Out of this World? – The JUPITER Trial

The American Heart Association (AHA) 2008 Scientific Conference held host to the long awaited results from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER).  This land-mark study could potentially alter our current primary prevention in the general population, but requires critical analysis. The study was designed to investigate whether statin therapy should be prescribed to apparently “healthy” patients with normal low-density lipoproteins (LDL) cholesterol but elevated CRP levels.

This randomised, double-blind, placebo-controlled, multi-centred trial included 17,802 men (aged over 50-years) and women (aged over 60-years) assigned to Rosuvastatin 20mg or a placebo group. The study population were selected on LDL levels less than 3.4mmol/L, currently below the recommended threshold for medical intervention. A CRP measurement of greater or equal to 2.0mg/L was used to identify higher-risk patients.

Rosuvastatin 20mg significantly reduced the all primary end points (55% non-fatal myocardial infarction, 47% non-fatal stroke and 47% all cause cardiovascular deaths) by 44% compared with placebo.  Amongst the patients treated with rosuvastatin, the median LDL levels reduced from 2.8mmol/L to 1.4mmol/L, with a 17% reduction in triglyceride levels at 12 months.  CRP levels also reduced significantly, from 4.2mg/L to 2.2mg/L at 12 months. Sub-group analysis based on age, sex, race and ethnicity showed similar benefits with rosuvastatin versus placebo.
Analysis of the absolute risk reduction (including myocardial infarction, stroke, re-vascularisation, hospitalisation for unstable angina and cardiovascular death) reported a significant 1.2% reduction in the rosuvastatin group compared to the placebo group.

The side-effects recorded in the Rosuvastatin arm included, development of diabetes mellitus and elevated HbAlc levels (3.0% versus 2.4% P=0.01).  The rosuvastatin group did not demonstrate a significant increase in myopathy, elevated liver function tests or cancer, compared to the placebo group.

THE DEBATE

But the big question remains as to the impact on clinical practice if the current guidelines are revised. Should the guidelines be expanded to offer statin treatment to previously felt “low risk” patients? And in what context should the CRP level be used?

Issues regarding the benefits of treatment versus the long-term safety and cost effectiveness have still to be addressed. There is no data on the long-term safety of LDL levels less than 1.4mmol/l as seen in the JUPITER trial. 

These low-risk patients to whom we would now be prescribing stains could potentially continue on over 20-years of therapy.  Rosuvastatin is one of the more expensive statins.   Currently the UK cost of using rosuvastatin to prevent one event based on the NNT of 95 would be approximately £73,000 over two years . This estimated cost does not include the use of CRP testing.

Lower CRP levels is not a new theory and two previous trials (PROVE-IT and REVERSAL ) identified lower cardiovascular events in the low CRP level group independent of LDL levels.

Despite a study design for 4-years, JUPITER was stopped early after 1.9-years, by an independent data monitoring board due to the significant reduction in the primary end-point in the rosuvastatin group. Short follow-up and lack of data on patients with low CRP levels (less than 2mg/L) are the main study limitations identified. No comparison made between those with and without CRP measurements, providing limited clinical use of CRP levels. Many have voiced concerns with the measurement of CRP levels, with a laboratory test which can be highly variable and elevated in infections and acute injuries .  It would seem reasonable that the CRP level must still be taken in the clinical context of asymptomatic individuals who have evidence of clinical risk factors, rather than a screening tool for the general population. Observers have commented that CRP levels could be used to add decisions regarding therapy in those patients with “borderline” hypertensive or “a little overweight” .
 
Needless to say the JUPITER trial has provided new data in the use of statins in primary prevention in those patients previously deemed to be “healthy” and not considered for statin therapy. Similarly the study has created much debate amongst Physicians and introduced the need to re-assess the current guidelines.