WHY THE JUPITER TRIAL?
Several biomarkers have been independently associated with the future risk of myocardial infarction and stroke. These include markers of inflammation, hemostasis and thrombosis, adipocyte function, and lipids. In terms of having prospective studies, a standardized assay, as well as additive value to lipid screening and the Framingham risk score, high-sensitivity C-reactive protein (hsCRP) is an interesting candidate for clinical use. To see the presentation on this subtopic click here.
The Physician's Health Study was the first large-scale prospective study to show that the relative risk of first myocardial infarction or stroke was directly related to hsCRP levels (1). A large-scale prospective study in postmenopausal women did a direct comparison of several markers of inflammation and found that hsCRP was the single highest predictor of cardiovascular events among the 12 markers studied (2). Another important observation was that prediction models incorporating both inflammatory markers and lipids were better at predicting risk than models based on lipid levels alone (2).
In a direct comparison of the predictive value of low-density-lipoprotein cholesterol (LDL-C) against hsCRP in predicting first ever cardiovascular events among 27,939 initially healthy American women, the relative predictive value of CRP was significantly stronger than LDL-C for total cardiovascular events, coronary events, ischemic stroke events and cardiovascular deaths (3). Combined LDL-C and hsCRP measurements have shown that individuals with low CRP and low LDL-C have the highest probability of CV event-free survival (3). CRP was also shown to add prognostic information at all levels of LDL-C and all levels of the Framingham Risk score (3), and to predict future vascular events in patients with the metabolic syndrome (4). It was also shown that very low or very high levels of CRP provide important prognostic information on cardiovascular risk (5).
CRP is now understood to also play a direct role in atherosclerosis (6, 7) and thrombosis (8). It was shown for the first time in 1998 that the statins, potent LDL-lowering drugs, are able to lower CRP levels and modulate the effect of CRP on the risk of coronary events (9).
Analysis of the AFCAPS/TexCAPS Study showed that not only individuals with high LDL cholesterol but also those with low LDL-C and high CRP may benefit from statin therapy in the primary prevention of coronary events (10). This hypothesis was tested in a trial called JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin).To see the presentation on this subtopic click here.
In 2005 results from two trials were published suggesting it is useful to test for hsCRP after starting statin therapy. Patients with acute coronary syndromes from the PROVE IT-TIMI 22 trial were tested for cholesterol and hsCRP thirty days after starting statin therapy, and a risk reduction for recurrent myocardial infarction or coronary death was observed that was attributable to CRP-lowering at all levels of achieved LDL-cholesterol, suggesting that both CRP and cholesterol should be monitored in patients on statin therapy (11). The second study, the REVERSAL trial, used intravascular ultrasound measurements to investigate the progression of atherosclerosis in patients with stable coronary artery disease, and found a reduction in the rate of atherosclerosis progression in patients achieving greater LDL- and CRP-lowering with statin therapy (12). To see the presentation on this subtopic click here.
ABOUT THE JUPITER TRIAL
The primary objective of the JUPITER trial was to determine whether long-term treatment with rosuvastatin (20 mg orally per day) will reduce the rate of first major cardiovascular events (a combined end point of cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, or arterial revascularization) among individuals with LDL-C levels <130 mg/dL (3.36 mmol/L) who are at high vascular risk due to inflammation as indicated by hsCRP levels >=2 mg/L. Secondary objectives of JUPITER were to evaluate the safety of long-term treatment with rosuvastatin in terms of total mortality, noncardiovascular mortality, and adverse events and to determine whether rosuvastatin reduces the incidence of type 2 diabetes; over 15, 000 participants were studied (6). To see the presentation on this subtopic click here.
The JUPITER trial was stopped early due to evidence of a reduction in cardiovascular morbidity and mortality in patients treated with rosuvastatin compared to placebo.
WHAT CAN BE LEARNT FROM THE JUPITER TRIAL
The JUPITER trial was designed to answer the question "Will statin therapy prevent first-ever cardiovascular events among those with LDL-C <130 mg/dL, but who are nonetheless at increased vascular risk because of elevated levels of hsCRP? This issue is of exceptional clinical importance, as half of all vascular events occur among those with normal or even low levels of LDL-C. Within the United States alone, as many as 25 to 30 million adults fall into this potentially high-risk category (6)." To see the presentation on this subtopic click here.
A strong positive finding from JUPITER has the potential to impact public health and prevention of cardiovascular disease, providing a rationale for broader use of statin therapy for primary prevention than currently recommended. By using rosuvastatin, the most potent of the statin drugs, JUPITER will also address whether aggressive LDL-C reduction has efficacy in primary prevention among those with relatively low LDL-C levels. "However, because JUPITER is evaluating an agent that dramatically lowers LDL-C as well as hsCRP, the JUPITER trial will not directly answer whether CRP reduction alone leads to reduced vascular risk. This hypothesis will require testing of agents with targeted vascular anti-inflammatory effects that lack proven beneficial effects such as LDL-C reduction. (6)."
Further information on the JUPITER trial can be obtained at www. JUPITERstudy.com or by calling 1-(888)-660-8254.
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The findings from the JUPITER trial released at the American Heart Association Scientific Sessions 2008 can be seen in a multimedia presentation by clicking on the button below.
