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A Signal From JUPITER
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Source: Brendan M; et al. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein. Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circulation. 2010;121:143-150.
Statins are now well established as powerful and favorable lipid-modifying drugs. They are primarily used for individuals with coronary artery disease or an abnormal lipid panel, and result in major decreases in morbidity and mortality. As yet, the role of statins for cerebrovascular disease has not been well delineated in published primary prevention studies. However, in subjects with diabetes or cardiovascular disease, statin drugs have been found to be clearly effective by decreasing cardiovascular morbidity and mortality. Rosuvastatin, the most potent statin available, can result in striking decreases in LDL-C and modest increases in HDL-C.
Thus, the use of rosuvastatin in normal subjects, except for elevated hs-CRP (high sensitivity c-reactive protein), an inflammatory biomarker, was assessed in the JUPITER trial. Since statins are known to reduce CRP levels, independent of LDL-C, the investigators hypothesized that high-potency statin therapy would reduce stroke risk in patients with normal levels of cholesterol but elevated levels of hs-CRP. Furthermore, they hypothesized that the lowest risk of stroke would be observed among those subjects who achieved the lowest levels of LDL-C and hs-CRP after initiation of statin therapy.
JUPITER is a large study of 17,802 subjects evaluated at 1,315 sites in 26 countries. Participants were middle-aged males 3 50 and women 3 60 with no overt cardiovascular disease or diabetes, an LDL-C < 130 mg/dL, and an hs-CRP of 3 2.0 mg/L, who underwent yearly surveillance for up to five years. Subjects were randomized and given either 20 mg of rosuvastatin or placebo and followed for 1.9 to 5 years. 15,548 individuals were ultimately randomized to rosuvastatin or placebo. Stroke was a predetermined end point of the JUPITER findings, which included unequivocal signs of a focal or global neurologic deficit with sudden onset and lasting > 24 hours. Stroke types and deaths were carefully confirmed with imaging techniques. The first occurrence of a stroke, non-fatal MI, unstable angina, or cardiovascular death were tracked and reported. LDL-C levels were evaluated as 3 70 or < 70 mg/dL at one year.
Results: Both groups had comparable baseline characteristics. At termination of the study, 33 strokes had occurred in the rosuvastatin group vs. 64 strokes in the placebo cohort. The incidence rates of stroke were 0.18 rosuvastatin and 0.34 placebo per 100 person-years of follow up in both groups, respectively (HR for rosuvastatin = 0.52; p = 0.002). Most strokes were ischemic, with incidence rates of 0.12 and 0.25 per 100 person-years in the rosuvastatin and placebo groups, respectively (HR , 0.49, p = 0.004). A similar benefit of rosuvastatin was seen for 88 of 97 observed non-fatal strokes (HR, 0.52; 0.33 to 0.80; p = 0.003).
Hemorrhagic stroke rates were 0.03 and 0.05 per 100 person-years in the rosuvastatin and placebo groups, respectively. TIAs were similar in frequency in both groups. The number needed to treat to prevent one event was projected at 31 at five years. Because of these results, JUPITER was stopped early on march 30, 2008, on the basis of a recommendation by the independent data and safety monitoring board.
Rosuvastatin was associated with equivalent benefit regardless of ethnicity, gender, and those with and without traditional risk factors, including smokers, patients > 70 years, high blood pressure, prior stroke, and those considered low risk, including low LDL, normal HDL, as well as high baseline CRP (> 5.0). Rosuvastatin reduced LDL-C at 12 months by 50% and hs-CRP by 37% (no relation to LDC level).
At one-year follow up in 15,548 subjects, the greatest decrease in stroke risk was seen in rosuvastatin-treated individuals who had an LDL-C < 70 mg/d and hs-CRP goal of < 2 mg/L. The authors concluded that, in apparently healthy persons without hyperlipidemia but with elevated hs-CRP levels, rosuvastatin significantly reduced the incidence of major cardiovascular events.
This important report strongly supports treatment of healthy older subjects with high hs-CRP levels with a potent statin. Reduction in risk with rosuvastatin was seen in all types of individuals, including smokers, low Framingham score, women, and non-smokers with little risk. Subjects assigned to rosuvastatin experienced major lowering of LDL-C (47 mg/dL) and hs-CRP, with a stroke risk reduction of almost 50%, more than in any similar trial yet published. There was no apparent health risk with the 20 mg dose of rosuvastatin, but this could be of concern and will need close monitoring.
How can this be? Surely the data are consistent with the powerful conclusion that potent lipid therapy in presumed high-risk subjects with normal lipids and a high hs-CRP are in some danger of a cerebrovascular event, with risk blunted by the statin therapy used in the JUPITER trial. Although hs-CRP is considered to be a marker of inflammation, no discussion of JUPITER mechanism(s) of outcome is provided, particularly with regard to hs-CRP. There have been dozens of favorable reports regarding LDL cholesterol, most with positive clinical outcomes. Mechanisms of hs-CRP remain somewhat of a mystery; in this report, hs-CRP turns out to be an important component of the lipid atherosclerosis conundrum. Could similar results be found in those individuals with a high LDL-C and normal CRP? Unfortunately, we have not seen a large cohort of such individuals; one must presume that for now, the adverse effects of high CRP are linked to the potential benefit of lipid therapy by decreasing the "inflammatory" actions of C-reactive protein. These data touch on another unresolved issue, i.e., how high a dose of statins should be used? The nearly 50% reduction of LDL is intriguing, raising the issue of whether such an elevated statin dose is safe, which seems true. Are we ready to accept rosuvastatin to 20 mg or greater as an optimal dose? The safety aspects of lipid side effects are not given much attention in the JUPITER study.
JUPITER suggests that higher statin doses than we usually use clinically should be considered in lipid therapy, along with much more attention and research dealing with hs-CRP. Nevertheless, long-term follow up of lipid problems cannot be assumed completely safe with large doses and sustained therapy, and lipid levels should be routinely monitored.