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The JUPITER trial

Introduction

Elevated high sensitivity C-reactive protein (hsCRP), a marker of inflammation, has been associated with an increased risk of cardiovascular disease (CVD).^1-3 HMG-CoA reductase inhibitors (or statins) have been shown to reduce hsCRP levels which may, in part, explain some of their nonlipid effects involved in reducing CVD risk. Current treatment guidelines recommend the use of statins as secondary prevention in patients with CVD and primary prevention for patients with elevated cholesterol and multiple risk factors.⁴ In addition, the Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) suggest using hsCRP testing to help determine whether to initiate therapy in patients with intermediate CVD risk.⁵ However, the use of statin therapy in low risk patients without hyperlipidemia but with elevated hsCRP levels has not been evaluated and was the objective of the trial discussed below.

JUPITER

Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER), a randomized, double-blind, placebo-controlled, multicenter study was designed to determine whether the rate of a first cardiovascular event could be reduced with rosuvastatin 20 mg in healthy patients with increased hsCRP (≥2 mg/L) and normal low-density lipoprotein (LDL) cholesterol levels (<130 mg/dL).^6-8 Men 50 years or older and women 60 years or older who did not have a history of CVD, met the hsCRP and LDL criteria and had triglyceride levels less than 500 mg/dL were included in the trial. Diabetes, uncontrolled hypertension, hypothyroidism, and chronic inflammatory conditions were among the conditions that led to exclusion. The primary outcome measure was the occurrence of a first major cardiovascular (CV) event, which included nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or death from CV causes. Components of the primary outcome were evaluated individually as secondary outcomes.

Over 17,000 patients were randomized to receive either rosuvastatin 20 mg or placebo with a planned duration of 5 years.^7,8 The trial, however, was terminated after the first interim analysis due to benefits of treatment and differences in death rates between groups. The median duration of follow up was 1.9 years. A review of the baseline characteristics demonstrates a relatively healthy population with respect to family CHD history, cholesterol, and glucose levels (see table 1 below). Patients on rosuvastatin achieved a median LDL of 55 mg/dL and median hsCRP of 2.2 mg/L at 12 months, which represented a 50% lower LDL and a 37% lower hsCRP compared to the placebo group. With the exception of hospitalization for unstable angina, the primary and other secondary outcome measures were significantly reduced with rosuvastatin treatment compared to placebo (see table 2 below). Although the relative risk reduction in the incidence of a major CV event was 43%, the absolute risk reduction was only 1.2%. Therefore, in order to prevent 1 major CV event, 95 patients would need to be treated for almost 2 years. Upon subgroup analysis, the benefits of rosuvastatin over placebo were evident in higher and lower risk groups such as those who were smokers or non smokers, those who were normal weight or overweight, those with Framingham risk scores of greater than or less than 10%, those with hypertension or normal blood pressure, those with or without metabolic syndrome and those with at least 1 risk factor or no risk factors.

Table 1. Select baseline characteristics of JUPITER participants.⁷

BMI= body mass index, calculated as weight (kg) divided by height (m 2); CHD=coronary heart disease; LDL=low-density lipoprotein; HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein; TG=triglycerides.

Table 2. Primary and secondary outcome results. 7

CV=cardiovascular; MI=myocardial infarction; CI=confidence interval.

Occurrences of muscle weakness, stiffness or pain, myopathy, hemorrhagic stroke, hepatic or renal dysfunction, and cancer were not significantly different between the 2 groups. Median hemoglobin A1C levels were 5.9% in the rosuvastatin group and 5.8% in the placebo group (p=0.001), and newly diagnosed diabetes occurred in 3% of patients receiving rosuvastatin compared to 2.4% of placebo recipients (p=0.01). According to the authors, the diagnosis was physician-reported and was not adjudicated by the steering committee. The authors concluded that rosuvastatin significantly reduced the rate of CV events in patients with high levels of hsCRP and no hyperlipidemia.

Editorial comments

Dr. Hlatky from the Stanford University School of Medicine in an editorial in the New England Journal of Medicine questions the clinical significance of a 0.9% absolute risk reduction in the incidence of hard cardiac events (MI, stroke, or CV deaths) with rosuvastatin treatment compared to placebo (1.8% vs. 0.9%).⁹ Furthermore, the statistically significant increase in the incidence of diabetes and higher glycated hemoglobin values in patients treated with rosuvastatin is of concern and requires further evaluation. The long-term safety of low LDL cholesterol levels such as those achieved in the JUPITER trial as well as the safety of treating patients with statin therapy for 20 years or more is unknown.

