NEW ORLEANS — Rosuvastatin reduced the risk of major cardiovascular events in healthy persons with elevated levels of high-sensitivity C-reactive protein but normal LDL cholesterol levels in a study of nearly 18,000 patients.
“In individuals not currently qualifying for statins, major cardiovascular events were reduced by 44% and mortality was reduced by 20%,” said Dr. Paul M. Ridker, reporting the results of JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) at the annual scientific sessions of the American Heart Association.
Dr. Ridker and his group previously demonstrated that increased levels of high-sensitivity C-reactive protein (hsCRP) are predictive for cardiovascular events. Because statins lower levels of hsCRP as well as serum cholesterol, the investigators hypothesized that individuals with elevated hsCRP but without hyperlipidemia might benefit from statin treatment.
The worldwide JUPITER study randomized 17,802 apparently healthy men aged at least 50 years and women aged at least 60 years with LDL cholesterol levels of less than 130 mg/dL and hsCRP levels of at least 2.0 mg/L to receive either 20 mg/day rosuvastatin or placebo. Although the study excluded patients with high LDL cholesterol levels, patients could have other risk factors for cardiovascular disease. Patients were followed for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
The trial was stopped early after a median follow-up of 1.9 years (maximum, 5 years) after the data and safety monitoring board determined that rosuvastatin had an “unequivocal benefit” on coronary-related death and disability.
Significant reductions were seen in all major end points. Rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively, producing a highly significant hazard ratio of 0.56 (P less than .00001). Rosuvastatin reduced LDL cholesterol levels by 50% and hsCRP levels by 37%. Half the treated patients achieved LDL cholesterol levels of less than 55 mg/dL, Dr. Ridker reported (N. Engl. J. Med. 2008;359:2195–207).
Risk was also significantly reduced by 54% for myocardial infarction; by 48% for stroke; by 47% for revascularization or unstable angina; by 47% for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes; and by 20% for death from any cause.
Consistent effects were observed in all subgroups. For subjects with elevated hsCRP and no other major risk factors other than increased age, the risk reduction was 37%, which was similar to that for higher-risk subjects, he added.
Adverse events were similar, with no increased rates of muscle weakness, myopathy, or cancer. Hemoglobin A1c levels, however, were slightly but significantly increased in the rosuvastatin group (5.9%), compared with placebo (5.8%), as was the rate of physician-reported diabetes (2.8% and 2.2%, respectively).
“These are extremely reassuring data for statins as a class,” Dr. Ridker maintained. In response to questions about a possible class effect with regard to prevention, he noted that all statins lower LDL cholesterol and hsCPR, “but the more potent the statin, the greater the benefit.” With rosuvastatin, he said, “we may have just hit the sweet spot by picking the right target and using the right drug.”
Over the course of the study, the number of patients needing to be treated to prevent one event was 95. Extrapolating to 5 years, the number needed to treat is just 25, Dr. Ridker reported.
“This compares very favorably to what is already accepted as cost effective for the treatment of hyperlipidemia in primary prevention,” he said. “The application of this approach over 5 years could prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in [the United States] alone.”
Professor Andrew Tonkin, head of the cardiovascular research unit at Monash University, Clayton, Victoria, Australia, emphasized the need to look at absolute benefit more than relative risk reduction, which he deemed more clinically important. “The absolute number of events was relatively low, which is why it is too early to say we should screen everyone, which would be a big undertaking.”
Nevertheless, he concluded, “The ultimate test is whether an intervention improves on outcomes, and JUPITER delivers in that regard. There was a very significant reduction in all events with rosuvastatin, the most potent of the LDL-lowering agents.”
Questions remain as to how rosuvastatin exerts its effects, and the extent to which CRP is important as a cardiovascular risk factor, he added. “We know that the effect of statins on these two variables is independent. We may be able to say that CRP is a risk marker, but we cannot say that it is a risk factor or a causal mediator.”
The findings may trigger a new look at the guidelines “to see where CRP sits in risk assessment,” he said. “We critically need to know the absolute risk reductions, including in subgroups, and based on this do cost-effective analyses” before recommending universal hsCRP testing.
The study was funded by Astra-Zeneca. Dr. Ridker has received research grant support and/or consulting fees from Astra-Zeneca and is a coinventor on patents relating to the use of inflammatory biomarkers in cardiovascular disease.
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