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NEW ORLEANS, Nov. 9 -- Intensive lipid-lowering with rosuvastatin (Crestor) for not even two full years significantly and dramatically reduced the rate of myocardial infarction, stroke, and cardiovascular death in "apparently healthy men and women," researchers reported here.

Participants who took 20 mg of rosuvastatin for 1.9 years reduced median LDL cholesterol to 55 mg/dL, down from a median of 108 mg/dL, said Paul M. Ridker, M.D., of Brigham and Women's Hospital in Boston and principal investigator of the JUPITER trial. The corresponding reduction in the rate of MI stroke, arterial revascularization, or cardiovascular death was 44% (P

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Dr. Ridker presented the findings at a late-breaking clinical trials session at the American Heart Association meeting here and the findings were published concurrently online in the New England Journal of Medicine.

Participants were recruited on the basis of an inflammatory marker, high-sensitivity C-reactive protein.

All participants had elevated highly sensitive CRP, defined as 2.0 mg/L or higher, and here, too, the results were impressive -- an average reduction of 37%.

Moreover, the results were quite different from those of trials that recruited on the basis of elevated LDL.

Those trials "generally reported a 20% reduction in vascular risk for each 1 mmol/L (38.7 mg/dL) absolute reduction in the LDL cholesterol level, an effect that would have predicted a proportional reduction in the number of events in our study of approximately 25%," the investigators wrote.

"However, the reduction in the hazard seen in our trial, in which enrollment was based on elevated high-sensitivity C-reactive protein levels rather than on elevated LDL cholesterol levels, was almost twice this magnitude and revealed a greater relative benefit than that found in most previous statin trials," they added.

The number needed to treat with rosuvastatin for two years to prevent the occurrence of one primary event was 95 and the number needed to treat for four years to prevent one primary event was 31.

If the risks were projected over five years, as is usually done in statin trials, the number needed to treat to prevent a primary endpoint drops to 25.

The trial randomized 17,802 men and women, mean age 66, with no history of atherosclerosis.

The population mirrored baby boomers in general, a little out-of-shape, with numbers nudging toward frank cardiovascular risk, but not meeting the current threshold for drug therapy.

The median blood pressure was 134/80 mm Hg, LDL 108 mg/dL, HDL 49 mg/dL, and triglycerides 118 mg/dL. Body mass index was 28.3, and 41% met criteria for metabolic syndrome.

Among the findings:

• A 54% relative reduction in MI (HR 0.46, 95% CI 0.30 to 0.70, PA 48% relative reduction in fatal and nonfatal stroke (HR 0.52, 95% CI 0.34 to 0.79 PA 47% relative reduction in need for arterial revascularization (HR 0.53, 95% CI 0.40 to 0.70 P

  
  Although the drug was well tolerated, there was one finding of concern -- an increase in physician-reported new onset diabetes. There were 270 cases in the rosuvastatin group versus 216 in placebo (P=0.01).

  
  That finding was "not adjudicated by the endpoint committee" and the increase occurred despite no significant difference in the fasting blood glucose levels or newly diagnosed glycosuria and a small, but significant, improvement in the 12-month median glomerular filtration rate in the rosuvastatin group.

  
  But there was significant difference in median glycosylated hemoglobin value that favored placebo -- 5.9% versus 5.8% (P=0.001).

  
  Primary prevention trials are often where promising cardiovascular treatments go to die. A trial that produces a significant reduction in hard events is usually termed a home run -- but JUPITER appears to be a grand slam. The response from the cardiology community seemed to confirm this first-blush reaction.

  
  The JUPITER findings raise two important questions, wrote Mark Hlatky, M.D., of Stanford, in an NEJM editorial that accompanied the JUPITER findings. The two questions were whether indications for statin use be expanded and how measurement of high-sensitivity CRP should be used in clinical practice.

  
  Currently, high-sensitivity CRP is considered an add-on test to be used to refine risk in patients with low to intermediate risk, but CRP is not used to make treatment decisions.

  
  Dr. Hlatky concluded that the answer to both questions was maybe, but more study was needed.

