JUPITER puts primary prevention into new orbit

Current guidelines recommend statin treatment for patients with known vascular disease, diabetes or elevated lipid levels. Yet half of myocardial infarctions and strokes occur in apparently healthy individuals with levels of low density lipoprotein (LDL) cholesterol that are below current threshold levels for treatment. High sensitivity C-reactive protein (CRP) is an inflammatory biomarker which can predict future vascular events and improves risk classification independently of LDL cholesterol level. Statin therapy has been shown to decrease CRP levels. However a question remains to be answered: Would healthy individuals with levels of LDL cholesterol below current treatment levels but with elevated levels of high sensitivity CRP benefit from statin therapy?

The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) Trial sought to answer this and was a randomised, double-blind, placebo controlled, multicentre trial conducted at 1315 sites in 26 countries. 17,802 apparently healthy individuals with LDL levels <3.4mmol/l and high sensitivity CRP levels of 2.0 mg/l or higher were randomly assigned to either rosuvastatin 20mg or placebo. The primary outcome was the occurrence of a first major cardiovascular event defined as non-fatal MI, non-fatal stroke, hospitalisation for unstable angina, an arterial revascularisation procedure, or confirmed death from cardiovascular causes.

Follow-up was planned for 4 years but this was terminated early, at 1.9 years when the data and safety monitoring board noticed a significant reduction in the primary end-point among individuals assigned to receive rosuvastatin (142 primary events vs. 251 in the placebo arm, hazard ratio 0.56, 95%CI 0.46-0.69). A similar reduction was also observed in the so called ‘hard outcomes’ of myocardial infarction, stroke or death from cardiovascular causes (83 events in the rosuvastatin group vs. 157 in the placebo group, hazard ratio 0.53, 95%CI 0.40-0.69). The rosuvastatin group did not have a higher incidence of myopathy or cancer but a higher incidence of physician reported diabetes was noted (3.0% vs 2.4%, p = 0.01).

Current guidelines state that CRP measurement can be used in primary prevention – where a patient is at intermediate risk, it can be used to decide whether to instigate treatment or not.  Although these guidelines may well change in light of the JUPITER trial, it should be noted that there was no control population without a CRP measurement in the trial design – perhaps they too would have shown a large benefit from rosuvastatin.  Furthermore, it is unusual for CRP to be elevated in the absence of traditional cardiovascular risk factors, and the results of the trial may only apply to a small subgroup of patients.    Nonetheless, for challenging our current risk-assessment paradigms, JUPITER is already being seen as a landmark trial in cardiology.

  • Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. N Engl J Med. 2008 Nov 20;359(21):2195-207. Epub 2008 Nov 9.