NPC Archive Item: Higher dose rosuvastatin in lower risk patients – the JUPITER study

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In the JUPITER study, rosuvastatin 20mg daily reduced the risk of major CV events compared with placebo in people with few elevated CV risk factors apart from a raised C-Reactive Protein. There was an increased risk of physician-reported diabetes, but no difference in risk of myopathy. The MHRA have previously advised caution in initiating this dose of rosuvastatin.

We should continue to follow the NICE lipid guidance to use simvastatin 40mg/day for most people who need a statin as this still represents rational, evidence-based practice. However, the Jupiter study does provide some reassurance about using rosuvastatin where no other statin is suitable.

What is the background to this?
Until the JUPITER trial, no published randomised controlled trials (RCTs) of rosuvastatin had shown a benefit in terms of people living longer or better. Indeed, rosuvastatin had been shown to be ineffective in two trials of people with heart failure (GISSI-HF and CORONA), despite most of the participants having ischaemic heart disease.

JUPITER was a large RCT in 17,802 men and women who, looking at conventional risk factors, would probably not have been considered at high risk of cardiovascular (CV) events. Almost certainly they would not have been estimated to have had a 10 year risk of CVD greater than 20% using the Framingham-based risk estimation tools recommended in recent NICE guidance (see trial details, below). However, they all had elevated high sensitivity C-reactive protein (hs-CRP) levels – the median level was 4.3mg/L, which, according to the American Heart Association, indicates a high risk of CV disease. Patients were randomised to rosuvastatin 20mg daily or placebo.

What were the results of this study?
Rosuvastatin 20mg daily for a median of 1.9 years reduced the hazard ratio (HR) of the primary composite endpoint (non-fatal MI, non-fatal stroke, hospitalisation for unstable angina, arterial revascularisation or death from CV causes) by 44% (HR 0.56, 95% CI 0.46 to 0.69, P<0.00001), number needed to treat (NNT) =82. The HR of the secondary endpoint of MI, stroke or death from CV causes was reduced by 47% (HR 0.53, 95%CI 0.40 to 0.69, P<0.00001), NNT=120. All-cause mortality was also reduced by 20% (HR 0.80, 95%CI 0.67 to 0.97, P=0.02), NNT=182.

There were no significant differences between the groups with regard to muscle, hepatic or renal adverse effects or newly diagnosed cancer, but there was a 25% relative increase in the risk of physician-diagnosed diabetes in the rosuvastatin group: number needed to harm (NNH)=165, P=0.01.

The hazard ratios look impressive at first sight. However, the absolute benefits and harms are that for every 1000 people who took rosuvastatin 20mg daily for 2 years, 8 people avoided having an MI or a stroke or dying from CV causes, but 6 people developed diabetes who would not have done otherwise.

So what?
JUPITER, as the first study to show that rosuvastatin can help people live longer or live better, provides reassurance for those people taking this drug when other statins are not suitable. However, there are some caveats.

JUPITER was designed to continue until 520 confirmed primary end points had been documented. However, the trial was stopped early when only 393 events had occurred because the data and safety monitoring board identified benefits to people taking active treatment. This meant JUPITER lasted only a median of 1.9 years instead of the planned 4 years. There are obviously ethical issues in continuing a placebo-trial in these circumstances, even when the absolute benefits are low. However, as the accompanying editorial states, the early termination of the study probably exaggerated the results to some degree. A different trial design would be required to demonstrate whether rosuvastatin 20mg is better than, worse than, or the same as other statins at reducing major CV events. Moreover, we need more data on the long-term safety of reducing LDL to very low levels, as in JUPITER.

The dose used in JUPITER was 20mg/day. The MHRA have advised caution in initiating this dose: patient should start on 10mg (5mg for Asian patients and those with pre-disposing factors for myopathy), including patients switched from other statins, and the dose should be titrated up after a four week trial.

How does this study relate to NICE guidance?
NICE guidance on risk assessment and lipid management and on type 2 diabetes (including lipid modification) was published earlier this year. In primary prevention of people without diabetes, NICE recommends simvastatin 40mg as first choice drug and dose for most people, with no lipid target. If simvastatin 40mg is not tolerated or is contraindicated, alternative statins may be used, such as pravastatin. Simvastatin 40mg is also recommended in people without diabetes with established CV disease, although patients and prescribers should consider increasing to simvastatin 80mg if a total cholesterol of less than 4mmol/L or an LDL cholesterol of less than 2mmol/L is not attained. However, these figures are intended to guide treatment, they are not targets patients are expected to attain. Most patients would not achieve these levels on 80mg simvastatin and modelling suggests that it is not cost-effective to try to take more patients to target using higher cost statins. Furthermore, as we have previously blogged, a single cholesterol measure may well under- or overestimate a person’s true average cholesterol by up to 14%.

