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Rosuvastatin for vascular events: the JUPITER study

The JUPITER study examined the use of statins to prevent future cardiovascular events such as myocardial infarction or stroke. Peter Burrill takes a look at the results of this controversial trial, and whether or not the end justified the means

Peter Burrill
BPharm(Hons) MRPharmS DipPresSci FCPP FFPMM
Specialist Pharmaceutical Adviser for Public Health
Derbyshire County Primary Care Trust

Rosuvastatin has been trialled against placebo in two previous studies. The CORONA study involved people with chronic heart failure of ischaemic cause, and in GISSI–HF, patients had chronic heart failure of any cause.1,2 In both studies, rosuvastatin 10 mg daily had no significant effect on patient-oriented outcomes.

For JUPITER, the investigators hypothesised that people with elevated high-sensitivity C-reactive protein levels, but without hyperlipidaemia, might benefit from statin treatment.3 The results received a lot of media attention; but was it justified?

Method
The JUPITER study was a randomized, double-blind, placebo-controlled trial conducted at 1,315 sites in 26 countries.

Men aged 50 plus and women aged 60 plus were eligible if they did not have a history of cardiovascular (CV) disease and if, at the initial screening visit, they had a low-density lipoprotein (LDL) cholesterol level of less than 3.4 mmol/L; a high sensitivity C-reactive protein level of 2.0 mg/L or more; and a triglyceride level of less than 5.6 mmol/L.

Exclusion criteria were numerous, and included previous or current use of lipid-lowering therapy, current use of postmenopausal hormone replacement therapy (HRT), evidence of hepatic dysfunction, diabetes, inflammatory conditions (such as severe arthritis and inflammatory bowel disease) and uncontrolled hypertension. All potentially eligible patients underwent a four-week run-in phase, during which they received placebo, in order to identify those who were willing and suitable to participate in the trial, and who demonstrated good compliance. Only those who successfully completed the run-in phase were enrolled.

Eligible subjects were randomly assigned in a 1:1 ratio to receive either rosuvastatin 20 mg daily or matching placebo. Randomisation appears to have been allocation concealed.

The primary outcome was the occurrence of a first major vascular event, defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalisation for unstable angina, an arterial revascularisation procedure, or confirmed death from cardiovascular causes. Secondary endpoints included the components of the primary endpoint considered individually – arterial revascularisation or hospitalisation for unstable angina, MI, stroke, or death from cardiovascular causes – and death from any cause.

JUPITER was an event-driven trial designed to continue until 520 confirmed primary endpoints had been documented, to provide a statistical power of 90% to detect a 25% reduction in the rate of the primary endpoint, with a two-sided significance level of 0.05.

The article states that primary analyses were performed on an intention-to-treat basis. The trial was financially supported by AstraZeneca.
 
Results
A total of 89,890 people were screened for enrolment and 17,802 were randomly assigned to a study group; 38.2% of the participants were women and 25.2% were black or Hispanic. The mean age was 66 years and 41.4% had the metabolic syndrome. At baseline in both groups, the median LDL-C level was 2.8 mmol/L, the HDL-C level was 1.3 mmol/L, and the triglyceride level was 1.3 mmol/L. The C-reactive protein level was 4.2 and 4.3 mg/L in the rosuvastatin and placebo groups respectively. The independent data and safety monitoring board voted to recommend early termination of the trial after a median follow-up of 1.9 years.

At the 12-month visit, the rosuvastatin group, as compared with the placebo group, had a 50% lower median LDL-C level, a 37% lower median high-sensitivity C-reactive protein level, and a 17% lower median triglyceride level (P

For the results of the primary endpoint and some of the secondary endpoints, see Table 1. The total number of reported serious adverse events was similar in both groups (P=0.60). However, physician-reported diabetes was more frequent in the rosuvastatin group (P=0.01) with a number needed to harm (NNH) of 167.

[[Tab 1 JUPITER]]

Discussion
The trial was stopped early, with only 1.9 of its proposed four years of follow-up concluded. JUPITER was designed to continue until 520 confirmed primary endpoints had been documented, whereas only 393 events had occurred. As 520 had been used in the power calculation, this will have resulted in underpowering. As the accompanying editorial states, the early termination probably exaggerated the results to some degree.4
The results will also be exaggerated by the run-in phase. As only compliant patients were randomised, the NNTs will be higher in the real world.

The absolute benefit of rosuvastatin was small. For every 1,000 people who took rosuvastatin 20 mg daily for two years, eight people avoided having an MI or a stroke, or dying from CV causes, but six people developed diabetes who would not have done so otherwise.5 Cost per event prevented calculates as £77,000.

The increased risk of diabetes was perhaps unexpected. The authors state, "Physicians' reports of diabetes were not adjudicated by the endpoint committee, and careful evaluation of participants' records will be needed to better understand this possible effect".

The endpoint of death from any cause only just reached statistical significance and given the small numbers and premature termination it must be queried how robust this result is.

An important question to consider is: what is the long-term safety of lowering LDL-C to very low levels in otherwise healthy people?

The dose used in JUPITER was 20 mg/day. The Medicines and Healthcare products Regulatory Agency (MHRA) has advised caution in initiating this dose: patients should start on 10 mg (5 mg for Asian patients and those with predisposing factors for myopathy), including patients switched from other statins, and the dose should be titrated up after a four-week trial.6

The population studied in JUPITER is one that would not qualify for statin therapy under national guidance. Should they be targeted? This would have to be regarded as service development and a business plan submitted. I cannot imagine it would be a local priority or be cost-effective and affordable. A British Medical Journal (BMJ) editorial comments, "No change in strategy is needed despite the hype surrounding the recent JUPITER study."7

References
1. Kjekshus J, Apetrei E, Barrios V et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61.
2. Gissi-HF Investigators, Tavazzi L, Maggioni AP et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9.
3. Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207.
4. Hlatky MA. Expanding the orbit of primary prevention - moving beyond JUPITER. N Engl J Med 2008;359:2280-2.
5. National Prescribing Centre (NPC). Higher dose rosuvastatin in lower risk patients – the JUPITER study. London: NPC. Available from: http://www.npci.org.uk/blog/?p=236
6. Medicines and Healthcare products Regulatory Agency. Rosuvastatin (Crestor): introduction of 5 mg starting dose. Current problems in pharmacovigilance 2006;31. Available from: http://www.mhra.gov.uk/Publications/Safetyguidance/CurrentProblemsinPhar...
7. Donner-Banzhoff N, Sönnichsen A. Statins and primary prevention of cardiovascular events. BMJ 2008;337:a2576.