To JUPITER and beyond: Statins, inflammation, and primary prevention

The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The 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 (hazard ratio for rosuvastatin, 0.56; 95% confi dence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent eff ects were observed in all subgroups evaluated. The rosuvastatin group did not have a signifi cant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. Conclusions In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin signifi cantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)


Results
The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The 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 (hazard ratio for rosuvastatin, 0.56; 95% confi dence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent eff ects were observed in all subgroups evaluated. The rosuvastatin group did not have a signifi cant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.

Conclusions
In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin signifi cantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)

Commentary
It is well known that statins reduce the risk of myocardial infarction, stroke, and death from cardiovascular events in patients with established vascular disease and in those with risk factors, such as diabetes or hyperlipidemia. Yet, half of all myocardial infarctions and strokes occur among otherwise healthy men and women without known vascular disease or risk factors [1]. Infl ammation is thought to play a central role in the development and progression of vascular disease. In addition to their lipidlowering eff ects, statins have anti-infl ammatory properties, reducing levels of high-sensitivity C-reactive protein (hsCRP), an acute-phase protein found in the blood that rises in response to infl ammation. HsCRP level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score [2]. What is not known, however, is whether statins might also benefi t patients with evidence of infl ammation but without vascular disease or hyperlipidemia.
Th e Justifi cation for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed to look at the eff ects of rosuvastatin in healthy patients with elevated hsCRP levels but without hyperlipidemia [1]. It was conducted in 1315 sites in 26 countries and fi nancially supported by AstraZeneca, the makers of rosuvastatin. Between 2003 and 2006, over 17,000 subjects were enrolled with a mean follow-up time of 1.9 years. As expected, treatment with rosuvastatin reduced LDL and hsCRP levels signifi cantly. Rosuvastatin reduced the primary endpoint of a fi rst major cardiovascular event (absolute risk 1.6% vs. 2.8%, hazard ratio 0.56, p<0.00001) as well as all secondary endpoints with the exception of hospitalization for unstable angina. Th e number needed to treat to prevent the occurrence of one primary endpoint in 2 years was 95, dropping to 31 for 4 years, and 25 for 5 years of therapy. Results of the study were consistent across clinically important subgroups. Total adverse events did not diff er between groups. Muscle weakness, stiff ness, or pain was fairly common but did not diff er between groups (16.0% vs. 15.4%, rosuvastatin vs. placebo, p=0.34). Myopathy was uncommon (<0.1%) and only a single case of rhabdomyolysis occurred, this in a 90-year old subject with infl uenza, pneumonia, and trauma-induced myopathy. Interestingly, physician-reported diabetes was more frequent in the rosuvastatin group.
Th is was a very large, well-conducted study using clinically meaningful endpoints which may expand the use of statins for primary prevention to new patient populations. A few limitations deserve mention. At baseline characteristics, patients were not entirely free of risk prior to randomization. Patients were overweight (median body-mass index 28) and over 40% had features of the metabolic syndrome. Furthermore, 16% were current smokers and 11% had a family history of premature coronary heart disease. Even so, prevalence of these risk factors actually increases the generalizability of this study, given their frequency in Western societies. Th e study did not include people with low levels of hsCRP and therefore does not address the use of statins in patients without evidence of infl ammation. However, as the authors note their prior work showed extremely low event rates and no evidence that statin therapy lowered vascular risk among healthy subjects with neither hyperlipidemia nor elevated hsCRP levels [3].
Statins, like many preventative measures, must be taken for years before yielding a benefi t. If guidelines were expanded to address C-reactive protein, it is estimated that an additional 6 to 8 million adults in the United States would have a statin indication based on JUPITER inclusion criteria [4]. Th ough not without cost, statin therapy is this patient population would be costeff ective, with a cost per quality adjusted life-year (QALY) of $40,457, well below the traditional cutoff of $50,000 per QALY [4].
Other than general medical interest, one might ask why this study would appeal to the intensivist. Th e antiinfl ammatory and anti-thrombotic properties of statins have prompted speculation that they may be useful in the treatment or prevention of severe sepsis [5], a syndrome characterized by dysregulation of infl ammation, coagulation, and other acute phase responses. In murine models of sepsis, statins improve survival [6][7][8]. A variety of observational studies in humans have examined the role of statins in the prevention or treatment of infection and sepsis, as recently reviewed [9]. Most suggest a clinical benefi t for statins, yet others show no benefi t, and one shows possible harm. Based on these fi ndings, several randomized trials of statins in infection are either planned, underway, or recently completed [10][11][12][13][14][15][16][17][18][19][20][21]. Unfortunately, these are small studies that are underpowered to address mortality or other clinically meaningful endpoints, with their primary endpoints focus ing on infl ammatory cytokines and markers of endo thelial function. In addition to their potential before or during severe infection, one study highlights the poten tial for statins after infection. In subjects who survived an initial hospitalization for community-acquired pneumonia, circulating IL-6 concentrations at hospital discharge were higher among subjects who subsequently died of cardiovascular diseases [22], raising the possibility of statin use to mitigate the eff ects of ongoing subclinical infl ammation after hospitalization for infection.

Recommendation
Statins reduced risk of fi rst major cardiovascular event in healthy subjects with elevated hsCRP but without hyperlipidemia. Furthermore, their use appears to be cost-eff ective from a societal perspective. Even so, society may wish to focus on aggressive reduction of traditional risk factors (obesity, hypertension, diabetes) before broadly increasing statin use. Th ough the results of statin trials in infection and severe sepsis are anxiously anticipated, larger studies will be needed before statins are routinely recommend in the management of severe infections.