Within NICE guidance, rosuvastatin might be considered when other statins are not tolerated or are contraindicated, and in patients with acute coronary syndrome or patients with type 2 diabetes who have established CV disease or increased albumin excretion rate. With regard to the latter group, NICE recommends initiating treatment with simvastatin 40mg, but to consider intensifying with a higher intensity statin or ezetimibe▼ to achieve at total cholesterol of less than 4 mmol/L or an LDL of less than 2 mmol/L.

Amongst other factors, when considering the choice of second line or intensive statins in line with NICE guidance, prescribers and localities may wish to bear in mind the potential effect of the expiry of the patent on atorvastatin (currently reported to be November 2011) on the future acquisition costs of these medicines.

What about hs-CRP testing?
Perhaps the biggest impact of JUPITER in the UK and internationally will be to stimulate further research into hs-CRP as an adjunct to CV risk estimation. The American Heart Association guidelines have recommended selective use of hs-CRP since 2003 but this is on the basis of mid- or low-level evidence. The recent NICE guidelines on cardiovascular risk estimation and the SIGN 2007 guidelines on the same topic are silent on this subject. This is not surprising since, as the American guidelines state, “No clinical trials have been completed in which a population has been randomly allocated to screening for hs-CRP and compared with a control population not allocated to hs-CRP screening and both groups followed up prospectively to determine the benefits and harms of the screening.”

This remains true, because JUPITER is a trial of statin therapy, not hs-CRP testing. It did not compare subjects with and without hs-CRP testing, nor did it compare hs-CRP with the use of other markers of CV risk, nor do we have any information on the benefits of rosuvastatin in patients with an hs-CRP value of less than 2.0mg/L.

Study details
Ridker P, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008;359:2195–207 (the JUPITER study)

Patients: 17,802 men and women (median 66 years, 38% women, median LDL 2.8 mmol/L, median HDL 1.3 mmol/L, median BP 134/80 mmHg, 84% non-smokers, high sensitivity C-reactive protein (hs-CRP) 4.2mg/L.

Note: According to the American Heart Association patients are at low risk of developing CV disease if their hs-CRP level is lower than 1.0mg/L; at average risk if their level is between 1.0 and 3.0mg/L; and at high risk for cardiovascular disease if their level is higher than 3.0mg/L. The BHS risk calculator (based on the Framingham equation and not taking into account hs-CRP) suggests a mean 10-year CV risk of approximately 10% for women with the median blood pressure and median lipid profile of people in the trial and 16-17% for men with that profile (not taking into account smoking status or family history of heart disease). In the placebo group, the observed rate of the primary composite endpoint (non-fatal MI, non-fatal stroke, hospitalisation for unstable angina, arterial revascularisation or death from CV causes) was 1.36% per 100 patient years, approximately equivalent to 13–14% per person over 10 years. The BHS calculator predicts the 10-year risk of non-fatal MI and stroke, coronary and stroke death and new angina pectoris – so this is not quite the same as the endpoints in the trial.

Intervention and comparison: Rosuvastatin 20mg a day, or placebo, for a median of 1.9 years (maximal follow-up 5.0 years)

Outcome: Primary composite endpoint (non-fatal MI, non-fatal stroke, hospitalisation for unstable angina, arterial revascularisation or death from CV causes) 0.77 vs 1.36 per 100 patient years (HR 0.56, 95%CI 0.46 to 0.69, P<0.00001; NNT=82), in the rosuvastatin and placebo groups, respectively. The HRs for all components of this endpoint were similar and benefits were similar across all subgroups. The rates/100 patient years of the composite endpoint of MI, stroke or death from CV causes were 0.45 and 0.85 respectively (HR 0.53, 95%CI 0.40 to 0.69, P<0.00001; NNT=120). All-cause mortality was also reduced (1.00 vs 1.25/100 patient years, HR 0.80, 95%CI 0.67 to 0.97, P=0.02; NNT 182). There were no differences between the groups with regard to muscle, hepatic or renal adverse effects or cancer, but there was a 25% increased risk of physician-diagnosed diabetes in the rosuvastatin group compared to the placebo group: 3.0% vs 2.4% respectively,(RR 1.25, P=0.01; NNH=165;). Median glycated haemoglobin was 5.7% in both groups at baseline and increased to 5.9% in the rosuvastatin group and 5.8% in the placebo group (P=0.001).

More information on lipid management can be found on the lipids section of NPC.

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