TheJUPITER trial (Justification for theUse of Statins in PrimaryPrevention: AnInterventionTrialEvaluatingRosuvastatin trial) was aclinical trial aimed at evaluating whetherstatins reduceheart attacks and strokes in people with normalcholesterol levels.
JUPITER was arandomizeddouble-blindplacebo-controlled study investigating the use ofrosuvastatin in theprimary prevention ofcardiovascular disease. The trial focused on patients with normallow-density lipoprotein (LDL)cholesterol levels but increased levels ofhigh-sensitivity C-reactive protein (hs-CRP). JUPITER was the firstclinical trial to indicate that statin therapy may provide benefit to patients with low-to-normal LDL levels and no known cardiovascular disease.[1][2] The trial, which began in 2003, was directed byPaul Ridker ofBrigham and Women's Hospital.[3]
Because half of all vascular events occur in patients with normal or low levels of LDL cholesterol, JUPITER was designed to determine whether hs-CRP testing could identify these patients, and whether statin therapy could prevent cardiovascular events among them.[4] Elevated hs-CRP levels are thought to be abiomarker of inflammation, and have beenassociated with an increased risk ofmyocardial infarction,stroke,peripheral arterial disease, andsudden cardiac death.[4]
The trial analyzed 17,802 patients without evidence of heart disease but with high CRP levels. In 2008, results presented at theAmerican Heart Association meeting and published in theNew England Journal of Medicine(NEJM) found that patients with low-to-normal LDL cholesterol receiving rosuvastatin had a lower rate of major cardiovascular events. Compared to patients taking aplacebo, patients given rosuvastatin had reductions in LDL and CRP levels, and a reduction of 0.2% to 0.6% in theirabsolute risk ofheart attack,stroke, and death at one year.[5][6][7] The study's authors estimated that thenumber needed to treat with rosuvastatin to prevent one cardiovascular event was 95 over two years, extrapolated to 25 over five years. The trial was stopped early, after just 1.9 years median duration, by the study's Independent Data Monitoring Board, because the interim results met the study's predefined stopping criteria (it had been predetermined that it would be unethical to continue the study once it became clear that the patients in one arm of the study had a significantly higher cardiovascular risk than the other arm's patients).[1][8]
The trial was sponsored byAstraZeneca, the marketer of Crestor (rosuvastatin).[3] The company saw an increase in its share of the U.S. statin drug market following the November 2008NEJM publication.[9]
Reports of serious adverse events within JUPITER were equally distributed between the study's rosuvastatin and placebo arms. There were no significant differences between the treatment groups with respect to muscle pain, muscle weakness, hepatic function, or renal function; however, the researchers noted small butstatistically significant increases in the rate of physician-reporteddiabetes andglycated hemoglobin values in the rosuvastatin group, an effect that has also been seen in studies with other statins.[5][8] Those latter findings, along with concerns over the safety of very low LDL levels, rosuvastatin's higher cost compared togeneric statins, and the validity of biomarkers used in the diagnosis of cardiovascular disease, have been cited by those urging caution before expanding indications for statin treatment.[10][11][12][13]
In 2010, Dr. Michel de Lorgeril, et al., published "a critical reappraisal" of the JUPITER Trial in theArchives of Internal Medicine. The article's authors critiqued what they saw as flaws in the trial, pointing out that the cardiovascular mortality rate and the case-fatality rate for myocardial infarction were much lower than they expected. They also raised concerns about conflict of interest in the trial design and leadership: nine of 14 authors of the main report had financial ties to the sponsor,AstraZeneca, and the lead investigator held the patent for the C-reactive protein test, whose use in screening would be promoted by the results as reported.[14] They also argued that the trial's premature termination may have distorted the results, and raised concerns that AstraZeneca scientists had controlled and managed the raw data. They concluded 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."[14]
In addition, some prior and some subsequent studies have contrasted with the JUPITER trial results. On the role of C-reactive protein, a 2009 study employingMendelian randomization, published in theJournal of the American Medical Association suggested that CRP does not play a causal role in cardiovascular disease; the results may argue against CRP's use as a marker of cardiovascular disease risk or for identifying subjects for statin therapy as in JUPITER, and more strongly argue against using CRP as a therapeutic targetper se.[15] The discordant results of this subsequent study provoked debate over the role and value of CRP as a biomarker and possible therapeutic target in heart disease.[16]
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