Rosuvastatin treatment of patients with better than average lipid profiles but with elevated high-sensitivity C-reactive protein (hsCRP) resulted in a 44% relative risk reduction in cardiovascular events and a 20% reduction in all-cause mortality, reports Paul Ridker, MD (pictured), lead investigator for the JUPITER Trial Study Group. JUPITER was an investigator-initiated trial sponsored by AstraZeneca.

“While current guidelines for the prevention of heart attack, stroke, and cardiovascular death endorse statins in patients with established vascular disease, diabetes, and hyperlipidemia, the tension in the field is that these treatment strategies are insufficient because the mantra is that half of all heart attacks and strokes that do occur are among individuals who simply don’t have overt hyperlipidemia,” says Dr. Ridker, Brigham and Women’s Hospital and Braunwald Professor of Medicine at Harvard Medical School, Boston.

While many physicians try to improve identifying high-risk individuals by measuring hsCRP, a strategy of treating patients without established cardiovascular risk factors with statins remains controversial.

“Trial results are often overlooked, and implementation would have to occur in family practice, and that is, indeed, where these patients were recruited,” says Andrew M. Tonkin, MD, Monash University, Melbourne, Australia. “Ultimately, if we see hsCRP is something to base treatment on, who do you screen?” Dr. Tonkin also points out that JUPITER patients did have other risks in that they were overweight and had a median systolic blood pressure of 134 mmHg.

In a statement issued today, American Heart Association president Timothy Gardner, MD, said, “(JUPITER) was not designed to answer the question of whether the impact on risk was due to a reduction in inflammation or a reduction in LDL. Statins lower both LDL cholesterol and hsCRP. Thus the findings presented today cannot determine whether lowering cholesterol, reducing inflammation, or a combination of both is responsible for the effects seen in this paper.” In 2003, the AHA and the Centers for Disease Control and Prevention concluded that hsCRP, at physician discretion, may be useful to determine the preventive measures needed for people at intermediate risk.

Trial Results
JUPITER included 17,802 participants from 216 countries with a median LDL of 108 mg/dL and a median HDL of 40 mg/dL. “These are lipid levels that all of us would consider excellent, if not outstanding, in a prevention setting,” notes Dr. Ridker. The mean hsCRP was elevated at 4.3 mg/L. They were randomized to receive rosuvastatin 20 mg daily or placebo and were to be followed for 3 to 4 years for the primary endpoint: occurrence of a first major cardiovascular event (nonfatal MI, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death). However, the Independent Data and Safety Monitoring Board discontinued the trial after a mean follow-up of 2 years due to a significant primary endpoint benefit in the rosuvastatin group.

Primary endpoint events were significantly reduced among rosuvastatin patients (HR 0.56, p<0.00001). Rates of hospitalization and revascularization were reduced by 47% within a 2-year period, suggesting that the hsCRP screening and treatment strategy used in JUPITER is cost-effective, Dr. Ridker explains. He adds that a number-needed-to-treat analysis indicated that 25 patients without traditional cardiovascular risk factors but with elevated hsCRP would require rosuvastatin treatment over 5 years to prevent one death. “When used for 5 years, this treatment strategy could conservatively prevent 250,000 first events,” he says.

Dr. Tonkin, however, says, “The importance of intervention for individuals being treated and for public health policy depends on the absolute risk reduction, not the relative risk reduction.” According to Dr. Tonkin, for example, the 20% relative risk reduction seen with rosuvastatin treatment in individuals with elevated hsCRP alone translates to a 0.055% absolute risk reduction. “We would need to treat 190 people over the course of the study to prevent one death,” he says.

Women and Minorities
Unlike many previous statin trials, JUPITER recruited 6,801 women and 5,117 minority patients. There has been controversy regarding whether statins confer the same event prevention and mortality benefits in these groups as seen in men.

“The trial had 26 prespecified subgroups, and the key is that all of them reached statistical significance on their own. Women are receiving the same benefit from rosuvastatin as men, and the results are very reassuring for minority patients,” says Dr. Ridker. There was no significant difference between effect in women versus men, those age 65 and older compared with younger patients, smokers versus nonsmokers, Caucasians versus minorities, or between those with elevated hsCRP alone and those with other risk factors, Dr. Ridker reports.

Safety Results
“Adverse events are very controversial with this agent,” Dr. Ridker says. While recent reports of elevated signals for cancer with rosuvastatin use have been prominently in the news, JUPITER results show a statistically significant increase in cancer deaths for placebo patients (p=.02). There were 314 cases of cancer among placebo patients and 298 among those taking rosuvastatin, and 58 cancer deaths among placebo patients compared with 35 in the rosuvastatin group.

However, Dr. Tonkin questions the short, 2-year duration of the trial. “While we have an enormous amount of data for statins as a class, showing no increased cancer risk, to detect a signal for solid organ cancers, one needs at least 5 years, up to 20 years of exposure,” he says.

As for other adverse events, there was a nominally significant increase in hemoglobin A1_c among rosuvastatin patients at 24 months (5.9% versus 5.8%; p=.01). There was also a marginally significant increase in physician-reported, incident diabetes among patients in the rosuvastatin group (p=.02). There were no differences between active treatment and placebo patients in the occurrence of muscle weakness, myopathy, rhabdomyolysis, hemorrhagic stroke, fasting glucose levels, or glucosuria.