Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin - JUPITER

Nov 10, 2015
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Summary Supplemental Reviewer:
Paul M. Ridker, MD, MPH, FACC
Trial Sponsor:
AstraZeneca
Date Presented:
11/10/2015
Date Published:
03/02/2015
Date Updated:
11/10/2015
Original Posted Date:
08/12/2012
References

Description:

Statins are currently recommended for primary prevention of cardiovascular disease in high-risk patients. The JUPITER trial 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/L, would benefit from taking rosuvastatin.

Contribution to the Literature: The JUPITER trial showed that rosuvastatin was associated with a reduction in cardiovascular events, compared with placebo, in healthy patients with LDL <130 mg/dl, but hs-CRP ≥2 mg/L.

Study Design

  • Blinded
  • Placebo Controlled
  • Randomized
  • Parallel

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

Patient Populations:

  • Males ≥50 years, females ≥60 years
  • No history of cardiovascular disease
  • LDL cholesterol <130 mg/dl 
  • hs-CRP ≥2.0 mg/L
  • 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

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

Drug/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/L). Median LDL, high-density lipoprotein (HDL), triglyceride, and glucose levels were 108, 49, 118, and 94 mg/dl, respectively.

The study was terminated early, 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.

Among individual participants, there was large variability in the percent reduction of LDL achieved. Among those who did not have a reduction in LDL, the association for rosuvastatin vs. placebo was HR 0.86, for those who achieved <50% reduction in LDL (HR 0.61), and for those who achieved ≥50% reduction in LDL (HR 0.41; p for trend < 0.00001).

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/L, 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 myopathy (0.1% vs. 0.1%, p = 0.82), rhabdomyolysis (0.01% vs. 0%, p > 0.05), incident cancer (3.4% vs. 3.5%, p = 0.51), cancer deaths (0.4% vs. 0.7%, p = 0.02), hemorrhagic stroke (0.07% vs. 0.10%, p = 0.44), for rosuvastatin vs. placebo, respectively. 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).

Among participants with at least one risk factor for diabetes, the use of rosuvastatin was associated with a 39% reduction in the primary outcome despite a 28% increase in incident diabetes. Among participants with no risk factors for diabetes, the use of rosuvastatin was associated with a 52% reduction in the primary outcome, with no increase in incident diabetes.

Incident fractures were 1.20 per 100 PY versus 1.14 per 100 PY (p = 0.53), respectively, for rosuvastatin vs. placebo.

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/L. Individuals who had the greatest percent reduction in LDL (not the absolute LDL level), experienced the greatest reduction in adverse events with rosuvastatin. Among those at risk for diabetes, rosuvastatin versus placebo was associated with an increased risk for developing diabetes. Rosuvastatin did not reduce the risk for fractures.

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/L and a comparison of their risk with the rosuvastatin arm in this trial may have helped answer this question. Although rosuvastatin was associated with an increase in incident diabetes among at-risk individuals, there was still net benefit (reduction in adverse events) from statin therapy.

References:

Presented by Dr. Paul M. Ridker at the American Heart Association Scientific Sessions, Orlando, FL, November 10, 2015.

Pena JM, Aspberg S, MacFadyen J, Glynn RJ, Solomon DH, Ridker PM. Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial. JAMA Intern Med 2015;175:171-7.

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.

Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention: An Analysis From the JUPITER Trial. Lancet 2012;380:565-71.

Presented by Dr. Paul M. Ridker at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Keywords: Fluorobenzenes, Follow-Up Studies, Pyrimidines, Risk Factors, Primary Prevention, Glucose, Glycated Hemoglobin A, Polymorphism, Genetic, Confidence Intervals, Sulfonamides, Stroke, Myocardial Infarction, Neoplasms, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Rhabdomyolysis, Metabolic Syndrome, C-Reactive Protein, Body Mass Index, Triglycerides, Lipoproteins, HDL, Diabetes Mellitus, Fasting, AHA Annual Scientific Sessions


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