Meta-analysis questions value of statins for primary prevention; JUPITER comes under attack

A new meta-analysis raises questions about the benefits of statins when given to people without a clinical history of heart disease. Kausik Ray and colleagues, in a paper in Archives of Internal Medicine, analyzed data from 65,229 subjects in 11 studies. There were 2793 deaths in the studies, 1447 among those taking placebo and 1346 among those taking a statin. The risk ratio of 0.91  did not achieve statistical significance (95% CI=0.83-1.101). They also observed that baseline LDL levels did not appear to have an impact on mortality.

The authors say their study is the first meta-analysis “based on data from only those individuals without clinically manifest CVD, including previously unpublished data, thus providing the most reliable effect estimates about the effect of statins in this population.” Ray et al acknowledge that a larger benefit might have been observed with more prolonged followup.

Their findings, write the authors, “further reinforce the notion that lowering lipid levels in a very high-risk primary prevention population is not likely to be harmful, but any mortality benefits are likely to be more modest than previously perceived. As a corollary, however, it may be inferred that in even more lower risk populations (such as subjects at low CVD risk prescribed statins for primary prevention of CVD), the benefits of mortality reduction are likely to be even more modest than observed in this meta-analysis, at least in the short term.”

JUPITER Under Attack

Ray and colleagues write that the 20% mortality reduction observed in JUPITER “is likely to be an extreme and exaggerated finding as often occurs when trials are stopped early.”  The same point, and many more, are hammered home forcefully in a second Archives paper by Michel de Lorgeril and colleagues. A third paper by Sanjay Kaul and colleagues is less brutal but also highly critical of JUPITER.

Among the key points of de Lorgeril et al:

  • The trial should never have been stopped early. The stopping point rule has not been adequately explained and the chairman of the independent safety-monitoring board “has been, and still is, involved in many other industry-sponsored lipid-lowering trials, raising issues of conflict of interest.” (For those without a program, Oxford’s Rory Collins was the chair of the JUPITER DSMB.)
  • There were only small differences in the “hard end points” of the primary end point.
  • All-cause mortality curves “were actually converging when the trial was ended.”
  • “The absence of cardiovascular mortality data in the published article is striking.” Sifting through the available data they conclude that the number of cardiovascular deaths was the same in both groups.
  • In the placebo group  of JUPITER the ratio of fatal MI to nonfatal MI– the case-fatality rate– is “incredibly low: 8.8%, a clinical inconsistency that suggests a major flaw in the study.”
  • There were no sudden cardiac deaths reported in the trial, though SCD “usually represents about 65% to 70% of total cardiac mortality.”
  • 9 of 14 JUPITER authors had financial ties to the sponsor and the PI was a co-holder of the patent for the CRP test.
  • The sponsor “controlled and managed the raw data.”

The authors conclude that “the results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.”

In the second paper on JUPITER, Sanjay Kaul, Ryan Morrissey, and George Diamond offer their own perspective on the trial, elaborating on a perspective Kaul provided to CardioBrief in April 2009.

  • Kaul et al argue that the trial does not provide any justification for routine measurement of hsCRP. They point out that the absence of a low-CRP population in the trial means that “JUPITER tells us nothing about hsCRP.”
  • They also agree that the magnitude of benefit observed in JUPITER was quite likely magnified because of the early termination of the trial. However, they don’t go as far as de Lorgeril and colleagues in that they acknowledge the beneficial effect is “real,” although they write: “do not expect 50% risk reductions in outcomes.”

In a lengthy story on heartwire, Paul Ridker offers a strong defense of the JUPITER trial. He receives an able assist from Steve Nissen, who calls the de Lorgeril article “troubling and frankly, offensive.” Nissen says that Ridker and DSMB chair Collins “are among the most respected physician scientists in all of medicine.”


  1. Karen moore says

    Hi Larry,
    A minor point to help me assess the validity of the analysis. It was not clear in the abstract whether the analysis was performed using patient-level or study-level data. Do you know? In a meta-analysis, analyzing data from 65,229 folks is preferable to an analysis using ‘collective’ data from each of 11 trials. Thanks, Karen

  2. Marilyn Mann says

    Of possible interest, here is a public radio debate between Steve Nissen and John Abramson. Abramson is one of the co-authors of the de Lorgeril paper.

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