The role of hsCRP testing in clinical practice remains unclear since the trial did not compare patients with lower hsCRP levels to those with higher levels. Also, the use of hsCRP was not compared with other markers of cardiovascular risk. The trial did not provide a direct assessment of the clinical value of hsCRP testing.

According to the author, the JUPITER trial provides evidence of the benefit of statin therapy in patients who, under current treatment recommendations, would not be considered candidates for pharmacologic therapy. It can, potentially, expand the number of patients treated with statins. However, the benefits of using rosuvastatin therapy in a greater portion of the population needs to be weighed against the long-term safety and cost of such therapy.

Conclusion

The results of the JUPITER trial provide evidence of benefit of rosuvastatin therapy for patients with high levels of hsCRP without hyperlipidemia. It brings into question whether hsCRP testing should be included in the current assessment of CV risk. A 2002 CDC/AHA workshop on markers of inflammation and cardiovascular disease suggest hsCRP levels be used to help determine whether to initiate primary prevention therapy in patients with intermediate CV risk (Framingham risk 10% to 20%).⁵ Although, the JUPITER trial does not provide a direct assessment of the clinical value of hsCRP testing, its results should lead to further study of the role of hsCRP testing in routine clinical practice as well as how it fits into the traditional assessment of CV risk.

Safety concerns that should be considered and further studied include the incidence of new onset diabetes as well as the effects of very low LDL cholesterol levels. Early termination of the trial prohibits making any conclusions of the drug’s long-term safety profile. Although renal function was not found to be significantly affected with rosuvastatin therapy, there is still concern regarding the drug’s long-term effect on kidney function in relation to proteinuria and hematuria. These effects were not measured in this trial. Also, the manufacturer’s prescribing information reports a 2-fold increase in rosuvastatin plasma concentrations in Asian patients.¹⁰ The recommended starting dose is 5 mg in this population. Only 1.6% of the JUPITER participants were Asian.⁸ Therefore, the safety of using 20 mg of rosuvastatin in Asians needs to be further studied as well.

The results of the JUPITER trial may certainly affect the frequency of hsCRP testing in clinical practice as well as rosuvastatin prescribing patterns. However, since the exact clinical utility of hsCRP testing was not assessed in this trial, clinicians should continue to use hsCRP testing as it is currently recommended – in intermediate risk patients to help determine whether primary prevention with pharmacologic therapy is required until more evidence on hsCRP testing is available. The overall benefit of rosuvastatin in those with hsCRP levels >2 mg/L provided a small absolute reduction in risk. Furthermore, the cost-effectiveness of this approach considering the generic availability of other statins as well as the long-term safety profile of rosuvastatin needs further evaluation.

References

1. Athyros VG, Kakafika AI, Karagiannis, A, Mikhailidis DP. Do we need to consider inflammatory markers when we treat atherosclerotic disease? Atherosclerosis. 2008;200(1):1-12.
2. Balk EM, Lau J, Goudas LC, Jordan HS, Kupelnick B, Kim LU, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease. Ann Intern Med. 2003;139(8):670-682.
3. Ahi-Saleh B, Iskandar SB, Elgharib N, Cohen MV. C-reactive protein: the harbinger of cardiovascular diseases. South Med J. 2008;101(5):525-533.
4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497.
5. Smith SC, Anderson JL, Cannon RO, Fadl YY, Koenig W, Libby P, et al. CDC/AHA Workshop on markers of inflammation and cardiovascular disease: application to clinical and public health practice: report from the clinical practice discussion group. Circulation. 2004;110(25):e550-e553.
6. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108(19):2292-2297.
7. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelstein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.
8. Ridker PM, Fonseca FAH, Genest J, Gotto AM, Kastelstein JJP, Khurmi NS, et al. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol. 2007;100(11):1659-1664.
9. Hlatky MA. Expanding the orbit of primary prevention-moving beyond JUPITER. N Engl J Med. 2008;359(21):2280-2282.
10. Crestor [package insert]. Wilmington, DE: Astra-Zeneca; 2007.