  
  Elizabeth G. Nable, M.D., director of the National Heart, Lung, and Blood Institute, said the institute planned to analyze the JUPITER findings along with results from two NIH-funded studies, both of which were also published online today and will be presented later this week at AHA.

  
  Using data from the 3,006 participants in NHLBI's Framingham Heart Offspring Study, Peter W.F. Wilson, M.D., of Emory University in Atlanta, and colleagues from NHLBI, Boston University, and Tufts USDA Nutrition Center found that using highly sensitive CRP levels to assess risk provided a more accurate risk assessment over traditional scores among patients otherwise considered at intermediate risk.

  
  Dr. Wilson and colleagues said their findings supported a two-stepped approach to assessing risk -- using traditional risk scores first, then adding highly sensitive CRP levels to those found to be at intermediate risk -- to guide clinical decisions. These results were published online in Circulation Cardiovascular Quality and Outcomes.

  
  The second NHLBI-funded CRP study -- also by Dr. Ridker -- used data from 10,724 men in the Physicians Health Study-II to prospectively develop the Reynolds Risk Score for Men, which added highly sensitive CRP levels and parental history of early heart disease to traditional risk factors to assess men's risk.

  
  The new assessment tool was significantly more accurate than traditional risk factors alone, Dr. Ridker and colleagues reported online in Circulation and scheduled for presentation here on Tuesday.

  
  As a result of all three findings, Dr. Nabel said the NHLBI has "engaged an expert panel to review and update the scientific evidence regarding the assessment and management of cardiovascular risk factors. Today's findings will be part of the rigorous scientific review to distill the scientific evidence and generate an evidence-based, comprehensive set of clinical guidelines for primary-care practitioners to help adult patients reduce their risk for cardiovascular disease."

  
  Elliot Antman, M.D., of Harvard University, said in an interview that the NHLBI review has already begun. He said he could not predict how quickly guidelines would be updated to reflect the findings of JUPITER and the other two trials, but said it would be reasonable to expect an update in less than a year.

  
  AHA president Timothy Gardner, M.D., director of the Center for Heart and Vascular Health of Christiana Care Health Services in Wilmington, Del., said that although the study "demonstrated a significant reduction in heart attacks and strokes" the study was "not designed to answer the questions of whether the impact on risk was due to a reduction in inflammation (marked by hs-CRP) or a reduction in LDL."

  
  Steven Nissen, M.D., director of Cardiovascular Medicine at the Cleveland Clinic, was less conservative in his assessment. In an interview he said the JUPITER findings were "unprecedented and landscape-changing."

  
  Moreover, he said the findings should silence those who have suggested that lower cholesterol does not translate into a reduction in hard endpoints -- and "lay to rest the talk about statins not benefiting women," Dr. Nissen said.

  
  In his own practice, he said, he will now have highly sensitive CRP measured in patients "even when the LDL numbers look all right," he said.

  
  Asked if the finding suggested a class effect, Dr. Nissen said he was unwilling to speculate but preferred to limit his comments to drug studied.

  
  Dr. Nissen was not involved in the study, but he is conducting a large intravascular ultrasound (IVUS) study that measures the effect of rosuvastatin versus atorvastatin (Lipitor) on atherosclerosis.

  JUPITER was funded by AstraZeneca, which markets rosuvastatin. Dr. Ridker is the co-inventor of the highly sensitive CRP test and along with Brigham and Women's Hospital he holds the patent on the test. Dr. Ridker also reported financial support from AstraZeneca, Novartis, Merck, Abbott, Roche, sanofi-aventis, Merck-Schering-Plough, Isis, Dade Behring, and Vascular Biogenics. Dr. Nissen reported that the Cleveland Clinic Coordinating Center for Clinical Research has received research support to perform clinical trials from Pfizer, AstraZeneca, Sankyo, Takeda, sanofi-aventis, Lilly, Roche, Daiichi-Sankyo, and Novartis. Dr. Nissen consults for many pharmaceutical companies, but says he requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Dr. Antman had no relevant disclosures. Dr. Gardner had no relevant disclosures.

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