, examined the findings of 11 randomized clinical trials involving a total of 65,229 patients to see if statins cut death rates among intermediate and high-risk people with no history of cardiovascular disease. In this study, too, the support for statin use was lacking.
In an editorial that accompanied the two articles, Dr. Lee Green of the University of Michigan in Ann Arbor said the de Lorgeril and Kay studies add fuel to a high-stakes debate.
"In the long term, although sincere advocates on both sides will try to convince us otherwise we really must admit that we do not know," Green wrote. "We need good research to find out, and, as de Lorgeril and colleagues point out, that search must be free of incentives to find any particular desired answer."