Title: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER — Presented at AHA 2008)
Trial Sponsor: AstraZeneca
Year Presented: 2008
Year Published 2008
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 11/9/2008 9:00:00 AM
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000); Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000)

Description
Statins are currently recommended for primary prevention of cardiovascular disease in high-risk patients. JUPITER was designed to assess whether apparently healthy persons with levels of low-density lipoprotein (LDL) that do not mandate statin treatment, as per current guidelines (<130 mg/dl), but with levels of high-sensitivity C-reactive protein (hs-CRP) =2 mg/dl, would benefit from taking rosuvastatin.
Hypothesis
Rosuvastatin would be associated with a reduction in first major cardiovascular events, as compared with placebo, in apparently healthy patients with LDL <130 mg/dl, but hs-CRP =2 mg/dl.
Drugs/Procedures Used
Rosuvastatin 20 mg daily or placebo
Concomitant Medications
Aspirin (16.6%)
Principal Findings
A total of 17,802 patients were randomized, 8,901 to rosuvastatin, and 8,901 to placebo. Baseline characteristics were fairly similar between the two groups. About 41% of the patients had metabolic syndrome. Baseline hs-CRP levels were similar between the two arms (median of about 4.3 mg/dl). Median LDL, high-density lipoprotein (HDL), triglyceride, and glucose levels were 108, 49, 118, and 94 mg/dl, respectively.

The study was terminated earlier, after a median of 1.9 years of follow-up (planned maximum follow-up was 5 years). Rosuvastatin was associated with a significant reduction in the incidence of the primary endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, unstable angina, arterial revascularization, or cardiovascular death, compared with placebo (0.77 vs. 1.36 events per 100 person-years (PY) of follow-up, hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.46-0.69, p < 0.00001). This translated into a number needed to treat with rosuvastatin of 95 patients for 2 years, and 31 patients for 4 years.

There was also a significant reduction in the incidence of individual endpoints: nonfatal MI (0.12 vs. 0.33 events per 100 PY, HR 0.35, 95% CI 0.22-0.58, p < 0.00001), nonfatal stroke (0.16 vs. 0.31 events per 100 PY, HR 0.52, 95% CI 0.33-0.80, p = 0.003), arterial revascularization (0.38 vs. 0.71 events per 100 PY, HR 0.54, 95% CI 0.41-0.72, p < 0.0001), as well as all-cause mortality (1.0 vs. 1.25 events per 100 PY, HR 0.80, 95% CI 0.67-0.97, p = 0.02). Various subgroup analyses were done, including based on gender, race, body mass index, and Framingham risk score, which all yielded consistent results for the primary outcome.

At 4 years, rosuvastatin was associated with a significant reduction in the levels of hs-CRP (median: 1.8 vs. 3.3 mg/dl, p < 0.0001), LDL (median: 55 vs. 109 mg/dl), triglycerides (99 vs. 118 mg/dl, p < 0.0001), but not HDL (50 vs. 50 mg/dl, p = 0.34).

The overall incidence of serious adverse effects was similar between the two groups (15.2% vs. 15.5%, p = 0.60), including muscle weakness, stiffness, or pain (16.0 vs. 15.4%, p = 0.34), and newly diagnosed cancer (3.4% vs. 3.5%, p = 0.51). The incidence of alanine aminotransferase (ALT) >3 x upper limit of normal was similar between the two groups (0.3% vs. 0.2%, p = 0.34). There was a higher incidence of physician-reported diabetes in the rosuvastatin arm (3.0% vs. 2.4%, p = 0.01), as well as higher median glycated hemoglobin at 2 years with rosuvastatin (5.9% vs. 5.8%, p = 0.001); the median fasting glucose at 2 years was similar between the two arms (98 vs. 98 mg/dl, p = 0.12).
Interpretation
The results of the JUPITER trial indicate that rosuvastatin is associated with a significant reduction in major cardiovascular events, including death, in apparently healthy persons with LDL cholesterol <130 mg/dl, but hs-CRP =2 mg/dl. This is a landmark study, and may require revision of current guidelines, which do not recommend lipid-lowering therapy in healthy patients whose LDL cholesterol levels are <130 mg/dl; hs-CRP may need to be introduced as a further risk stratification tool.

Some of the issues that need further clarification include the long-term safety, efficacy, and cost-effectiveness of utilizing statins in asymptomatic, apparently healthy patients, as well as whether these findings can be considered as a class effect of statins, or as specific to rosuvastatin, which exhibits several pharmacokinetic differences from other statins. It is also not entirely clear whether the observed benefit in this trial is from LDL cholesterol lowering, hs-CRP lowering, or both.

Further, there are some conflicting data regarding a direct correlation between elevated levels of hs-CRP and cardiovascular risk. A recent study found no relationship between genetic polymorphisms resulting in high hs-CRP levels and cardiovascular risk. Inclusion of patients with levels of hs-CRP <2.0 mg/dl and a comparison of their risk with the rosuvastatin arm in this trial may have helped answer this question. Last, the higher risk of new-onset diabetes with rosuvastatin, as compared with placebo, will need to be examined in future statin trials.

Conditions
Prevention/Primary

Therapies
Lipid-lowering agent / HMG CoA Reductase Inhibitor / Rosuvastatin

Study Design
Placebo controlled. Randomized. Blinded. Parallel.

Patients Screened: 89,890
Patients Enrolled: 17,802
Mean Follow-Up: 1.9 years (median)
Mean Patient Age: 66 years (median)
% Female: 38

Primary Endpoints

Nonfatal MI
Nonfatal stroke
Unstable angina
Arterial revascularization
Cardiovascular death

Secondary Endpoints

Arterial revascularization or hospitalization for unstable angina
MI
Stroke
Cardiovascular death
All-cause mortality
Patient Population

Males =50 years, females =60 years
No history of cardiovascular disease
LDL cholesterol <130 mg/dl
hs-CRP =2.0 mg/dl
Triglyceride level <500 mg/dl
Exclusions:

Previous or current use of lipid-lowering agents
Current use of hormone replacement therapy
Hepatic dysfunction
Diabetes
Uncontrolled hypertension
Cancer within 5 years of enrollment
Uncontrolled hypothyroidism
Recent history of drug or alcohol abuse
Inflammatory conditions such as rheumatoid arthritis, lupus, or inflammatory bowel disease
Patients on immunosuppressive medications such as cyclosporine, tacrolimus, azathioprine, or long-term oral corticosteroids
References: Presented by Dr. Paul M. Ridker at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Ridker PM, Danielson E, Fonseca FA, et al., on behalf of the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.

Source
Content provided by the American College of Cardiology Foundation